THE BIOLOGICALLY BEST TIME TO FATHER BABIES FOR THE HEALTH AND HAPPINESS OF THE CHILD

James Crow Dies

2012-01-11T10:15:00.000-08:00

James Crow Dies

January 11, 2012

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James Crow, who was a population geneticist at the University of Wisconsin-Madison, has died, reports The New York Times. He was 95. Crow studied mutational load, and was part of on a National Academy of Sciences committee that assessed mutational damage to the populations of Hiroshima and Nagasaki following the use of atomic bombs there. He also was on a committee that paved the way for using DNA forensics in court. The Times notes that when Crow began teaching in the 1940s and 1950s, the field of genetics underwent rapid changes. "When anxious students asked Dr. Crow what would be in the exams, he would tell them that the questions were the same every year but that the answers were different," the Times says.

High Frequencies of De Novo CNVs in Bipolar Disorder and Schizophrenia.

2012-01-07T09:40:00.001-08:00

Neuron. 2011 Dec 22;72(6):951-63.

High Frequencies of De Novo CNVs in Bipolar Disorder and Schizophrenia.

Malhotra D, McCarthy S, Michaelson JJ, Vacic V, Burdick KE, Yoon S, Cichon S, Corvin A, Gary S, Gershon ES, Gill M, Karayiorgou M, Kelsoe JR, Krastoshevsky O, Krause V, Leibenluft E, Levy DL, Makarov V, Bhandari A, Malhotra AK, McMahon FJ, Nöthen MM, Potash JB, Rietschel M, Schulze TG, Sebat J.

Source

Beyster Center for Genomics of Psychiatric Diseases, University of California, San Diego, La Jolla, CA 92093, USA; Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093, USA; Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 12824, USA.

Abstract

While it is known that rare copy-number variants (CNVs) contribute to risk for some neuropsychiatric disorders, the role of CNVs in bipolar disorder is unclear. Here, we reasoned that a contribution of CNVs to mood disorders might be most evident for de novo mutations. We performed a genome-wide analysis of de novo CNVs in a cohort of 788 trios. Diagnoses of offspring included bipolar disorder (n = 185), schizophrenia (n = 177), and healthy controls (n = 426). Frequencies of de novo CNVs were significantly higher in bipolar disorder as compared with controls (OR = 4.8 [1.4,16.0], p = 0.009). De novo CNVs were particularly enriched among cases with an age at onset younger than 18 (OR = 6.3 [1.7,22.6], p = 0.006). We also confirmed a significant enrichment of de novo CNVs in schizophrenia (OR = 5.0 [1.5,16.8], p = 0.007). Our results suggest that rare spontaneous mutations are an important contributor to risk for bipolar disorder and other major neuropsychiatric diseases.

Copyright © 2011 Elsevier Inc. All rights reserved.

Cereb Cortex. 2011 Aug 4. [Epub ahead of print]

2011-08-06T10:37:00.000-07:00

http://www.ncbi.nlm.nih.gov/pubmed/21817090

Cereb Cortex. 2011 Aug 4. [Epub ahead of print]
Parental Age Effects on Cortical Morphology in Offspring.
Shaw P, Gilliam M, Malek M, Rodriguez N, Greenstein D, Clasen L, Evans A, Rapoport J, Giedd J.
SourceChild Psychiatry Branch, Intramural Program of the National Institute of Mental Health.

Abstract
The age at which a parent has a child impacts the child's cognition and risk for mental illness. It appears that this risk is curvilinear, with both age extremes associated with lower intelligence and increased prevalence of some neuropsychiatric disorders. Little is known of the neural mechanisms underpinning this phenomenon. We extracted lobar volumes, surface areas, and cortical thickness from 489 neuroanatomic magnetic resonance images acquired on 171 youth. Using linear mixed model regression, we determined the association between parental age and offspring's neuroanatomy, adjusting for offspring's age, sex, intelligence, and parental socioeconomic class. For gray matter volumes, quadratic paternal and maternal age terms contributed significantly (maternal quadratic age effect: t = -2.2, P = 0.03; paternal quadratic age effect: t = -2.4, P = 0.02) delineating an inverted "U" relationship between parental age and gray matter volume. Cortical volume increased with both advancing paternal and maternal age until around the early 30s after which it fell. Paternal age effects were more pronounced on cortical surface area, whereas maternal age impacted more on cortical thickness. There were no significant effects of parental age on white matter volumes. These parental age effects on cerebral morphology may form part of the link between parental age extremes and suboptimal neurocognitive outcomes.

PMID:21817090[PubMed - as supplied by publisher]

A Strategy to Identify de Novo Mutations in Common Disorders such as Autism and Schizophrenia.

2011-06-30T08:38:00.000-07:00

http://www.ncbi.nlm.nih.gov/pubmed/21712793

Vis Exp. 2011 Jun 15;(52). pii: 2534. doi: 10.3791/2534.
A Strategy to Identify de Novo Mutations in Common Disorders such as Autism and Schizophrenia.
Julie G, Hamdan FF, Rouleau GA.
SourceCentre of Excellence in Neuromics, CHUM Research Center and the Department of Medicine, Universite de Montreal.

Abstract
There are several lines of evidence supporting the role of de novo mutations as a mechanism for common disorders, such as autism and schizophrenia. First, the de novo mutation rate in humans is relatively high, so new mutations are generated at a high frequency in the population. However, de novo mutations have not been reported in most common diseases. Mutations in genes leading to severe diseases where there is a strong negative selection against the phenotype, such as lethality in embryonic stages or reduced reproductive fitness, will not be transmitted to multiple family members, and therefore will not be detected by linkage gene mapping or association studies. The observation of very high concordance in monozygotic twins and very low concordance in dizygotic twins also strongly supports the hypothesis that a significant fraction of cases may result from new mutations. Such is the case for diseases such as autism and schizophrenia. Second, despite reduced reproductive fitness(1) and extremely variable environmental factors, the incidence of some diseases is maintained worldwide at a relatively high and constant rate. This is the case for autism and schizophrenia, with an incidence of approximately 1% worldwide. Mutational load can be thought of as a balance between selection for or against a deleterious mutation and its production by de novo mutation. Lower rates of reproduction constitute a negative selection factor that should reduce the number of mutant alleles in the population, ultimately leading to decreased disease prevalence. These selective pressures tend to be of different intensity in different environments. Nonetheless, these severe mental disorders have been maintained at a constant relatively high prevalence in the worldwide population across a wide range of cultures and countries despite a strong negative selection against them(2). This is not what one would predict in diseases with reduced reproductive fitness, unless there was a high new mutation rate. Finally, the effects of paternal age: there is a significantly increased risk of the disease with increasing paternal age, which could result from the age related increase in paternal de novo mutations. This is the case for autism and schizophrenia(3). The male-to-female ratio of mutation rate is estimated at about 4-6:1, presumably due to a higher number of germ-cell divisions with age in males. Therefore, one would predict that de novo mutations would more frequently come from males, particularly older males(4). A high rate of new mutations may in part explain why genetic studies have so far failed to identify many genes predisposing to complexes diseases genes, such as autism and schizophrenia, and why diseases have been identified for a mere 3% of genes in the human genome. Identification for de novo mutations as a cause of a disease requires a targeted molecular approach, which includes studying parents and affected subjects. The process for determining if the genetic basis of a disease may result in part from de novo mutations and the molecular approach to establish this link will be illustrated, using autism and schizophrenia as examples.

PMID:21712793[PubMed - in process]

Influence of paternal age in schizophrenia

2011-06-28T09:07:00.000-07:00

Encephale. 2011 Jun;37(3):199-206. Epub 2011 Apr 2.
[Influence of paternal age in schizophrenia.]
[Article in French]
Hubert A, Szöke A, Leboyer M, Schürhoff F.
SourcePôle de psychiatrie du CHU de Créteil, groupe hospitalier Henri-Mondor-Albert-Chenevier, AP-HP, 40, rue Mesly, 94000 Créteil, France; Inserm unité 955, IMRB, département de génétique, équipe 15, 94000 Créteil, France; Faculté de médecine, université Paris-Est Créteil, IFR10, 94000 Créteil, France; Fondation Fondamental, fondation de coopération scientifique, hôpital Chenevier, 40, rue Mesly, 94000 Créteil, France.

Abstract
BACKGROUND: Schizophrenia is an aetiologically heterogeneous syndrome, with a strong genetic component. Despite a reduced fertility in this disorder, its prevalence is maintained and could be explained by de novo genetic mutations. Advanced paternal age (APA) is a major source of new mutations in human beings and could thus be associated with an increased risk of developing schizophrenia in offspring. New mutations related to APA have been implicated as a cause of sporadic cases in several autosomal dominant diseases and also in neurodevelopmental diseases, autism, intellectual disabilities, and social functioning. The aim of the present study was to summarize the results of studies investigating the role of APA, and to discuss some interpretations.

METHODS: All relevant studies were identified through the National Library of Medicine (PubMed(®) database). Keywords used for research were "age" and "schizophrenia" linked to "paternal or father". We have identified and analysed eight cohort studies, five case-control studies, two meta-analyses, and one review concerning different father's mutations potentially transmitted, two studies comparing paternal age at conception between sporadic versus familial cases of schizophrenia. All studies selected have been published between 2000 and 2009.

RESULTS: After controlling for several confounding factors including maternal age, the relative risk of schizophrenia increased from 1.84 to 4.62 in offspring of fathers with an older age of fatherhood. Mother's age showed no significant effects after adjusting for paternal age. There was a significant association between paternal age and risk of developing schizophrenia, there was a weaker association with psychosis.

DISCUSSION: The results of these different studies are confirmed by two recent meta-analyses which found an increased risk of schizophrenia in offspring of fathers older than 35 years. Two main hypotheses could explain these results. The first one is based on the presence of new mutations in the spermatogonia, possibly because of accumulating replication errors in spermatogonial cell lines. This hypothesis is confirmed by Malaspina et al. (2002) [19], who found that patients without a family history of schizophrenia had significantly older fathers than probands with a positive family history of schizophrenia. However, this result has not been confirmed by other studies, and paternal age effect could be also explained by a mechanism called imprinting, which is a form of gene regulation. The second hypothesis is based on the fact that fathers with schizophrenia spectrum personality disorder, known to be genetically related to schizophrenia, could have an advanced age at conception. However, regarding this hypothesis, advanced maternal age at conception should be a risk factor for schizophrenia, and this is not the case. Thus, the first hypothesis seems more plausible than the second. APA has been identified as a risk factor for other psychiatric disorders such as autism, bipolar disorder, obsessive-compulsive disorder, and phobia, and thus seems to be a non-specific risk factor. Furthermore, its association with impaired neurocognitive outcomes during infancy and childhood in normal populations raises the question of the phenotype linked to APA.

CONCLUSION: APA at conception appears to be a risk factor for schizophrenia. This risk factor probably interacts with genetic factors in a gene-environment interaction. To date, there is no validated cut-off at which the risk is significantly increased in offspring. In the future, studies could benefit from analyzing the phenotype related to APA.

Copyright © 2010 L’Encéphale, Paris. Published by Elsevier Masson SAS. All rights reserved.

PMID:21703435[PubMed - as supplied by publisher]

Delayed fathering and risk of mental disorders in adult offspring.

2011-01-12T08:11:00.000-08:00

Early Hum Dev. 2011 Jan 8. [Epub ahead of print]

Delayed fathering and risk of mental disorders in adult offspring.
Krishnaswamy S, Subramaniam K, Ramachandran P, Indran T, Abdul Aziz J.

University of New England, Locked bag 4, NSW 2351, Australia.

Abstract
INTRODUCTION: Delayed parenting and child bearing at a very young age impose various risks to development of the offspring.

OBJECTIVE: This study aims to investigate the association between disparities in parental age and increased risk factor for common mental disorders in the progenies during adulthood.

METHODOLOGY: The Malaysian Mental Health Survey (MMHS) was analysed for this study. Respondents were asked to estimate the age of their parents at their birth. Presence of common mental disorders (CMD) was determined by referring to the diagnosis given by the Clinical Interview Schedule-Revised (CIS-R) instrument in the Programmed Questionnaire System (PROQSY) format. The association between parental age disparities and CMD was studied using logistic regression.

RESULT: Fifty three percent (n=1972) of the MMHS respondents (N=3666) knew the age of both parents and were included in the study. Three percent (n=53) had significant disparity in parental age, or a difference of 11years or more. Respondents born to parents with significant age disparity had a prevalence rate of 24% (95% CI=22.12-25.89) for CMD in comparison to 6% (95% CI=5.99-6.11) in their counterparts and 3.4 times higher risk for CMD, after adjusting for demographic factors, paternal age at birth and presence of family history of mental disorders. Amongst those born to older fathers aged 50 and above, the presence of disparity increased the rate for CMD to 42% (95% CI=39.82-44.18).

DISCUSSION: Disparity in parental age was significantly associated with increased risk for CMD. Various psychosocial factors contributing to age disparity in both the father and the mother could predispose to stress and mental health problems.

Copyright Â© 2010 Elsevier Ltd. All rights reserved.

Father's age increase miscarriage, malformation, risk of autism, schizophrenia, and bipolar troubles in children.

2010-09-04T08:12:00.000-07:00

J Gynecol Obstet Biol Reprod (Paris). 2010 Apr;39(1 Suppl):36-8.

[Influence of paternal age]
[Article in French]

Velez de la Calle JF, Broussin B, Lelaidier C, Fallet C.

Unité FIV, Clinique Pasteur, 34, Rue du Moulin à Poudre, Brest, France.

Abstract
Father's age increase miscarriage, malformation, risk of autism, schizophrenia, and bipolar troubles in children.

PMID: 20728806 [PubMed - in process]

Older paternal age strongly increases the morbidity for schizophrenia in sisters of affected females.

2010-08-19T08:08:00.000-07:00

Older paternal age strongly increases the morbidity for schizophrenia in sisters of affected females.
Perrin M, Harlap S, Kleinhaus K, Lichtenberg P, Manor O, Draiman B, Fennig S, Malaspina D.

Department of Psychiatry, New York University School of Medicine, New York, New York.

Abstract
The effect of a family history of schizophrenia on the risk for this disorder in the offspring has rarely been examined in a prospective population cohort accounting for the sex of the proband and the first-degree relatives, and certainly not with respect to later paternal age. The influence of affected relatives on offspring risk of schizophrenia was estimated using Cox proportional hazards regression in models that accounted for sex, relation of affected first degree relatives and paternal age in the prospective population-based cohort of the Jerusalem Perinatal Schizophrenia Study. Of all first-degree relatives, an affected mother conferred the highest risk to male and female offspring among the cases with paternal age <35 years, however, female offspring of fathers >/=35 years with an affected sister had the highest risk (RR = 8.8; 95% CI = 3.9-19.8). The risk seen between sisters of older fathers was fourfold greater than the risk to sisters of affected females of younger fathers (RR = 2.2, 95% CI 0.7-6.7). The test for interaction was significant (P = 0.03). By contrast, the risk of schizophrenia to brothers of affected males was only doubled between older (RR = 3.3, 95% 1.6-6.6) and younger fathers (RR = 1.6, 95% CI 0.7-3.5). The most striking finding from this study was the very large increase in risk of schizophrenia to sisters of affected females born to older fathers. The authors speculate that the hypothesized paternally expressed genes on the X chromosome might play some role in these observations. (c) 2010 Wiley-Liss, Inc.

PMID: 20718003 [PubMed - as supplied by publisher]

Paternal age increases the risk for autism in an Iranian population sample.

2010-08-04T09:38:00.000-07:00

Mol Autism. 2010 Feb 22;1(1):2.

Paternal age increases the risk for autism in an Iranian population sample.
Sasanfar R, Haddad SA, Tolouei A, Ghadami M, Yu D, Santangelo SL.

Department of Psychiatry, Harvard Medical School, Boston, MA, USA. ssantangelo@pngu.mgh.harvard.edu.

Abstract
ABSTRACT: BACKGROUND: Autism is a neurodevelopmental disorder which is known to have a strong genetic component and is most likely oligogenic. However, the necessary role of environmental factors has been well documented. Prior research suggests that parental characteristics, such as age and level of education, may be associated with a risk of autism. Parental age has been shown to be associated with many disorders, such as schizophrenia, childhood cancer and fetal death. However, results from studies of parental age and autism are inconsistent. METHODS: In the present study, we investigated the association of autism with parental age in 179 autism cases and 1611 matched cohort children from Iran. Each case was matched with nine cohort controls on parental education, sex, order of birth, consanguineous marriage, urbanism and province of residence. The Cox regression model was used to carry out conditional logistic regression on the matched data. RESULTS: There was a significant association between higher paternal age, but not maternal age, and an increasing risk of autism. An analysis of the combined effect of parental age and education also revealed that parents with higher education had an increased risk of having autistic children, with a dose-response effect of parental age. CONCLUSIONS: This study, which is the first epidemiological study of autism in Iran, provides evidence of the association of paternal age and risk of autism.

2010-03-19T15:26:00.001-07:00

Men: Your Biological Clocks are Ticking

2010-01-31T09:29:00.000-08:00

Men: Your Biological Clocks are Ticking!
by Whitney Rhodes on January 30, 2010

For many years, it was tacitly assumed that while women have a “Sell By” date when it comes to fertility, men become fertile at puberty and remain so until a ripe old age.

Actually, although there is some truth in that myth, to the extent that males do not have a hormonal menopause as women do; the fact is that fertility in men does begin to decline after a certain age.

Men don’t completely stop being fertile at any age.

However, older fathers are prone to problems that younger fathers usually don’t experience.

What are Some of the Problems Experienced by Older Fathers?

A study that was conducted recently at the University of California, Berkeley, on a test group of men aged 22 to 80 showed that the sperm of older men are fewer in number with less mobility, as well as being less able to move in a straight line.

This research also showed an increased risk of achondroplasia, a genetic mutation that produces a kind of dwarfism.

Nor was this the only risk.

Older fathers were shown to have an increased risk of siring children with autism, or who were mentally retarded, or have behavioral problems with conditions such as schizophrenia.

Downs Syndrome, although associated with older mothers, doesn’t seem so far to be one of the risks of older fathers, but testing is still in progress.

It is believed that many times, male fertility problems caused by age and/or a medical condition might be mistaken as a potency issue, and mistakenly treated with a prescription for Viagra or a similar medication.

Investigating male infertility, and research of male sperm is gaining much new ground these days, as specialists recognize that infertility is not any more likely to rest with the female half of a couple than the male.

Today, more than ever, men and women alike are waiting longer to start families. This has given rise to an increasing frequency of fertility problems encountered with older parents.

So, although men are never completely infertile due to age, research has shown that the quality and quantity of sperm decrease with age.

Advanced paternal age is associated with alterations in discrete behavioural domains and cortical neuroanatomy of C57BL/6J mice.

2010-01-29T08:17:00.000-08:00

Eur J Neurosci. 2010 Jan 25. [Epub ahead of print]

Advanced paternal age is associated with alterations in discrete behavioural domains and cortical neuroanatomy of C57BL/6J mice.
Foldi CJ, Eyles DW, McGrath JJ, Burne TH.

Queensland Brain Institute, The University of Queensland, St Lucia, Qld 4072, Australia.

Abstract Advanced paternal age (APA) is associated with an increased risk of neurodevelopmental disorders such as autism and schizophrenia. A previous study in mice suggested that the offspring of aged sires have altered locomotion and avoidance learning. The aim of the current study was to conduct a comprehensive behavioural screen in adult offspring of mice of APA. We also examined brain morphology in neonate and adult mice. The adult offspring of 12- to18-month-old (APA) and 4-month-old (control) male C57BL/6J mice underwent a behavioural test battery comprising tests for locomotion, anxiety, exploration, social behaviour, learned helplessness and sensorimotor gating. The brains of these mice were collected at 3 months and imaged ex vivo using a 16.4T MRI scanner to assess gross neuroanatomy. Neuroanatomy was also examined at birth in a separate cohort of animals. Overall, the APA mouse model was associated with subtle behavioural changes and altered cortical morphology. The behavioural phenotype of female APA mice included increased anxiety-related behaviour, increased exploration and decreased learned helplessness compared to control females. Male APA mice had thinner cortices at birth and increased cortical volume as adults. This animal model may assist in exploring the mechanism of action linking APA with disorders such as schizophrenia and autism.

PMID: 20105239 [PubMed - as supplied by publisher]

Paternal Age and Schizophrenia

2010-01-08T07:37:00.000-08:00

Paternal Age and Schizophrenia
Research Date:
03/23/2006
An Expert Interview with Dolores Malaspina, M.D., M.P.H.

Great Neck, NY - March 23, 2006) — Scientists have linked paternal age to genetic diseases since the 1950s, and some have suggested an association between the age of the father and the risk for schizophrenia. In 2001, Dolores Malaspina, M.D., M.P.H., and her colleagues reported their research identifying a relationship between paternal age and the occurrence of schizophrenia. On behalf of Medscape* Jessica Gould interviewed Dr. Malaspina, Professor of Clinical Psychiatry at Columbia University and Research Psychiatrist at New York State Psychiatric Institute in New York City. Dr. Malaspina elaborates on her research and speaks about new directions in genetic research on schizophrenia. (NARSAD NOTE: Dr. Malaspina was a NARSAD 1993 and 1995 Young Investigator and a 2001 Independent Investigator.)

Medscape: Tell me about your research on paternal age and schizophrenia.

Dolores Malaspina: I have been compelled by the idea that schizophrenia is not a single disease. The consensus in the field is that schizophrenia is a syndrome, and a syndrome is a collection of different disorders. Yet there is still some controversy over whether or not there are variants of schizophrenia that might have separate causes and respond differently to various medications.

Since beginning my research in the late 1980s, I have focused on this heterogeneity, and one way that I've done that is by examining aspects of the disease in people who come from densely affected families, where two or more relatives have schizophrenia, and comparing them with cases of schizophrenia that have no family history of any chronic psychosis.

Now, in genetic research, it's known that for human genetic diseases, when a new case presents itself in a family, the mutation almost always arises during spermatogenesis. We have known for almost 100 years that the late born children in a family have more new genetic diseases. In the 1950s, a scientist named Penrose showed that only the age of the father predicts these genetic diseases. Over the last decade, it was shown that the risk for many complex genetic diseases was also correlated with paternal age. I thought that if schizophrenia cases with no family history were due to new genetic events, maybe they would also be correlated with the father's age.

I have the good fortune to be funded by the National Institutes of Health to study a very special birth cohort in Israel of about 100,000 pregnancies. We have a rich amount of demographic and clinical data on the parents, including the age of the father. The analysis showed what we considered to be a striking effect of the age of the father on the risk for schizophrenia.

Medscape: Could you tell me more about this group of research subjects from Israel?

Dr. Malaspina: The offspring were born between 1964 and 1976, and the original birth cohort was designed to examine the health of women during pregnancy as well as fetal outcomes. Israel maintains a high-quality psychiatric case registry. Working with the people at the Ministry of Health in Israel, my colleagues linked the birth cohort data to the psychiatric case registry data. The results showed that the risk of schizophrenia was tripled for the offspring of the oldest group of fathers.

We found that paternal age explained over a quarter of the risk for schizophrenia in the population. At the time, people were skeptical. But the findings have been replicated many times now, and not a single study has failed to find this strong relationship between father's age and the risk for schizophrenia. And at this point, other explanations for the relationship have been ruled out, including social factors in the family, prenatal care, and parental psychiatric ailments. There simply seems to be a relationship between paternal age and schizophrenia risk.

Medscape: Can you explain why the relationship between paternal age and schizophrenia exists?

Dr. Malaspina: When Penrose found that paternal age predicted new human genetic diseases, he proposed the Copy Error Theory. He said that each time the spermatozoa are copied there's an opportunity for a new mutation. Sperm cells divide every 16 days after puberty, so the DNA in the sperm of a 20-year-old father has been copied 100 times, but sperm DNA from a 50-year-old father has been copied more than 800 times. By comparison, egg cells from the mother only undergo a few dozen cell divisions all together. It is clear that there are many more opportunities for mutations to occur during spermatogenesis and that these increase with the age of the father. That is why new mutations are introduced in mammals in proportion to paternal age.

To further establish that paternal age is associated with schizophrenia risk, we went back to examine if paternal age is related to other factors associated with schizophrenia risk. We looked at intellectual functioning at age 17 in our birth cohort. Those data were available because adolescents in Israel are screened for military service. Working with personnel at the Israeli Defense Force, we examined whether intelligence was related to paternal age. And what we found was a very strong specific effect of paternal age on performance IQ. Very young mothers and very old mothers had offspring with impairments in verbal and performance intelligence. While there was no effect of late fathers' age on verbal IQ, there was a strong effect on performance intelligence, or nonverbal intelligence, which we have published.

In a parallel study, we examined the effect of late paternal age in a mouse model. Working with my colleague, Jay Gingrich, we studied several cohorts of inbred mice to compare offspring with younger and older fathers. The mouse model demonstrated striking effects of paternal age on the behavior of mice.

Those three lines of evidence provide converging data that paternal age does influence neural functioning and that paternal age is a plausible risk factor for schizophrenia.

Medscape: Could you describe what is meant by sporadic schizophrenia and how that relates to paternal age?

Dr. Malaspina: This goes along with the issue of whether schizophrenia is one single disease or several different variants, several different diseases. If it is several diseases, we could make much more progress if we knew how to separate individuals who have one variant of the disease from individuals who have the other variant, such as for treatment studies.

So, we have this finding that father's age predicts schizophrenia, but we don't know if the genetic changes are in the same genes that cause familial schizophrenia or if they occur at a different place. Some of the birth cohorts have actually looked to see how the risk of schizophrenia with paternal age is related to the family history of schizophrenia. The finding is that father's age is not connected to the risk of schizophrenia when it runs in families, but only for cases with no family history. That is called sporadic schizophrenia.

We have also looked at patients, with the help of funding from the National Alliance for Research on Schizophrenia and Depression, and we have examined whether or not cases with late paternal age and no family history have different symptoms and brain abnormalities from those of other cases. That work is under way.

Medscape: You also looked at the duration of the parents' marriage.

Dr. Malaspina: Yes, and we found that the duration of marriage was protective against the risk for schizophrenia. This goes in the opposite direction of paternal age, but it's an independent factor. Couples that have a very long marriage are less likely to have offspring with schizophrenia. One possibility is that parents who have mental disorders themselves may have shorter marriages. Another possibility is that there is an increased risk of schizophrenia when there is a marital separation.

Medscape: A variety of environmental factors can influence the development of schizophrenia. How do you control for that?

Dr. Malaspina: On the one hand, there may be scores of different intrauterine exposures that increase the risk for schizophrenia through different pathways. Another possibility, though, is that there are only a few final common pathways through which various intrauterine adversities are linked to the risk for schizophrenia.

The Barker hypothesis deals with the area of fetal programming. Research shows that the risk for many adult-onset chronic diseases, such as cardiovascular disease, obesity, diabetes, and hypertension, is related to fetal development. The mechanism may be that an adverse fetal environment compromises the development of organs and tissues and changes lifelong gene expression. The fetus survives, but its health is compromised. Effects on the developing nervous system could contribute to schizophrenia risk. So that's a possible pathway for the risk for schizophrenia, through a variety of prenatal exposures.

The benefit of our study in Israel is that we had such a wealth of obstetric data. The birth cohort involved early pregnancy interviews with the mom. It also involved evaluations of the progress of the pregnancy and records of the delivery. Our study was able to show that other prenatal exposures did not explain the linkage of paternal age to the risk of schizophrenia. Also, there have been many excellent studies after ours was conducted that have looked at numerous fetal exposures and found that those also do not explain the risk of paternal age for schizophrenia.

I do, however, believe that many fetal exposures can increase the risk of schizophrenia. I would suggest that the mechanism of these events may be via changes in lifelong gene expression.

Medscape: What about the influence of environmental factors after birth, during childhood and adolescence?

Dr. Malaspina: I think three of the interesting factors that have been linked to the risk of schizophrenia are severe stress in a stress-sensitive person who has underlying genes for schizophrenia, traumatic brain injury in those with underlying genes for schizophrenia, and, very importantly, cannabis exposure in early adolescence.

Medscape: Your research about paternal age became public in 2001. Do you think fewer men over a certain age might choose to have children as a result?

Dr. Malaspina: I haven't heard that. I would personally not discourage anyone from having a child at any age. People weigh their own risks. For the offspring of older fathers, the risk of schizophrenia is about 3 percent. That means that 97percent of the offspring do not have schizophrenia. Other cognitive diseases linked to paternal age include mental retardation of unknown etiology and Alzheimer's disease, and there is a strong relationship between paternal age and autism.

Medscape: What do you expect to be the future of your research in this area?

Dr. Malaspina: The genes for schizophrenia that we have identified lately are very interesting; they explain a large degree of the risk of the disease. Attention probably should turn toward factors that affect the expression of these genes and other genes. This is the area of epigenetics, the code that determines whether or not genes will be expressed.

We're pursuing a gene expression hypothesis for paternal age and schizophrenia. Humans have dozens or hundreds of genes that are expressed, not on the basis of being dominant or recessive, but on the basis of which parent we have inherited them from. So genes that control the growth of the fetus tend to be expressed on the basis of inheritance from the father. Other genes are expressed only on the basis of inheritance from the mother. These are called "parent of origin genes" or "parentally-imprinted genes." In these genes, the father's copy is expressed and the mother's is silenced, or vice versa. We are interested in this mechanism of gene-silencing. For the male parent, the silencing, or the activation/expression of genes from dad, takes place late in spermatogenesis. So our hypothesis and model right now for how paternal age affects the risk for schizophrenia is that it has altered the expression of genes inherited from the father.

Even exposures that interact with genetic susceptibility may act by changing gene expression, such as traumatic brain injury, cannabis, and stress. Maybe we can integrate our understanding of the many exposures tied to schizophrenia and the many genes tied to schizophrenia with the understanding that certain exposures may act by changing gene expression.

Meanwhile, some individuals who develop schizophrenia have a good outcome and stability without much deterioration -- but not as many as we would like. If we can't prevent the disease, perhaps we can learn the risk factors for deterioration and how to prevent it.

Although I see schizophrenia as a syndrome of separate illness variants, I think the field has benefited from considering it as a single disease. From here forwards, we may be diluting our ability to find risk factors and optimize outcome by considering the disease as a whole. To go forward in schizophrenia, we need to better understand how similar symptoms may arise from abnormalities in different neural circuits; that the set of symptoms we call schizophrenia could reflect a common pathway, but that the underlying biology may differ for groups of people, and that those differences may explain which medications they should receive, or which factors are more adverse for them. I think the field needs to move toward a finer understanding of the variants that exist. The identified genes may be clearly explanatory for some cases but not for others.

Funding Information

This interview is published in collaboration with NARSAD: The Mental Health Research Association, and is supported by an educational grant from Pfizer.

Dolores Malaspina, M.D., Professor of Clinical Psychiatry, Columbia University, New York, NY;
Director of Clinical Neurobiology, New York State Psychiatric Institute and Columbia University Medical Center, New York, N.Y.

Disclosure: Jessica Gould has disclosed no relevant financial relationships.

Disclosure: Dolores Malaspina, MD, has disclosed no relevant financial relationships.

*Reprinted with permission from Medscape Psychiatry & Mental Health 2006:11(1) http://www.medscape.com/viewarticle/520009 © 2006, Medscape. Please be advised that Medscape requires free registration to view articles.

Advancing Paternal Age Is Associated with Deficits in Social and Exploratory Behaviors in the Offspring: A Mouse Model

2009-12-30T08:15:00.000-08:00

Advancing Paternal Age Is Associated with Deficits in Social and Exploratory Behaviors in the Offspring: A Mouse Model

Accumulating evidence from epidemiological research has demonstrated an association between advanced paternal age and risk for several psychiatric disorders including autism, schizophrenia and early-onset bipolar disorder. In order to establish causality, this study used an animal model to investigate the effects of advanced paternal age on behavioural deficits in the offspring.

C57BL/6J offspring (n = 12 per group) were bred from fathers of two different ages, 2 months (young) and 10 months (old), and mothers aged 2 months (n = 6 breeding pairs per group). Social and exploratory behaviors were examined in the offspring.

The offspring of older fathers were found to engage in significantly less social (p = 0.02) and exploratory (p = 0.02) behaviors than the offspring of younger fathers. There were no significant differences in measures of motor activity.

Given the well-controlled nature of this study, this provides the strongest evidence for deleterious effects of advancing paternal age on social and exploratory behavior. De-novo chromosomal changes and/or inherited epigenetic changes are the most plausible explanatory factors.

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Abstract
Introduction
Results
Discussion
Methods
Author Contributions
References
Rebecca G. Smith1#, Rachel L. Kember1#, Jonathan Mill1, Cathy Fernandes2*, Leonard C. Schalkwyk1, Joseph D. Buxbaum3,4, Abraham Reichenberg1,3

1 Medical Research Council Social Genetic and Developmental Psychiatry Centre, King's College London, London, United Kingdom, 2 Department of Psychological Medicine and Psychiatry, King's College London, London, United Kingdom, 3 Department of Psychiatry, Mount Sinai School of Medicine, New York, New York, United States of America, 4 Laboratory of Molecular Neuropsychiatry, and the Seaver Autism Center for Research and Treatment, Mount Sinai School of Medicine, New York, New York, United States of America

Abstract Top
Background
Accumulating evidence from epidemiological research has demonstrated an association between advanced paternal age and risk for several psychiatric disorders including autism, schizophrenia and early-onset bipolar disorder. In order to establish causality, this study used an animal model to investigate the effects of advanced paternal age on behavioural deficits in the offspring.

Methods
C57BL/6J offspring (n = 12 per group) were bred from fathers of two different ages, 2 months (young) and 10 months (old), and mothers aged 2 months (n = 6 breeding pairs per group). Social and exploratory behaviors were examined in the offspring.

Principal Findings
The offspring of older fathers were found to engage in significantly less social (p = 0.02) and exploratory (p = 0.02) behaviors than the offspring of younger fathers. There were no significant differences in measures of motor activity.

Conclusions
Given the well-controlled nature of this study, this provides the strongest evidence for deleterious effects of advancing paternal age on social and exploratory behavior. De-novo chromosomal changes and/or inherited epigenetic changes are the most plausible explanatory factors.

Citation: Smith RG, Kember RL, Mill J, Fernandes C, Schalkwyk LC, et al. (2009) Advancing Paternal Age Is Associated with Deficits in Social and Exploratory Behaviors in the Offspring: A Mouse Model. PLoS ONE 4(12): e8456. doi:10.1371/journal.pone.0008456

Editor: Kenji Hashimoto, Chiba University Center for Forensic Mental Health, Japan

Received: October 28, 2009; Accepted: December 2, 2009; Published: December 30, 2009

Copyright: © 2009 Smith et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: This study was supported by the Beatrice and Samuel A. Seaver Foundation, by a British Medical Association Margaret Temple Award, and National Institute of Health Research (NIHR) Biomedical Research Centre (BRC) for Mental Health at the South London and Maudsley National Health Service (NHS) Foundation Trust and Institute of Psychiatry, King's College London (KCL) Pilot Award to Drs. Jonathan Mill and Abraham (Avi) Reichenberg. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

* E-mail: cathy.fernandes@kcl.ac.uk

# These authors contributed equally to this work.

Introduction Top
Accumulating evidence from epidemiological research has demonstrated an association between advanced paternal age and risk for several psychiatric disorders including autism [1], schizophrenia [2] and early-onset bipolar disorder [3]. Despite the methodological advantages of epidemiological research, a major limitation is that techniques are limited to observation. In order to establish causality, experimental evidence in the form of randomized-controlled trials or the development of animal models is required [4]. Animal models are particularly important as they allow environmental and genetic confounds to be controlled.

The lack of complete specificity in the association between advancing paternal age and psychiatric disorders may suggest that advancing paternal age is related to phenotypes shared across disorders. One phenotype in-common to schizophrenia, autism and bipolar disorder is abnormalities in social cognition broadly defined severe social deficit [5], [6], [7], [8]. A recent epidemiological study found an association between advancing paternal age and impaired social functioning in male offspring in the general population [9].

In this study we examined the effect of older paternal age on social and non-social behavior in mice. To the best of our knowledge this is the first fully-controlled animal study of the effects of paternal age on these behaviors.

Results Top
Social Behavior
Offspring of old fathers engaged in less social activity than the offspring of young fathers, spending less time socially-interacting with the conspecific mice (t = 2.23, d.f. = 22, p = 0.02, one-tailed test, Figure 1). This result was consistently observed across all measures of social behavior. There were no significant differences in overall locomotor activity.

Figure 1. Results of social behavioral data from male offspring of young fathers (n = 12) and old fathers (n = 12).

* shows a p-value of less than 0.05, † shows p-value of 0.06. A. Mean time (±SEM) displaying all social behaviors toward a conspecific mouse (broken down into components in B, C and D). B. Mean time (±SEM) displaying allogrooming behavior towards a conspecific mouse. C. Mean time (±SEM) displaying anogenital sniffing behavior towards a conspecific mouse. D. Mean time (±SEM) displaying sniffing behavior towards a conspecific mouse.

doi:10.1371/journal.pone.0008456.g001
Exploration in the Holeboard
Offspring of old fathers demonstrated reduced exploration in the holeboard, making fewer nose pokes and spending less time nose poking than offspring of young fathers (t = −2.21, d.f. = 22, p = 0.02; Figure 2A). No significant differences were evident in distance moved or time spent in the centre of the Holeboard arena.

Figure 2. Results of holeboard and open field data from male offspring of young fathers (n = 12) and old fathers (n = 12).

* shows a p-value of less than 0.05. A. Mean number of nose pokes (±SEM) into holes in the holeboard trial. B. Mean time spent in each area of arena (±SEM) in the open field task.

doi:10.1371/journal.pone.0008456.g002
Exploration in the Open Field
Offspring of old fathers were less exploratory in the Open Field, taking longer to enter the central zone of the arena (t = 1.7837, d.f. = 22, p = 0.04). However, there were no significant differences inthe time spent in the middle (t = −0.9548, d.f. = 22, p = 0.1785) or central zones (t = −1.3166, d.f. = 22, p = 0.1056) (Figure 2B) or in overall locomotor activity between offspring of old fathers and offspring of young fathers in the open field.

To further explore these findings we examined the same set of behaviors in a small group of mice that were the offspring of very old fathers (aged >12 months, n = 9 male offspring generated from 7 breeding pairs). The behavioral results of reduced social behavior and exploration were seen in the offspring of very old fathers, but the numbers are too small to allow for a reliable statistical test (data not shown).

Discussion Top
Using a mouse model we documented deleterious effects of advancing paternal age on offspring behavior. Male offspring of older fathers engaged in less social behavior and exhibited less exploration in a novel environment. These effects were not confounded by differences in overall locomotor activity. Abnormalities in social behavior characterize psychiatric disorders previously linked to advancing paternal age, suggesting a common phenotype affected by paternal age.

There are several advantages for the mouse model used in this study. First, given the tractable nature of animal work, the environment was tightly controlled, minimizing any environmental confounds. Second, the age of all the mothers of the offspring was standard such that differences observed in the offspring cannot be accounted for by maternal age.

Finally, the most common reference inbred strain of mouse was used (C57BL/6J), reducing genetic variation.

In men, it is thought that the spermatogonial stem cell divisions occurring over the life-course of males result in higher mutational rates and cytogenetic abnormalities in the sperm of older men [10], [11]. Numerous neurological and psychiatric disorders have been related to genomic alterations [12]. A number of studies have uncovered an increased prevalence of de-novo copy-number variants (CNVs), and other forms of genomic alterations in autistic and in schizophrenia cases [13], [14].

An alternative explanation is that epigenetic dysfunction underlies some paternal age effects. Epigenetic dysfunction has been associated with several neuropsychiatric disorders, including schizophrenia and bipolar disorder [15]. A study by Flanagan and colleagues [16] reported intra- and inter-individual epigenetic variability in the male germline, and found a number of genes that demonstrated age-related DNA-methylation changes. Epigenetic signals are generally reprogrammed in the germline, although it appears that such reprogramming may not be fully complete across all regions of the genome [17]. In particular, repetitive and transposable elements in the genome, which are generally hypermethylated, are often not efficiently reprogrammed [18]. It is thus plausible that de novo structural mutations, which are often associated with repetitive DNA sequence motifs, may also be subjected to differential epigenetic reprogramming implicating both mutagenic and epigenetic processes in the phenotypic manifestation of increased paternal age.

Despite the advantages of this model, the results of this study should be interpreted in light of some limitations. We only examined one strain of male mice. This was a-priori decided in order to follow common practice in animal research aimed at limiting variation caused by sex differences in behaviors. Hence, findings should not be generalized across sexes. In addition, behavior was assessed at one developmental stage (12 weeks, young adulthood). Thus, the developmental nature of these differences could not be determined.

In conclusion, this study provides the strongest evidence to date for the behavioral effects of advancing paternal age on the offspring. Studies are ongoing to investigate the role of molecular changes in mediating the effects of advancing paternal age on social and exploratory behaviors in offspring, by assessing de-novo CNV events and alterations in DNA methylation.

Methods Top
Breeding Strategy
C57BL/6J mice were bred and maintained in the Biological Services Unit at the Institute of Psychiatry, Kings College London using stocks purchased from Charles River Laboratories. All housing and experimental procedures were performed in accordance with the UK Home Office Animals (Scientific Procedures) Act 1986. Typical breeding age for mice starts at 2 months. Male breeders are generally retired after 7–8 months. Therefore, females aged 2 months were bred with males of two different ages; young males of 2 months (n = 6 breeding pairs), and old males of 10 months (n = 6 breeding pairs). The average litter size within each age group was 7 (male to female ratio 1:1) and total progeny generated was 40 mice in the young fathers group and 44 mice in the old fathers group. Two males were randomly selected from each litter (n = 12 males per group) and weaned aged 4–5 weeks and pair housed with their siblings and then individually housed for two weeks prior to testing. Mice were housed in standard cages measuring 30.5×13×11 cm, with food and water available ad libitum. The housing room was maintained on a standard light/dark cycle with white lights on from 08:00 to 20:00. Ambient temperature in all rooms was maintained at 21±2°C with 45% humidity.

Offspring Behavioral Testing
Offspring were aged 12 weeks at the start of testing and all testing took place during the light phase with a light level <30 lux in the test room. Each apparatus was wiped clean with 1% Trigene® between subjects to avoid olfactory cueing behaviors. Behaviors for all tests were recorded on videotapes for further detailed analysis. Mice were returned to their home cage at the end of each test.

Social Behavior
The social behavior of the test mice towards a juvenile conspecific was assessed in a 5 minute trial [19]. The test mouse is habituated in an arena (36×20×14 cm) for 5 minutes, after which a male juvenile conspecific of the same strain (aged 4 weeks) was introduced for a further 5 minutes. During this trial, social behavior (including social sniffing, anogenital sniffing and allogrooming) by the test mouse towards the conspecific were scored from videotape by an observer blind to the group factor of paternal age.

Holeboard
The holeboard test is used to measure activity and exploration in a novel arena [20]. The Truscan Photo Beam Activity System (Coulbourn Instruments, Whitehall, PA) was used, which consists of an arena (25.4 cm square) and a nose poke floor with 16 holes (4×4 array) with sensor rings to track movement. The beams are spaced 1.52 cm apart providing a 0.76 cm spatial resolution. Animals were placed in the arena and the movement, the number of nose pokes and the time spent nose poking were recorded automatically by beam breaks for 5 minutes using the Truscan program.

Open Field
The open field [21] used a square white acrylic box with dimensions 72×72×33 cm. The animal was placed in the outer part of the arena facing an outer wall and allowed to freely explore the arena for 5 minutes. A video camera placed above the arena allowed movement to be tracked using an automated tracking system (Ethovision, Noldus Information Technologies). The number of faecal boli and urination were recorded at the end of the test. A square of equal distance from the periphery (36×36 cm) was defined in Ethovision as the ‘outer’, ‘middle’ and ‘central’ zones in order to determine the number of entries into, and time spent in, these zones in the arena. In addition, the latency to enter the inner zones as well as locomotor activity in all three zones of the arena were measured by the tracking system.

Statistical Analysis
Behavioral performances of offspring of young fathers and offspring of old fathers in the social interaction task, holeboard and open field were compared using unpaired, one-tailed Students t-tests. Significance level was set at 0.05.

Author Contributions Top
Conceived and designed the experiments: JM CF LCS AR. Performed the experiments: RGS RLK. Analyzed the data: RGS RLK CF. Contributed reagents/materials/analysis tools: JDB. Wrote the paper: RGS RLK JM CF LCS AR.

References Top
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Torrey EF, Buka S, Cannon TD, Goldstein JM, Seidman LJ, et al. (2009) Paternal age as a risk factor for schizophrenia: how important is it? Schizophr Res 114: 1–5. Find this article online
Frans EM, Sandin S, Reichenberg A, Lichtenstein P, Langstrom N, et al. (2008) Advancing paternal age and bipolar disorder. Arch Gen Psychiatry 65: 1034–1040. Find this article online
Rothman KJ, Greenland S (1997) Modern Epidemiology: Lippincott Williams and Wilkins.
Geschwind DH (2009) Advances in autism. Annu Rev Med 60: 367–380. Find this article online
Green MF, Penn DL, Bentall R, Carpenter WT, Gaebel W, et al. (2008) Social cognition in schizophrenia: an NIMH workshop on definitions, assessment, and research opportunities. Schizophr Bull 34: 1211–1220. Find this article online
Green MF (2006) Cognitive impairment and functional outcome in schizophrenia and bipolar disorder. J Clin Psychiatry 67: e12. Find this article online
Brotman MA, Skup M, Rich BA, Blair KS, Pine DS, et al. (2008) Risk for bipolar disorder is associated with face-processing deficits across emotions. J Am Acad Child Adolesc Psychiatry 47: 1455–1461. Find this article online
Weiser M, Reichenberg A, Werbeloff N, Kleinhaus K, Lubin G, et al. (2008) Advanced parental age at birth is associated with poorer social functioning in adolescent males: shedding light on a core symptom of schizophrenia and autism. Schizophr Bull 34: 1042–1046. Find this article online
Crow JF (2000) The origins, patterns and implications of human spontaneous mutation. Nat Rev Genet 1: 40–47. Find this article online
Buwe A, Guttenbach M, Schmid M (2005) Effect of paternal age on the frequency of cytogenetic abnormalities in human spermatozoa. Cytogenet Genome Res 111: 213–228. Find this article online
Reichenberg A, Mill J, MacCabe J (In Press) Epigenetics, Genomic Mutations and Cognitive Function. Cognitive Neuropsychitry. Find this article online
Marshall CR, Noor A, Vincent JB, Lionel AC, Feuk L, et al. (2008) Structural variation of chromosomes in autism spectrum disorder. Am J Hum Genet 82: 477–488. Find this article online
Sebat J, Lakshmi B, Malhotra D, Troge J, Lese-Martin C, et al. (2007) Strong association of de novo copy number mutations with autism. Science 316: 445–449. Find this article online
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Flanagan JM, Popendikyte V, Pozdniakovaite N, Sobolev M, Assadzadeh A, et al. (2006) Intra- and interindividual epigenetic variation in human germ cells. Am J Hum Genet 79: 67–84. Find this article online
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High Paternal Age Risk New Sporadic Dominant Mutations

2009-11-27T06:29:00.000-08:00

Clin Dysmorphol. 2009 Nov 24. [Epub ahead of print]

Limb malformations with associated congenital constriction rings in two unrelated Egyptian males, one with a disorganization-like spectrum and the other with a probable distinct type of septo-optic dysplasia.
Temtamy SA, Aglan MS, Ashour AM, El-Badry TH.

Departments of aClinical Genetics bOrodental Genetics, Division of Human Genetics and Genome Research, National Research Centre, Cairo, Egypt.

In this report, we describe two unrelated Egyptian male infants with limb malformations and constriction rings. The first case is developing normally but has severe limb anomalies, congenital constriction rings, scoliosis because of vertebral anomalies, a left accessory nipple, a small tumor-like swelling on his lower back with tiny skin tubular appendages, a hypoplastic scrotum, and an anchored penis. The second case is developmentally delayed with limb malformations, congenital constriction rings, a lumbar myelomeningeocele, hemangioma, and tiny tubular skin appendages on the back. The patient also had bilateral optic atrophy. The constellation of features in our patients cannot be fully explained by the amniotic disruption complex. The first patient may represent an additional case of the human homolog of the mouse disorganization mutant. The presence of bilateral optic atrophy in the second case, although without an absent septum pellucidum nor other brain anomalies resembles the infrequently reported disorder of septo-optic dysplasia with limb anomalies. Both cases were sporadic and could be caused by a new dominant mutation because of the high paternal age of case 1 and the history of paternal occupational exposure to heat for both fathers. We draw attention to the phenotypic overlap between the disorganization-like syndrome and septo-optic dysplasia with limb anomalies.

PMID: 19940763 [PubMed - as supplied by publisher]

Is Your Sperm Too Old?

2009-11-22T18:28:00.000-08:00

Is Your Sperm Too Old?
Turns out that it’s not just women who have a biological clock.
By Kevin Conley,
While you've never been against the idea of a serious relationship, you are in no particular rush to become a schlub. The attendant trappings of new fatherhood—the preschool viewings, the sleepless nights, the humiliation of carrying a diaper bag—aren't exactly calling out to you the way, say, another night slinging Pisco sours would. The ever-intensifying din of the proverbial biological clock? That's for the opposite sex to worry about—you know, like periods, frizz and whether Mr. Big will dump "Carrie in the Sex and the City" sequel. As far as you know, your little swim team of DNA carriers will be competing at Olympic level into Letterman age. So what's the rush?

"I always thought my biological clock was the 36 hours I had left after I took my Cialis pill," says Zack, a 30-year-old producer in Los Angeles. "That's the only clock I've ever felt ticking." Turns out, Zack might want to consider the unsung glories of fatherhood.

According to a study released last March in the Public Library of Science Medicine, children born to fathers who were 20 scored an average of 2 points higher on an IQ test than children born to 50-year-old fathers. And that's not all. Recent studies from Israel, California and Sweden have connected "late paternal age" with any number of serious medical conditions: The longer you wait, the more likely it is that your kid will be affected by schizophrenia, dwarfism, bipolar disorder, autism, Marfan syndrome, certain childhood cancers, or even, later in life, Alzheimer's. In some cases, the risk factors skyrocket. A 2005 study conducted by the University of California, Los Angeles, found a fourfold rise in Down syndrome among babies born to men 50 and older. Worse still, those risk factors aren't limited to your tweed-sporting years: Statistically, "late paternal age" starts at 30, as in Zack's age. A 2006 study conducted by Mount Sinai School of Medicine found that fathers in their 30s have children with about 1.5 times the risk of developing autism compared with fathers in their teens and 20s. That factor jumps to five times for dads in their 40s. The cherry on the cake? The American Society for Reproductive Medicine recommends that sperm banks do not accept specimens from men over 40.

"The biological clock for men and women is really the same," says Dr. Dolores Malaspina of Bellevue Hospital Center in New York City and New York University, who conducted one of the first studies. "It's just that men can keep having babies."

The biology behind this isn't hard to grasp: Starting in puberty, spermatogonia, the master copies for sperm production, replicate themselves every couple of weeks. After 300 to 500 copies—somewhere in your 30s—a meaningful number of small copy errors, or point mutations, start to emerge, which accumulate over time.

Yet, despite the alarming new science, most men greet parenthood with a sense of urgency that's more in line with Zack's than Angelina Jolie's. The reason is simple: While women are inculcated with the risks of late-age motherhood in sixth-grade sex ed, men remain blissfully ignorant. Since the recent studies have been published, the bad news still doesn't seem to be making it to the doctor's office. Scott, a 32-year-old schoolteacher from Babylon, N.Y., decided to start a family when he was Zack's age, strictly because he wanted to raise his child while he was young. "For me the doctors were like, 'Hey, this is going to be good. You're still active,'" Scott says. "Nobody ever told me about the medical risks of being an older dad."

That's because men don't usually get this news flash until they're looking through a microscope at a batch of fugly sperm with no sense of direction. Swain, a 37-year-old IT professional in Dallas, wishes he had heard sooner. His wife is four years younger than he is, and they decided to wait. "What I did was let her clock be the one in control," Swain says. "I would have been happy having kids five, six years ago, but she just wasn't ready. The female clock seems to dominate the conversation."

But don't expect sweeping social change anytime soon. "Tell a man he's got a chance of having kids with genetic abnormalities, and it's like he's going through the stages of the acceptance of death," says Dr. Harry Fisch, a professor of urology and the author of The Male Biological Clock. "They'll say, 'I'm losing my manliness, my sexual ability.' To them it all comes under the same umbrella."

The good news is that no one, not even Malaspina, is suggesting that older men eschew the joys of fatherhood. But if you're a younger guy who hasn't thought twice about postponing it, be forewarned: The female of the species is about to get her just rewards. That bell tolling? It's for you.

Later Paternal Age and Sex Differences in Schizophrenia Symptoms.

2009-11-21T06:55:00.000-08:00

Later Paternal Age Accounts for at least one quarter of all schizophrenia cases.

Scientists discover link between older dads and genetic diseases

2009-10-26T07:49:00.000-07:00

October 26, 2009
Scientists discover link between older dads and genetic diseases
Mark Henderson
http://www.timesonline.co.uk/tol/news/science/genetics/article6889878.ece");
Recommend? (4)

Scientists have moved a step closer to understanding why older fathers are more likely to have children with certain genetic diseases.
They have discovered a surprising genetic link between the formation of benign testicular tumours called spermocytic seminomas and several rare growth disorders, which are more common among the children of older fathers.
The abnormal testicular cells that form these rare tumours also produce sperm carrying mutant genes that cause serious inherited diseases, research at the University of Oxford and Copenhagen University Hospital in Denmark has shown.
The findings offer important new insights into the origin of several rare genetic disorders, including a cause of dwarfism called achondroplasia, and also promise to illuminate more common conditions such as autism, schizophrenia and breast cancer.

All three of these are known to be affected by genetics, and to be more prevalent among the children of older fathers, but few of the DNA mutations responsible have yet been identified. Scientists behind the research believe that abnormal testicular cells of the sort that develop into tumours could be partially responsible.
Professor Andrew Wilkie, of the University of Oxford, who led the research, said: “What we have seen so far may just be the tip of a large iceberg of mildly harmful mutations being introduced into our genome. These mutations would be too weak and too rare to be picked up by our current technology, but their sheer number would have a cumulative effect, leading to disease.
“It may be that process we have identified might contribute to part of the excess risk for older fathers to have children with higher risks of, for example, breast cancer, schizophrenia, or autism. We have no direct evidence for this as yet.”
Details of the research are published in the journal Nature Genetics . Professor Wilkie’s team, which is funded by the Wellcome Trust, is now planning further research to investigate whether testicular abnormalities might be linked to conditions such as autism and schizophrenia.
Spermatocytic seminomas are rare tumours of the testes, almost always benign, which affect about one in 100,000 men. They are caused by the accumulation of genetic mutations in testicular cells, which can sometimes then divide to trigger tumours.
“We think most men develop these tiny clumps of mutant cells in their testicles as they age,” Professor Wilkie said. “They are rather like moles in the skin, usually harmless in themselves. But by being located in the testicle, they also make sperm - causing children to be born with a variety of serious conditions.”
The new study, has identified genetic mutations of the sort that cause achondroplasia and other rare inherited conditions in cells from spermatocytic seminomas. It appears that these mutations help the tumour cells to divide, but cause abnormal growth when transmitted to the offspring via sperm. “We call them ‘selfish’ because the mutations benefit the germ cell but are harmful to offspring,” Professor Wilkie said.
As the mutations cause the tumour cells to profilerate in the testes, they also increase the chances that a sperm that fertilises an egg will be abnormal.
The results will help doctors to explain to parents why children have developed these disorders, and to advise them about the risks of having further children. In most cases, these families will not have a high risk of having another affected child, though it will be higher than in the general population.
“The major implication is for older fathers,” Professor Wilkie said. “We already knew that men in their 50s have a risk of having children with various individually rare genetic disorders — achondroplasia is a well known one — about tenfold higher than men in their early 20s.
“Adding all these risks together, the total additional risk is still only a fraction of 1 per cent because each of these disorders is rare.”

Fertility wanes, risks increase with age.

2009-08-22T12:21:00.000-07:00

Fertility wanes, risks increase with age. (A reprint of an article)
Mark Teich Premium Health News Service
August 21, 2009

Paternal age as a risk factor for schizophrenia: How important is it?

2009-08-18T14:08:00.000-07:00

1: Schizophr Res. 2009 Aug 13. [Epub ahead of print]
Paternal age as a risk factor for schizophrenia: How important is it?
Torrey EF, Buka S, Cannon TD, Goldstein JM, Seidman LJ, Liu T, Hadley T, Rosso IM, Bearden C, Yolken RH.
The Stanley Medical Research Institute, 8401 Connecticut Ave., Suite 200, Chevy Chase, MD 20815, USA.

Advanced paternal age has been widely cited as a risk factor for schizophrenia among offspring and even claimed to account for one-quarter of all cases. We carried out a new study on 25,025 offspring from the Collaborative Perinatal Project (CPP), including 168 diagnosed with psychosis and 88 with narrowly defined schizophrenia. We also conducted a meta-analysis of this and nine other studies for which comparable age-cohort data were available. The mean paternal age for the CPP cases was slightly, but not significantly, higher than the matched controls (p=0.28). Meta-analyses including these new results were conducted to determine the relative risk associated with alternative definitions of advanced paternal age (35, 45 or 55years and older). These yielded pooled odds ratios and 95% confidence intervals of 1.28 (1.10, 1.48), 1.38 (0.95, 2.01) and 2.22 (1.46, 3.37), respectively. Thus, increased paternal age appears to be a risk factor for schizophrenia primarily among offspring of fathers ages 55 and over. In these 10 studies, such fathers accounted for only 0.6% of all births. Compared with other known risk factors for schizophrenia, advanced paternal age appears to be intermediate in magnitude. Advanced paternal age is also known to be a risk factor for some chromosomal and neoplastic diseases in the offspring where the cause is thought to be chromosomal aberrations and mutations of the aging germline. Similar mechanisms may account for the relationship between advanced paternal age and schizophrenia risk.

Paternal and maternal ages at conception and risk of bipolar affective disorder in their offspring.

2009-07-25T18:41:00.000-07:00

Psychol Med. 2009 Jul 23:1-9. [Epub ahead of print]
Paternal and maternal ages at conception and risk of bipolar affective disorder in their offspring.
Menezes PR, Lewis G, Rasmussen F, Zammit S, Sipos A, Harrison GL, Tynelius P, Gunnell D.
Department of Preventive Medicine, University of Sao Paulo, Brazil.
BACKGROUND: A consistent association between paternal age and their offspring's risk of schizophrenia has been observed, with no independent association with maternal age. The relationship of paternal and maternal ages with risk of bipolar affective disorders (BPAD) in the offspring is less clear. The present study aimed at testing the hypothesis that paternal age is associated with their offspring's risk of BPAD, whereas maternal age is not.MethodThis population-based cohort study was conducted with individuals born in Sweden during 1973-1980 and still resident there at age 16 years. Outcome was first hospital admission with a diagnosis of BPAD. Hazard ratios (HRs) were calculated using Cox's proportional hazard regression. RESULTS: After adjustment for all potential confounding variables except maternal age, the HR for risk of BPAD for each 10-year increase in paternal age was 1.28 [95% confidence interval (CI) 1.11-1.48], but this fell to 1.20 (95% CI 0.97-1.48) after adjusting for maternal age. A similar result was found for maternal age and risk of BPAD [HR 1.30 (95% CI 1.08-1.56) before adjustment for paternal age, HR 1.12 (95% CI 0.86-1.45) after adjustment]. The HR associated with having either parent aged 30 years or over was 1.26 (95% CI 1.01-1.57) and it was 1.45 (95% CI 1.16-1.81) if both parents were >30 years. CONCLUSIONS: Unlike schizophrenia, the risk of BPAD seems to be associated with both paternal and maternal ages.
PMID: 19627644 [PubMed - as supplied by publisher]
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Newsweek Covers the Male Genetic Biological (Time Bomb) Clock

2009-04-22T16:40:00.000-07:00

For Whom The Clock Ticks
A growing body of research supports the idea that there are biological disadvantages to late-in-life fatherhood. But will society's view of male fertility ever change?

By Daniel Heimpel | Newsweek Web Exclusive
Apr 22, 2009

In season two of Bravo's wildly popular television series "Millionaire Matchmaker," host Patti Stanger rants against older men who perpetually search for 20-somethings to date. What Stanger knows intuitively and what researchers are illustrating empirically, is that men 50 and older, no matter their financial stability, aren't always the greatest catch.

Even if they can theoretically father children till the day they die, a growing compendium of knowledge points to a male "biological clock" largely driven by the replication of sperm with damaged DNA. According to a number of recent studies, offspring of older men have increased chances of a wide range of problems from autism to psychiatric disorders such as schizophrenia. Unlike women, who are equipped with their life's supply of eggs at birth, men replicate sperm from their bar mitzvah to their funeral. It's like a Xerox copy of a Xerox copy millions of times over. The damage can be caused by glitches in the process of replicating DNA millions of times over, reduced efficiency of the DNA repair mechanism, or attributed to environmental factors like stress, smoking or heavy drinking.

But the bottom line is: as men age, the percentage of damaged sperm they carry in their testes tends to increase. "Men are making millions of sperm all the time, and the chance for a copy error is much higher," says Dr. Ethylin Jabs, director of the Center for Craniofacial Development and Disorders at Johns Hopkins, who has conducted extensive research on paternal age and mutations within sperm. Where older women may be concerned about the viability of their remaining eggs, the problem for men, says Jabs, is "quantity not quality."

Semen samples of men over 45 showed impairment to sperm in three categories: their motility (swimming capability), vitality and DNA integrity, according to Dr. Sergey Moskovtsev of Mount Sinai Hospital's Department of Pathology and Laboratory Medicine in New York. Moskovtsev's research shows that men older than 45 have twice as much damage to their sperm as men under 30. Researchers believe that an increase in the percentage of damaged sperm can have a number of consequences.

A report released in PLoS Medicine last month establishes a link between reduced intelligence and children who were fathered by older men. Using a sample of 33,000 children tested at the ages of 8 months, 4 years and 7 years, John McGrath of Australia's Queensland Centre for Mental Health Research and colleagues found that children of older fathers ranked consistently lower in cognitive ability tests than the offspring of younger fathers. For example, 7-year-old children born to 50-year-old dads performed two IQ points lower than peers born to 20-year-old fathers. This difference in IQ is of course subtle, and McGrath says that the results of his study shouldn't be cause for individual men to stop having children.

But he cautions that the mounting studies pointing to a male biological clock are worth considering on a macro level. "As a researcher, I am concerned that we have neglected the issue of paternal age," McGrath says. "Worryingly, the mutations associated with advanced paternal age can be passed on to the next generation. As the population delays parenthood, these mutations could, theoretically, accumulate. Other researchers—not me—have called this process a 'mutational time-bomb'."

Normally, individual sperm with impaired DNA would perform a kind of cell hara-kiri, killing themselves in a process called apoptosis. But research out of the University of Washington has shown that the sperm of men over 35 are less likely to go through that process. Coupled with higher amounts of semen bearing damaged DNA, the likelihood of a child born with an abnormality increases. In a study of hundreds of thousands of psychiatric records conducted by the Israeli draft board in the 1980s, Dr. Abraham Reichenberg of the Mount Sinai School of Medicine, New York, and the Institute of Psychiatry, King's College London, and colleagues showed a six-time increase in autism spectrum disorders for children of fathers over 40, compared with those 29 years and younger.

Since that report came out in 2006, Reichenberg says that efforts to link autism and other psychological disorders to older dads have been bolstered by similar results among sample groups from different countries. Another psychological disorder that has been linked to damaged sperm is schizophrenia. Men over 50 are 3 times as likely to have offspring with the debilitating mental disorder than fathers under the age of 25....

Your Old Man

2009-04-01T08:47:00.000-07:00

The Way We Live Now
Your Old Man
BY LISA BELKIN
Published: April 1, 2009
Read between the lines of a recent study out of Australia and you can see hints of a coming shift in the gender conversation. Researchers at the University of Queensland found that children born to older fathers have, on average, lower scores on tests of intelligence than those born to younger dads. Data they analyzed from more than 33,000 American children showed that the older the man when a child is conceived, the lower a child’s score is likely to be on tests of concentration, memory, reasoning and reading skills, at least through age 7.

It was a small difference — just a few I.Q. points separated a child born to a 20-year-old and a child born to a 50-year-old. But it adds weight to a new consensus-in-the-making: there is no fountain of youth for sperm, no “get out of aging free” card. The little swimmers, scientists are finding, one study at a time, get older and less dependable along with every other cell in the male body.

And men don’t have to be all that old to be “too old.” French researchers reported last year that the chance of a couple’s conceiving begins to fall when the man is older than 35 and falls sharply if he is older than 40. British and Swedish researchers, in turn, have calculated that the risk of schizophrenia begins to rise for those whose fathers were over 30 when their babies were born. And another Swedish study has found that the risk of bipolar disorder in children begins to increase when fathers are older than 29 and is highest if they are older than 55. British and American researchers found that babies born to men over the age of 40 have significantly greater risk of autism than do those born to men under 30. (The age of the mother, in most of these studies, showed little or no correlation.)

Lay this latest I.Q. news atop the pile, and you find yourself reaching the same conclusion as Dr. Dolores Malaspina, a professor of psychiatry at New York University Medical Center, who has done some of the schizophrenia research: “It turns out the optimal age for being a mother is the same as the optimal age for being a father.”

For decades men have been diligently discovering their feminine side, and couples have been announcing “we’re pregnant”; yet the hows and whens of having a baby are still juggled primarily by women. We are the ones who hold the time lines and calendars in our heads, who have to surrender space in our bodies and clear time in our lives. Too soon could derail a career. Too late could risk infertility. Becoming a mother means compromising with biology — “settling” for a mate or for single-parenthood or for an ill-timed career interruption — in order to beat that clock.

The clock determines not only the odds of having a baby but also the odds of having a healthy baby. It doesn’t help that after age 35, a first-time mom finds “elderly primigravida” scrawled on her chart in the OB’s office. With each year comes greater risks of Down syndrome and low birth weight and prematurity. The message to women: you are the direct cause of your baby’s health; the message to men: you, too, could be Tony Randall. Women: you’d better hurry up. Men: you have all the time in the world.

The push and pull between timetables and dreams, between our bodies and our babies, is at the core of many women’s worldview, which also means it is at the core of relationships between the sexes. This tension feeds the stereotype of woman as eager to settle down and men as reluctant, and it’s the crux of why we see women as “old” and men as “distinguished.”

If those underlying assumptions were to change, would all that follows from them change as well? A world in which each man heard his clock tick even a fraction as urgently as each woman could be a very different world indeed. All those silver-haired sex symbols, and balding sugar daddies, and average-Joe divorced guys who are on their second families because they can be while their exes are raising their first set of kids — what if all of them became, in women’s eyes, too darned old?

What if 30-year-old women started looking at 50-year-old men as damaged goods, what with their washed-up sperm, meaning those 50-year-olds might actually have to date (gasp!) women their own age? What if men, as the years passed, began to look with new eyes at Ms. Almost Right? Would men of all ages come to understand — firsthand, not just from the sidelines — the fear that the very passage of time will put your not-yet-conceived baby at risk?

It could happen. True, the results of these studies are incremental and preliminary — a few I.Q. points here, a few hundred schizophrenia cases there. Yet for better or worse, we humans have proved that we’ll upend our lives over a few bits of cautionary data. This seems particularly true when it comes to parenting, where our responses are often visceral, not intellectual. Suggest that something might keep a child safer, or ensure his happy future, or get her into college, and today’s parents will bite.

Contrasting Effects of Maternal and Paternal Age on Offspring Intelligence

2009-03-13T13:43:00.000-07:00

Contrasting Effects of Maternal and Paternal Age on Offspring Intelligence
The clock ticks for men too
Mary Cannon

Funding: MC is supported by a Clinician Scientist Award from the Health Research Board, Ireland, a Grable Independent Investigator award from NARSAD (US), and the Wellcome Trust. The funders played no role in preparing this article.

Competing Interests: The author has declared that no competing interests exist.

Citation: Cannon M (2009) Contrasting Effects of Maternal and Paternal Age on Offspring Intelligence. PLoS Med 6(3): e1000042 doi:10.1371/journal.pmed.1000042

Published: March 10, 2009

Copyright: © 2009 Mary Cannon. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Mary Cannon is in the Department of Psychiatry, Royal College of Surgeons in Ireland and Beaumont Hospital, RCSI Education and Research Centre, Beaumont Hospital, Dublin, Ireland. E-mail: marycannon@rcsi.ie

Provenance: Commissioned; not externally peer reviewed

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Both maternal and paternal ages are increasing in the developed world. The average age of mothers at time of childbirth has increased from 26.4 years in 1974 to 29.3 years in 2002, while the average age of fathers has increased from 29.2 years in 1980 to 32.1 years in 2002 [1]. This increase in the average parental age is most likely due to the societal trend for couples to delay starting a family for career or financial reasons. The concept of the female “biological clock” (the effect of increasing maternal age on reducing fertility) is well known and is a source of anxiety for many women [2]. In contrast, the consequences of increasing paternal age on fertility and other adverse reproductive outcomes are rarely discussed [3].

Effects of Paternal Age on Offspring Outcomes
Evidence is accumulating that advanced paternal age may exhibit a wider range of effects on the health and development of the offspring than increased maternal age (which is largely confined to risk for Down syndrome). Advanced paternal age is a risk factor for childhood conditions such as cleft lip and palate; childhood cancers and congenital heart defects [1]; and neuropsychiatric conditions such as autism [4], schizophrenia [5,6], epilepsy [7], and bipolar disorder [8]. Advanced paternal age also appears to affect mortality, and an intriguing analysis of family history data from European nobility found that older age of fatherhood (greater than 45 years) is associated with a reduction of about two years in the life span of daughters [9].

Linked Research Article
This Perspective discusses the following new study published in PLoS Medicine:

Saha S, Barnett AG, Foldi C, Burne TH, Eyles DW, et al. (2009) Advanced paternal age is associated with impaired neurocognitive outcomes during infancy and childhood. PLoS Med 6(3): e1000040. doi:10.1371/journal.pmed.1000040

Using a sample of children from the US Collaborative Perinatal Project, John McGrath and colleagues show that the offspring of older fathers exhibit subtle impairments on tests of neurocognitive ability during infancy and childhood.

Some of these associations (notably that for schizophrenia) are more extensively replicated than others, but the body of evidence implicating paternal age as a risk factor for a range of adverse offspring outcomes should not be ignored. What is the postulated mechanism for these associations?

Putative Genetic Mechanisms of Paternal Age Effect
Most commentators attribute these associations to some form of genetic effect, with the greatest consensus in favour of spontaneous mutation. Genomic studies show that sperm cells undergo more mutations than ova during the life span [10]. Thus delaying fatherhood might contribute to an increased incidence of mutations that can give rise to developmental and neuropsychiatric disorders in the population. Epigenetic mechanisms, such as hypermethylation, increase with age and may be an alternative explanation [11,12].

Intermediate Phenotypes
Rather than a direct genetic effect, paternal age could increase risk for a range of neuropsychiatric outcomes in an indirect manner by increasing the likelihood of an “at-risk” or precursor phenotype in offspring. Support for this hypothesis comes from a study by Weiser and colleagues, who analysed data from an Israeli cohort of 10,000 male conscripts and found that offspring of both very young fathers (less than 20 years) and older fathers (greater than 45 years) had impaired social function [13]. Sons of older mothers (greater than 40 years) also had poorer social function. Poor social function has been shown to be a precursor for many psychiatric disorders, such as schizophrenia [14].

Parental Age and Intelligence of Offspring
A new study by John McGrath and colleagues in this issue of PLoS Medicine examines the association between paternal and maternal age and impaired neurocognitive ability in childhood (another putative intermediate phenotype) [15]. The authors use data from the Collaborative Perinatal Project, a large birth cohort of more than 50,000 individuals born between 1959 and 1965 in 12 centres in the United States, who were followed up throughout childhood. Cognitive measures were collected at three time points: eight months, four years, and seven years. The use of a cohort from the 1960s means that the association between parental age and offspring intelligence is largely unconfounded by the possible neurocognitive effects of assisted reproductive technology (which began in 1978) or the possible psychosocial effects of complex (or blended) stepfamily structures, which have become more common over the past decade.

McGrath and colleagues show remarkable contrasting effects of paternal and maternal age on the cognitive abilities of the offspring [15]. Increasing maternal age is associated with superior performance on intelligence tests in a linear fashion whereas increasing paternal age is associated with significantly poorer performance on five out of six of the measures tested.

A second notable aspect of this study is the effect of adjustment for socio-economic factors. Controlling for parental mental health and socio-economic status, measured using a composite score that indexes maternal and paternal education as well as family income, resulted in a marked attenuation of the effect of both maternal and paternal age on the intelligence scores. For instance, the average difference in IQ between the offspring of a father aged 20 and a father aged 50 decreases from six points to three points after adjustment for socio-economic factors.

These intriguing findings give rise to two questions: (1) Why should the offspring of older fathers, but not older mothers, have poorer performance on intelligence tests? and (2) If genetic effects are responsible, then what role do social factors play?

The Role of Social Factors
Social advantage (in the form of economic security and increased education) may compensate to a certain extent for the biological risks in delaying motherhood [16]. McGrath and colleagues find that delayed fatherhood does not appear to convey this social advantage in the form of better cognitive test scores [15]. Is this due to some inherent difference in the way in which older fathers and older mothers interact with their children? Or is this due to spontaneous mutation—bearing in mind that studies in rodents show that paternal age significantly influences developmental and behavioural outcomes in offspring [12]? Of course, both effects could be operating in conjunction in humans. For instance, Reichenberg and colleagues have postulated that the incidence of genetic mutations may be influenced by age at fatherhood, which in turn may be influenced by the socio-cultural environment or by personality characteristics [4].

Conclusion
McGrath and colleagues show the importance of taking socio-economic factors into account when examining the issue of paternal age [15]. Could the paternal age effect on offspring intelligence be due to so-called residual confounding, whereby adjustment does not fully remove the effect of a confounder [17]? In other words, if we could adjust the association for every relevant socio-economic and interpersonal variable (both known and unknown) using precise measures, then perhaps we could eliminate the effect of paternal age on intelligence completely. New explanatory models are needed that can encompass socio-cultural and interpersonal factors as well as biological variables. Perhaps then we can decide when is the best time to be a mother…or father.

References
Bray I, Gunnell D, Davey Smith G (2006) Advanced paternal age: How old is too old? J Epid Comm Health 60: 851–853. Find this article online
Bewley S, Davies M, Braude P (2005) Which career first? The most secure age for childbearing remains 20–35. BMJ 331: 588–589. Find this article online
Lewis BH, Legato M, Fisch H (2006) Medical implications of the male biological clock. JAMA 296: 2369–2371. Find this article online
Reichenberg A, Gross R, Weiser M, Bresnahan M, Silverman J, et al. (2006) Advancing paternal age and autism. Arch Gen Psychiatry 63: 1026–1032. Find this article online
Malaspina D, Harlap S, Fennig S, Heiman D, Nachon D, et al. (2001) Advancing paternal age and the risk of schizophrenia. Arch Gen Psychiatry 58: 361–367. Find this article online
Zammit S, Alleback P, Dalman C, Lundberg I, Hemmingson T, et al. (2003) Paternal age and risk for schizophrenia. Br J Psychiatry 183: 405–408. Find this article online
Vestergaard M, Mork A, Madsen KM, Olsen J (2005) Paternal age and epilepsy in the offspring. Eur J Epid 20: 1003–1005. Find this article online
Frans E, Sandlin S, Reichenberg A, Lichtenstein P, Langstrom N, et al. (2008) Advancing paternal age and bipolar disorder. Arch Gen Psychiatry 65: 1034–1040. Find this article online
Gavrilov LA, Gavrilova NS (1997) When should fatherhood stop? Science 277: 17–21. Find this article online
Buwe A, Guttenbach M, Schmid M (2005) Effect of paternal age on the frequency of cytogenetic abnormalities in human spermatozoa. Cytogenet Genome Res 111: 213–228. Find this article online
Perrin MC, Brown AS, Malaspina D (2007) Aberrant epigenetic regulation could explain the relationship of paternal age to schizophrenia. Schizophr Bull 33: 1270–1273. Find this article online
Garcia-Palomares S, Pertusa JF, Minarro J, Garcia-Perez MA, Hermenegildo C, et al. (2008) Long-term effects of delayed fatherhood in mice on postnatal development and behavioural traits of offspring. Biol Reprod 80: 337–342. Find this article online
Weiser M, Reichenberg A, Werbeloff N, Kleinhaus K, Lubin G, et al. (2008) Advanced parental age at birth is associated with poorer social functioning in adolescent males: Shedding light on a core feature of schizophrenia and autism. Schizophr Bull 34: 1042–1046. Find this article online
Cannon M, Jones PB, Gilvarry C, Rifkin L, McKenzie K, et al. (1997) Premorbid social adjustment in schizophrenia and bipolar disorder: Similarities and differences. Am J Psychiatry 154: 1544–1550. Find this article online
Saha S, Barnett AG, Foldi C, Burne TH, Eyles DW, et al. (2009) Advanced paternal age is associated with impaired neurocognitive outcomes during infancy and childhood. PLoS Med 6: e1000040. doi:10.1371/journal.pmed.1000040. Find this article online
Stein Z, Susser M (2000) The risks of having children in later life. Social advantage may make up for biological disadvantage. BMJ 320: 1681–1682. Find this article online
Leon DA (1993) Failed or misleading adjustment for confounding. Lancet 342: 479–481. Find this article online

University of Queensland research has revealed the older a dad is the more likely his children will have reduced cognitive abilities.

2009-03-13T13:25:00.000-07:00

University of Queensland research has revealed the older a dad is the more likely his children will have reduced cognitive abilities.

Professor John McGrath, from UQ's Queensland Brain Institute, said the study could have implications for a society that is having children later in life.

He said while recent research had shown a link between the age of a father and an increased chance of schizophrenia and autism in the children, there has been less focus on the age of father and cognition.

"The results were quite startling as it was thought that the age of the father was less of a concern compared to the age of the mother," Professor McGrath said.

"Now we are getting more evidence of the age of the father being just as important.

"The older a dad is, the worse his children tend to do in intelligence tests."

The research, published in medical journal PLoS Medicine today (Tuesday, March 10), re-analysed data from one of the largest studies of children in the United States, the Collaborative Perinatal Project.

More than 33,000 children were tested at eight months, four years and seven years on a variety of intelligence tests, and when Professor McGrath and his colleagues looked at the results against the age of the fathers a pattern soon became clear.

"Frankly, we were surprised to come up with such a clear cut finding," Professor McGrath said.

"We are concerned that older men accumulate more mutations in the developing sperm cells.

"These mistakes then pile up and increase the risks of problems in the children, and it is possible that these mistakes will carry on into the next generation."

Professor McGrath said the difference in intelligence was the exact opposite for children of older women, which made the findings even more startling.

"Offspring of older women do better in similar tests, but this is usually put down to socio-economic status of women," he said.

"But with the older dads, we wonder if the association is related to mutations in the developing sperm."

Professor McGrath and colleagues at QBI and the Queensland Institute of Medical Research are currently using mouse models in order to find the underlying genetic factors that may explain the association between advance paternal age and child development.

Source : Research Australia

James Watson co-discoverer of DNA make the connection between older paternal age (35plus) and schizophrenia in son

2009-03-07T19:49:00.000-08:00

From The Sunday Times
March 8, 2009
Not too bright? Now the blame is on your old man
Jonathan Leake, Science Editor

CHILDREN with older fathers seem to perform worse in intelligence tests, according to a study due out this week.
They tended to obtain significantly lower scores in a variety of cognitive tests than those born to younger fathers, researchers have found.
The results could be controversial. Until recent years it had been thought that it was a mother’s age that had most impact on the health and abilities of children. The father’s age, by contrast, was thought to be much less important.
The research, led by John McGrath, of the Queensland Brain Institute at the University of Queensland in Australia, suggests such ideas need rethinking.
“The offspring of older fathers show subtle impairments on tests of neurocognitive ability during infancy and childhood,” he said. “In light of the trends to delay fatherhood, the clinical implications and the mechanisms underlying these findings warrant closer scrutiny.”
Other research has shown linkage between advanced paternal age (men over 35) and an increased risk of neurodevelopmental disorders, such as autism and schizophrenia, as well as dyslexia. Such findings prompted James Watson, co-discoverer of the structure of DNA, to speak of his concern. His son Rufus suffers from schizophrenia and as more is uncovered about its causes Watson has publicly questioned if he is to blame. “I worry that I was 42 with Rufus,” he says. “I read that the frequency of schizophrenia goes up with the age of both parents.”
The tests, designed to measure the ability to think and reason, also generated a second startling finding — that children with older mothers gain higher intelligence scores.
McGrath analysed data on 33,437 Americans born between 1959 and 1965. All were tested at eight months, four years and seven. The data set, despite its age, remains one of the best resources. McGrath also used advanced statistical techniques to remove environmental influences.
For McGrath one of the key questions is the underlying biological mechanisms. One idea is that as men age the cells that produce sperm suffer increasing numbers of mutations, which are passed on to an offspring.
Why, though, would children born to older mothers tend to have higher intelligence? McGrath suggests this is because women’s eggs are formed when they are still in the womb and so their DNA is protected from mutation until they are used.

Men Must Contend With a Biological Clock, Too Older males face higher risk of fathering children with medical problems, research finds

2009-02-14T08:57:00.000-08:00

Men Must Contend With a Biological Clock, Too Older males face higher risk of fathering children with medical problems, research finds
By Kathleen DohenyHealthDay Reporter
SATURDAY, Feb. 14 (HealthDay News) -- It wasn't all that long ago that any suggestion that a man had a "biological clock" like a woman, and should father children sooner rather than later, would have been given short scientific shrift.
Not anymore. Today, a growing body of evidence suggests that as men get older, fertility can and does decline, while the chances of fathering a child with serious birth defects and medical problems increase.
Some studies have linked higher rates of serious health problems such as autism and schizophrenia in children born to men as young as their mid-40s.
And doctors and researchers are busy trying to figure out how men who choose to delay fatherhood -- either by choice or necessity, such as a lack of a partner -- can offset the effects of their biological clocks as those clocks wind down.
Interestingly, problems with reduced fertility can start long before middle age, said Dr. Harry Fisch, one of the pioneers in the field in male fertility and director of the Columbia University College of Physicians and Surgeons' Male Reproductive Center, in New York City.
"We know after age 30, testosterone levels decline about 1 percent per year," said Fisch, author of the book The Male Biological Clock.
Research done at the University of Washington has found that "as men age, DNA damage occurs to their sperm," said Dr. Narendra P. Singh, a research associate professor in the department of bioengineering, who co-authored a study on the subject.
Several other studies point to problems in the offspring of older fathers, as well as older men experiencing fertility problems.
For instance, Fisch and his colleagues found that if a woman and a man were both older than age 35 at the time of conception, the father's age played a significant role in the prevalence of Down syndrome. And this effect was most detectable if the woman was 40 or older -- the incidence of Down syndrome was about 50 percent attributable to the sperm.
Other researchers have found that children born to fathers 45 or older are more likely to have poor social skills, and that children born to men 55 and older are more likely to have bipolar disorder than those born to men 20 to 24 years of age at the time of conception.
On other fronts, researchers at Mount Sinai School of Medicine in New York City found that children of men aged 40 or older were about six times more likely to have autism. Still another study found that the children of fathers who were 50 or older when they were born were almost three times more likely to be diagnosed with schizophrenia...
But Fisch did say, "The sooner, the better."...

Recent reports have also suggested that children of men who were 40 or older may be up to 6 times more likely to develop autism, jumping

2009-02-13T12:33:00.000-08:00

(Recent reports have also suggested that children of men who were 40 or older may be up to 6 times more likely to develop autism, jumping to a nine-fold risk when the father's age reaches 50 and beyond.)
Gender equality: Aging egg and sperm are both problematic

By Cindy Haines, M.D., Special to the Beacon
Posted 10:30 a.m. Fri., Feb. 13 - The trend is clear. Women and men are postponing starting -- or adding to -- their families until their mid to late 30's and beyond. While the proverbial biological clock has historically been in reference solely to females, a growing body of evidence points to a tick-tick factor for males, as well. The number of births in the United States to men aged 40 to 49 has almost tripled between 1980 and 2004, according to the National Center for Health Statistics, making this biological clock analysis more relevant than ever.
Aging dad and infertility
When one thinks of infertility, thoughts may go directly to the female, with a secondary thought of whether or not the male is able to produce viable sperm. If sperm production is a "go", a common assumption may be made that difficulties conceiving or delivering a healthy baby are factors resting exclusively on the woman. Not necessarily so, according to accumulating data on the subject.
In an analysis of couples struggling with fertility problems, lower pregnancy rates and increased risk of miscarriage were seen in cases whereupon the man was age 35 and older. This finding comes from study presented in 2008 at the European Society of Human Reproduction and Embryology annual conference in Barcelona.
French researchers studied over 12,000 couples seeking care at a fertility clinic where the majority was being treated due to the man's infertility. Collectively, the couples underwent a total of 21,239 intrauterine inseminations (IUIs). Not surprisingly, women over age 35 had a reduced pregnancy rate compared to younger women (8.9 vs. 14.5 percent, respectively).
"But we also found that the age of the father was important in pregnancy rates -- men over 35 had a negative effect. And, perhaps more surprisingly, miscarriage rates increased where the father was over 35," said Dr. Stephanie Belloc, of the Eylau Center for Assisted Reproduction in Paris and author of the study. "Our research proves for the first time that there is a strong paternal age-related effect on IUI outcomes, and this information should be considered by both doctors and patients in assisted reproduction outcomes."
Dr. Peter Ahlering, medical director of SHER Institutes for Reproductive Medicine in St. Louis, agrees that age of would-be fathers may well have an effect on successful pregnancies. "Much of this impact is likely due to environmental exposures which may have an impact on sperm quality," he said
More information
The American Society for Reproductive Medicine on infertility
SHER-St. Louis
Archives of General Psychiatry:
Abstract - Frans
Full Text (subscription or payment may be required)
Ahlering uses HRSS -- high resolution sperm selection -- in the quest for the highest quality sperm. "You can select out under high magnification the sperm to use during [assisted reproductive technologies]," he explains. "You can select out sperm with visible abnormalities which has the effect of increasing fertilization efforts." And the chance of a healthy baby, to boot.
Aging dad and mental illness in his offspring
Advanced paternal age has also been linked with an increased risk of birth defects, including cleft palate and dwarfism. Recent reports have also suggested that children of men who were 40 or older may be up to 6 times more likely to develop autism, jumping to a nine-fold risk when the father's age reaches 50 and beyond. Other mental illness seen more commonly in offspring of aging dads: schizophrenia. A child born to a 40-year-old father may have double the risk of schizophrenia than if the child is born to a father 30 years old or younger.
Children of older fathers may also have a higher risk of bipolar disorder (alternating bouts of mania and depression), according to the results of research published in the September issue of the Archives of General Psychiatry. Over 13,420 subjects with a diagnosis of bipolar disorder were studied. Children of men who were at least 55 years old had a 37 percent greater chance of a bipolar diagnosis compared to children of men ages 20 to 24. The risk was even greater in cases of early-onset disease, suggesting greater severity of disease linked with advancing paternal age.
The science of aging sperm
Ahlering recommends that women nearing their late 30s and beyond get fertility screening. "For men, screen 'at-risk' populations," he says. And adhering to general good health guidelines is important as well...including smoking cessation, healthy diet and regular exercise.
Unlike women, who are born with all the eggs they will have (and which age along with them), a man's reproductive arsenal replenishes itself on a continuous basis. And because sperm is constantly being manufactured, it could be that genetic mutations are created over time.
Identifying the genetically aberrant sperm and selecting it out is a capability of modern medicine. "Some of the testing/screening/treatment we can do may lead to ability to utilize sperm selection techniques that may minimize risk of paternal effects," Ahlering said. But he cautions that nothing is certain. "It is all speculative at this time whether there is an association and whether the HRSS helps...but a lot of science and studies lend credence."
Dr. Cindy Haines is managing editor of Healthday-Physician's Briefing and president of Haines Medical Communications Inc., a full-service medical communications and consulting firm. As a board-certified family physician, Haines is well-versed in all areas of health care, with particular interest in fitness, nutrition, and psychological health. You can listen to Dr. Haines' House Call on KTRS .
Her column runs each week in the St. Louis Beacon. To contact her, contact Beacon health editor Sally J. Altman.

Missing in the octuplets debate: Their father

2009-02-10T16:32:00.000-08:00

Missing in the octuplets debate: Their father
By Paul Raeburn on February 10, 2009 in About Fathers
The Suleman octuplets are the product of Nadya Suleman and a sperm donor. They don't have a father.

It's tempting to put it that way, isn't it? But of course they have a father. Will it trouble them that they might never know him?

Advanced parental age at birth is associated with poorer social functioning in adolescent males: shedding light on a core symptom of schizophrenia and

2009-02-04T16:42:00.000-08:00

autism

Schizophr Bull. 2008 Nov;34(6):1042-6. Epub 2008 Sep 15. Links
Advanced parental age at birth is associated with poorer social functioning in adolescent males: shedding light on a core symptom of schizophrenia and autism.Weiser M, Reichenberg A, Werbeloff N, Kleinhaus K, Lubin G, Shmushkevitch M, Caspi A, Malaspina D, Davidson M.
Department of Psychiatry, Sheba Medical Center, Tel-Hashomer, Ramat Gan, Israel. mweiser@netvision.net.il

BACKGROUND: Evidence indicates an association between older parents at birth and increased risk for schizophrenia and autism. Patients with schizophrenia and autism and their first-degree relatives have impaired social functioning; hence, impaired social functioning is probably an intermediate phenotype of the illness. This study tested the hypothesis that advanced father's age at birth would be associated with poorer social functioning in the general population. To test this hypothesis, we examined the association between parental age at birth and the social functioning of their adolescent male offspring in a population-based study. METHODS: Subjects were 403486, 16- to 17-year-old Israeli-born male adolescents assessed by the Israeli Draft Board. The effect of parental age on social functioning was assessed in analyses controlling for cognitive functioning, the other parent's age, parental socioeconomic status, birth order, and year of draft board assessment. RESULTS: Compared with offspring of parents aged 25-29 years, the prevalence of poor social functioning was increased both in offspring of fathers younger than 20 years (odds ratio [OR] = 1.27, 95% confidence interval [CI] = 1.08-1.49) and in offspring of fathers 45 years old (OR = 1.52, 95% CI = 1.43-1.61). Male adolescent children of mothers aged 40 years and above were 1.15 (95% CI = 1.07-1.24) times more likely to have poor social functioning. CONCLUSIONS: These modest associations between parental age and poor social functioning in the general population parallel the associations between parental age and risk for schizophrenia and autism and suggest that the risk pathways between advanced parental age and schizophrenia and autism might, at least partially, include mildly deleterious effects on social functioning.

PMID: 18796466 [PubMed - indexed for MEDLINE]

From an E Mail January 22, 2009

2009-01-22T14:11:00.000-08:00

Dear Mrs. Feldman,
Really, for a man, 25-30 years are the fine age. That is a notion not enough spread in Occident.
Warmly,
Maurice Auroux

Reproduction, Vol. 4, No. 7, pp. 794-797, 1989
© 1989 European Society of Human Reproduction and Embryology

--------------------------------------------------------------------------------

other

Paternal age and mental functions of progeny in man
Maurice R. Auroux1, Marie J. Mayaux2, Marie L. Guihard-Moscato2, Maurice Fromantin3, Jean Barthe3 and Daniel Schwartz2
2INSERM U 292, Santé Publique. Epidémiologie, Reproduction Humaine, CHU Bicêtre 94271 Le Kremlin-Bicêtre 3Ministère de la Défense, Inspection Technique des Services Médicaux de 1‘Hygiène et de I’Epidémiologie dans les Armées, Hôpital du Val de Grace 75230 Paris, France Biologie de la Reproduction et du Développement, CHU Bicêtre 94271 Le Kremlin-Bicêtre

Correspondence: 1To whom correspondence should be addressed

The effects of maternal age on the quality of offspring are well known. Those due to the father's age are less obvious, apart from the role of increasing paternal age in the onset of many dominant autosomal disorders. But an experimental model has demonstrated that, in rats, increasing paternal age, without any other anomalies, might produce a decreased learning capacity in progeny. The object of the epidemiological investigation presented here was to verify whether this effect might also occur in man. The study involved the distribution of scores obtained in psychometric tests by 18-year-old male subjects, according to their father’s age at the time of their birth. This distribution indicated not only that increasing paternal age is accompanied by effects similar to those observed in animals, but also that very young paternal age was also related to these effects. Thus, the curve of such scores produced an inverted U-shape, with maximum scores obtained when the father was about thirty years of age. Maternal age did not appear to play a part in this event. These results pose the problem of identifying genetic and/or psychosocial factors which might have an impact on the quality of the conceptus.

Key words: paternal age/spermatogenesis/mental functions in adult male progeny/epidemiological study in man

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Long-Term Effects of Delayed Fatherhood in Mice on Postnatal Development and Behavioral Traits of Offspring
Biol Reprod, February 1, 2009; 80(2): 337 - 342.
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K. J. Tsuchiya, K. Matsumoto, T. Miyachi, M. Tsujii, K. Nakamura, S. Takagai, M. Kawai, A. Yagi, K. Iwaki, S. Suda, et al.
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Men also have a biological clock

2009-01-21T14:35:00.000-08:00

Health NewsView archive | RSS Feed Men also have a biological clock
Published: Jan. 21, 2009 at 4:04 PMOrder reprints | Feedback
VALENCIA, Spain, Jan. 21 (UPI) -- Mammalian males can reproduce until late in life, but their children may have more abnormalities, researchers in Spain said.

Although mammalian males can reproduce until late in life, evidence of hazards to offspring has emerged in human and animal models, the researchers said.

Silvia Garcia-Palomares of the University of Valencia in Spain and colleagues said that their study, published in the Biology of Reproduction, provides clear, well-controlled data of deleterious effects on the offspring of aged male mice mated to females of prime reproductive age.

The offspring from the elderly males exhibit abnormalities not only in several behavioral traits, but also in reproductive fitness and longevity -- the offspring fathered by old mice had a shorter life span.

Moreover, mating the offspring from aged males resulted in the production of pups exhibiting decreased weights at weaning when compared with pups from the offspring of younger males.

Garcia-Palomares said the defects causing these abnormalities in offspring are unknown and should be the objective of intriguing studies in the future.

Older men are having children, but the reality of a male biological clock makes this trend worrisome

2009-01-17T12:00:00.000-08:00

January 15, 2009

By Harry Fisch, MD

Feature Article
Dr Fisch is Professor of Clinical Urology, Department of Urology, Columbia University College of Physicians and Surgeons, Columbia University Medical Center, New York City.

Disclosure: The author states that he has no financial relationship with any manufacturers in this area of medicine.

ABSTRACT

Couples are waiting longer to have children, and advances in reproductive technology are allowing older men and women to consider having children. The lack of appreciation among both medical professionals and the lay public for the reality of a male biological clock makes these trends worrisome. The age-related changes associated with the male biological clock affect sperm quality, fertility, hormone levels, libido, erectile function, and a host of non-reproductive physiological issues. This article focuses on the potentially adverse effects of the male biological clock on fertility in older men. Advanced paternal age increases the risk for spontaneous abortion as well as genetic abnormalities in offspring due to multiple factors, including DNA damage from abnormal apoptosis and reactive oxygen species. Increased paternal age is also associated with a decrease in semen volume, percentage of normal sperm, and sperm motility. Older men considering parenthood should have a thorough history and physical examination focused on their sexual and reproductive capacity. Such examination should entail disclosure of any sexual dysfunction and the use of medications, drugs, or lifestyle factors that might impair fertility or sexual response. Older men should also be counseled regarding the effects of paternal age on spermatogenesis and pregnancy.

Fisch H. The aging male and his biological clock. Geriatrics. 2009;64(1):14-17.

Keywords: apoptosis, hypogonadism, male biological clock, male infertility, paternal age, spermatogenesis, testosterone

The phrase "biological clock" commonly refers to the declining fertility, increasing risk for fetal birth defects, and altered hormone levels experienced by women as they age. Abundant scientific evidence suggests that men also have a biological clock.1,2 The hormonal and physiological effects of the male clock are linked with testosterone and fertility declines, as well as pregnancy loss and an increased risk of birth defects.3 In this article, we review the effects of the male biological clock, and the association between advanced paternal age and decreased spermatogenesis, pregnancy rates, and birth outcomes.

Male testosterone levels (both total and free) decline roughly 1% per year after age 30.4 The rate of decline in one study4 was not significantly different between healthy men and those with chronic illnesses or multiple comorbidities. This decline can shift men whose testosterone levels are in the low end of the normal spectrum to levels considered below-normal, or hypogonadal (testosterone <325 ng/mL) as they age. An estimated 2 to 4 million men in the United States fall in this category, either from age-related declines, illness, injury, or congenital conditions.5 The population of hypogonadal men is increasing due both to the aging of the general population and unknown factors that appear to be suppressing the average levels of testosterone in more recent birth cohorts.6 The increasing prevalence of abnormally low testosterone levels in elderly men was demonstrated in the Baltimore Longitudinal Study on Aging, which determined that hypogonadal testosterone levels were present in approximately 20% of men over 60, 30% over 70, and 50% over 80 years of age.7

Sub-normal testosterone levels are associated not only with decrements in fertility and sexual response, but also a wide range of other health problems such as declines in muscle mass/strength, energy levels, and cognitive function, as well as increased incidence of weight gain (particularly central adiposity), type 2 diabetes, the metabolic syndrome, and cardiovascular disease. Testosterone replacement therapy to address the wide range of health problems related to hypogonadism is becoming increasingly popular. Delivery via gels or transdermal patches can result in physiologically normal levels of testosterone, which is preferable to the spiky levels obtained via testosterone injections. Oral formulations are under development but none have progressed beyond the clinical trial phase. Fears that testosterone replacement therapy may promote the growth of prostate carcinomas has abated in light of findings from several studies that find no such link.8

Declining fertility and increasing birth defects

It has long been recognized that female fertility declines with age and, obviously, ceases with menopause. Only relatively recently, however, has it been proven that male fertility also declines with age—often significantly so—and that semen quality and the related risk for birth defects is also sensitive to aging. Studies demonstrate that men older than age 35 are twice as likely to be infertile (defined as the inability to initiate a pregnancy within 12 months) as men younger than 25 years.9 Among couples undergoing fertility treatments with intra-uterine insemination, the amount of time necessary to achieve a pregnancy rises significantly with the age of the male. Further, after controlling for maternal age, couples in which the male is older than 35 have a 50% lower pregnancy rate compared with couples in which men are 30 or younger.10

The risk of birth defects is also now known to be related to paternal age. A significant association has been found between advancing paternal age and the risk of autism spectrum disorder (ASD) in children.11 Offspring of men 40 years or older were 5.75 times more likely to have ASD compared with offspring of men younger than 30 years, after controlling for year of birth, socioeconomic status, and maternal age.

Another study finds a link between paternal age and a higher risk of fathering a child with schizophrenia.12 Men older than 40 were more than twice as likely to have a child with schizophrenia as men in their 20s. A similar influence of paternal age on the risk of having a child with Down syndrome has been reported by several research teams,1 with paternal age a factor in half the cases of Down syndrome when maternal age exceeded 35 years. Other investigators have found that the rate of miscarriages increases with rising paternal age when maternal age was older than 35.13 Thus, there is convincing evidence for an effect of paternal age alone, as well as a combined effect of advancing paternal and maternal age, on increased risks of genetic abnormalities leading to miscarriage or disease in their children. A retrospective multi-center European study revealed that the effects of advanced paternal age and maternal age are cumulative. If both partners are advanced in age, the risk of spontaneous abortion is higher.

Mechanisms behind biological clock effects

The precise genetic and physiological malfunctions underlying the observed links between advanced paternal age and congenital abnormalities remain uncertain although clues have been discovered in recent years. Studies in the murine model, for example, have shown that changes in testicular architecture affect semen quality. At 18 months (defined as "older" in a mouse), several age-related changes occur, including increased number of vacuoles in germ cells and thinning of the seminiferous epithelium. At the age of 30 months, seminiferous epithelia with scant spermatocytes were identified. Overall, total sperm production was significantly reduced and mutation frequency was significantly increased in "older" mice.14

Such changes in testicular architecture, as well as changes in the germinal epithelium, prostatic epithelium, and a host of genetic alterations, undoubtedly underlie the well-documented declines in human semen parameters observed over the years. The literature (11 of 16 published studies) clearly shows, for example, a decrease in semen volume with advanced age. In 2 studies, which adjusted for the confounder of abstinence duration, a decrease in semen volume of 0.15-0.5% was reported for each increase in year of age.15 The semen volume of men aged 50 or older was decreased by 20-30% when compared with men younger than age 30. An association between advanced paternal age and decreased sperm motility is also apparent. In a review of 19 studies, 13 found a decrease in sperm motility with increasing age. Five studies adjusted for the duration of abstinence—a key potential confounder—and found statistically significant declines. A comparison of men age 50 or older to men younger than 30, revealed a 3% to 37% decline in motility.

Abnormal sperm morphology is also tied to advanced paternal age. In 14 studies reviewed, 9 studies found decreases in the percentage of normal sperm with advancing age with the rates of decline ranging from 0.2% per year to 0.9% per year of age when controlling for confounders of duration of abstinence and year of birth.16

The male biological clock also "ticks" at the level of genes. The genetic integrity of sperm has been shown in several studies to decline with age. For example, age is associated with declines in the number of Leydig and Sertoli cells, as well as with an increase in arrested division of germ cells. There also seems to be an increasing failure of the body's ability to "weed out" genetically inferior sperm cells via the mechanism of apoptosis. Spermatozoa are continuously produced and undergo lifelong replication, meiosis, and spermatogenesis. An essential aspect of spermatogenesis that ensures selection of normal DNA is the process of apoptosis of sperm with damaged DNA. Since the rate of genetic abnormalities (such as double-strand breaks) during spermatogenesis increases as men age, the rate of apoptosis should rise as well. This, however, does not seem to be the case, for reasons that remain unknown, which results in higher levels of genetically damaged sperm in older men.

Oxidative stress may also play a role in the observed rise in the frequency of numerical and structural aberrations in sperm chromosomes with increasing paternal age. Spermatozoa have low concentrations of antioxidant scavenging enzymes, which makes them particularly susceptible to DNA damage from reactive oxygen species. A recent study found that seminal reactive oxygen species levels are significantly elevated in men older than 40 years of age.17

Aneuploidy errors in germ cell lines also occur at higher rates with advancing paternal age. The aneuploidy error of trisomy 21, for example, is responsible for Down syndrome. The rate of many autosomal dominant disorders such as Apert syndrome, achrondroplasia, osteogenesis imperfecta, progeria, Marfan syndrome, Waardenburg syndrome, and thanatophoric dysplasia increases with advanced paternal age. Apert syndrome, for example, is the result of an autosomal dominant mutation on chromosome 10, mutating fibroblast growth factor receptor 2 (FGFR2). With increasing paternal age, the incidence of sporadic Apert syndrome increases exponentially, resulting in part from an increased frequency of FGFR2 mutations in the sperm of older men.

The role of medications and comorbidities

The effects of the male biological clock can be exacerbated by both medications and comorbidities. Pharmacologically mediated fertility declines and/or sexual dysfunction has been demonstrated for antihypertensive drugs, antidepressants, and hormonal agents. Seminal emission can be blocked by alpha blocker medications, which are used to treat many symptoms of the lower urinary tract. Gonadotropin-releasing hormone agonists, which are used for prostate cancer treatment, can directly affect sperm production and testosterone levels. High doses of anabolic steroids, sometimes used for enhancement of performance and muscle enlargement, cause reduction of sperm production, which may be permanent. Erectile dysfunction, ejaculatory disorders, and decreased libido can be caused by the 5-alpha reductase inhibitors.

Sexual function and reproductive function can substantially decline in males treated for prostate cancer. Treatments such as radiotherapy, surgery or hormones, alone or in combination, can result in these dysfunctions in treated men of any age, though the severity of effects increases with age. A report found that ultrasound-guided needle biopsy of the prostate was associated with some abnormal semen parameters.18 Since prostate biopsy is more common in men 50 or older, this can be an issue for older would-be fathers.

Conclusions

The fact that men and women are waiting longer to have children, and that advances in reproductive technology are allowing older men and women to consider having children, carries a generally unrecognized public health risk in the form of increased infertility and risk for birth defects and other reproductive problems. CDC birth statistics show the average maternal age rose from 21.4 years of age in 1974 to 25.1 years of age in 2003. Paternal age is rising as well.

The lack of appreciation among both medical professionals and the lay public for the reality of a male biological clock makes these trends worrisome. This article has demonstrated a host of potential reproductive problems among older men. Semen parameters as well as semen genetic integrity decline with age, which leads to an increased risk for spontaneous abortion as well as genetic abnormalities in offspring. The decreasing apoptotic rate and increase in reactive oxygen species among the rapidly replicating spermatogonia are possible mechanisms behind an amplification of errors in germ cell lines of older men. Such errors may account for the observed increases in Down syndrome, schizophrenia, and autosomal dominant disorders in children born to older fathers.

Future research may elucidate in greater detail the etiology and manifestation of the male biological clock in older men. Novel methods to reverse or slow the clock may be discovered by improved understanding of the cellular and biochemical mechanisms of gonadal aging. This research may diminish potential adverse genetic consequences in offspring and increase the chances that older couples will have a healthy child.

References

1. Fisch H, Hyun G, Golden R, et al. The influence of paternal age on Down syndrome. J Urol. 2003:169(6):2275-2278.

2. Eskenazi B, Wyrobek AJ, Sloter E, et al. The association of age and semen quality in healthy men. Hum Reprod. 2003;18(2):447-454.

3. Lewis BH, Legato M, Fisch H. Medical implications of the male biological clock. JAMA. 2006;296(19):2369-2371.

4. Feldman HA, Longcope C, Derby CA, et al. Age trends in the level of serum testosterone and other hormones in middle-aged men: longitudinal results from the Massachusetts male aging study. J Clin Endocrinol Metab. 2002;87(2):589-598.

5. Rhoden EL, Morgentaler A. Risks of testosterone-replacement therapy and recommendations for monitoring. N Engl J Med. 2004;350(5):482-492.

6. Travison TG, Araujo AB, O'Donnell AB, et al. A population-level decline in serum testosterone levels in American men. J Clin Endocrinol Metab. 2007;92(1):196-202.

7. Harman SM, Metter EJ, Tobin JD, et al. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. J Clin Endocrinol Metab. 2001;86(2):724-731.

8. Imamoto T, Suzuki H, Yano M, et al. The role of testosterone in the pathogenesis of prostate cancer. Int J Urol. 2008;15(6):472-480.

9. Ford WC, North K, Taylor H, et al. Increasing paternal age is associated with delayed conception in a large population of fertile couples: evidence for declining fecundity in older men. Hum Reprod. 2000;15(8):1703-1708.

10. Mathieu C, Ecochard R, Bied V. Cumulative conception rate following intrauterine artificial insemination with husband's spermatozoa: influence of husband's age. Hum Reprod. 1995;10(5):1090-1097.

11. Reichenberg A, Gross R, Weiser M, et al. Advancing Paternal Age and Autism. Arch Gen Psychiatry. 2006;63(9):1026-1032.

12. Malaspina D, Harlap S, Fennig S, et al. Advancing Paternal Age and the Risk of Schizophrenia. Arch Gen Psychiatry. 2001;58(4):361-367.

13. de la Rochebrochard E, Thonneau P. Paternal age and maternal age are risk factors for miscarriage: results of a multicentre European study. Hum Reprod. 2002;17(6):1649-1656.

14. Walter CA, Intano GW, McCarrey JR, et al. Mutation frequency declines during spermatogenesis in young mice but increases in old mice. Proc Natl Acad Sci. 1998;95(17):10015-10019.

15. Andolz P, Bielsa MA, Vila J. Evolution of semen quality in North-eastern Spain: a study in 22,759 infertile men over a 36 year period. Hum Reprod. 1999;14(3):731-735.

16. Auger J, Kunstmann JM, Czyglik F, et al. Decline in semen quality among fertile men in Paris during the past 20 years. N Engl J Med. 1995;332(5):281-285.

17. Cocuzza M, Athayde KS, Agarwal A, et al. Age-related increase of reactive oxygen species in neat semen in healthy fertile men. Urology. 2008;71(3):490-494.

18. Manoharan M, Ayyathurai R, Nieder AM, Soloway MS. Hemospermia following transrectal ultrasound-guided prostate biopsy: a prospective study. Prostate Cancer Prostatic Dis. 2007;10(3):283-287.

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"Since 1980 there has been about a 40 percent increase in 35- to 49-year-old men fathering children, and a 20 percent decrease in fathers under 30,"

2008-12-31T21:26:00.000-08:00

Father's Age May Contribute to Genetic Birth Defects
07 June, 2006 01:27 GMT

Sperm declines in quality as men age, swimming more slowly and becoming more genetically defective, researchers reported on Monday. The finding adds to some recent studies that have found that even though men make fresh sperm every day and can father children well into old age, they become less fertile and also tend to have more children with birth defects.
"This study shows that men who wait until they are older to have children are not only risking difficulties conceiving, they could also be increasing the risk of having children with genetic problems," Andrew Wyrobek of Lawrence Livermore National Laboratory in California said in a statement.

For centuries, this tendency toward birth defects with aging was blamed on the woman, whose fertility plummets with age and disappears at menopause. Women are born with all their eggs, and these egg cells mature and ripen as women age.

Men Have Biological Clock

Older eggs are often defective and contribute both to lower female fertility and a tendency to genetic defects such as Down syndrome.

"Although it is well known that as women age, they are at increased risk for infertility, spontaneous abortion, and genetic and chromosomal defects among offspring, the association of male aging with these outcomes has been less well characterized," the researchers wrote in their report, published in the Proceedings of the National Academy of Sciences.

"Our research suggests that men, too, have a biological time clock only it is different," said Brenda Eskenazi of the University of California Berkeley's School of Public Health.

Abnormal DNA Fragmentation

For their study the researchers examined sperm samples from 97 men aged 22 to 80, all working at or retired from a government research laboratory.

They disqualified current cigarette smokers and men with current fertility or reproductive problems or who had undergone chemotherapy or radiation treatment for cancer.

They examined the sperm for obvious features which includes the ability to swim quickly, and harder-to-find qualities such as what is known as DNA fragmentation index a measure of damage that has been associated with male fertility, successful conception, and sustained pregnancy.

Men usually started to have an abnormal DNA fragmentation index at the age of 56, the researchers found.

They said it was important to understand the effects of men having children at ever-older ages.

"Since 1980 there has been about a 40 percent increase in 35- to 49-year-old men fathering children, and a 20 percent decrease in fathers under 30," they wrote.

Study: Bipolar Disorder Linked to Older Dads

2008-12-31T08:33:00.000-08:00

Study: Bipolar Disorder Linked to Older Dads
at：2008-12-31 05:25:14 Click: 12
Schizophrenia, autism and now bipolar disorder are all linked with older fathers. Here is the Associated Press story by Lindsey Tanner that ran two days ago discussing the newest study.

CHICAGO (AP) — Children born to older fathers face a greater chance of developing bipolar disorder, according to one of the largest studies linking mental illness with advanced paternal age.

Previous research has connected schizophrenia and autism with older dads, and a Danish study published last year added bipolar disorder to the list. The new study led by researchers at Sweden's Karolinska Institute strengthens the evidence.

The leading theory is that older men's sperm may be more likely to develop mutations. Even so, the odds of a person becoming bipolar are so low that the study's authors said it shouldn't dissuade older men from becoming fathers.

Researchers analyzed Swedish national registry data from more than 80,000 people, including 13,428 with bipolar disorder who were born between 1932 and 1991.

The risks started increasing around age 40 but were strongest among those 55 and older. Children born to these dads were 37 percent more likely to develop bipolar disorder than those born to men in their 20s.

They also faced more than double the risk of developing bipolar disorder before age 20. Scientists call that early onset disease, and while they have long known that bipolar disorder tends to run in families, early onset disease has been thought to be most strongly linked with genetics.

The age of the mothers didn't appear to be much of a factor.

The study, released Monday, appears in September's Archives of General Psychiatry.

While the findings don't explain what might cause some older men to have bipolar children, it "reinforces the notion that there's a strong biological component to this," said Dr. Harold Pincus, vice chair of psychiatry at Columbia University.

Bipolar disorder causes dramatic mood swings, from deep depression to manic highs. It affects more than 5 million Americans.

Lifetime risks for it have been estimated at roughly 1 percent to 4 percent. The study results suggest that having an older father might increase that slightly. The findings aren't definitive, but even if the link proves to be real, Pincus noted that still means most people with older fathers won't ever get bipolar disorder.

Factors involving mothers, including age and health, have long been thought to be most closely linked with birth defects and other abnormalities. But the new study adds to mounting evidence that paternal factors also play an important role, said New York University researcher Susan Harlap.

Sperm are produced throughout a man's lifetime, and scientists believe that as men age there is a greater chance for mutations that could contribute to disorders in their children.

Advanced paternal age also has been linked with birth defects, and some sperm banks have age limits for donors because of that.

While important for scientists, the study results shouldn't discourage older men from fathering children, said Emma Frans, the lead author.

She said the results suggest that similar mechanisms might contribute to risks for bipolar disorder, schizophrenia and autism. Each of these disorders is thought to have many causes including biologic and outside factors.

On the Net:
Archives: http://www.archgenpsychiatry.com
National Institutes of Health bipolar information: http://tinyurl.com/2wjbv7

Comments
Les at : 2008-12-31 08:25:35
Type 1 diabetes, MS, Alzheimer's, cerebral palsy, epilepsy, breast, prostate, leukemia, and early childhood cancer are among the many other disorders that rise in incidence with increasing paternal age. Some sperm US banks refuse sperm of a man past his 35th birthday to try an avoid paternal age related genetic disease. By the age of 33-35 men are rapidly accumulating mutations in their sperm making cells. http://how-old-is-too-old.blogspot.com/

- + Does a younger dad mean a healthier child?

2008-12-15T10:01:00.000-08:00

minutes ago, 12:20 EST, December 15, 2008 Toolbox

- + Does a younger dad mean a healthier child?
Medicine & Health / Health
New studies from Tel Aviv University suggest that waiting until a man can give his son "all the advantages" may have a disadvantage, too.

Tel Aviv University researchers found in several consecutive studies that older dads are more likely to have boys with autism and lower IQs. Most recently, they found that the older a father's age, the greater the chance that his son will display poor social abilities as a teen. Dr. Mark Weiser from TAU's Sackler School of Medicine and his team of researchers are now studying what causes this phenomenon.

"There is a growing body of data showing that an advanced age of parents puts their kids at risk for various illnesses," says Dr. Weiser. "Some illnesses, such as schizophrenia, appear to be more common the older parents get. Doctors and psychologists are fascinated by this, but don't really understand it. We want to know how it works."

Questions and Answers

To explore this important question, Dr. Weiser looked at data collected by the Israeli army. Subjects included more than 450,000 male teens, aged 16 and 17. The teens were asked these questions: How many good friends do you have? Do you have a girlfriend? Do you generally prefer to be with or without a group of friends? How often do you go out on Friday evenings? Do you tend to be at the center of a party?

Controlling for the variables of IQ, mother's age, socioeconomic status and birth order, the researchers found that the prevalence of poor social functioning increased by 50% in boys with fathers 45 years old and up.

Cause for Concern?

Dr. Weiser, who also works at the Chaim Sheba Medical Center at Tel Hashomer hospital, cautions that the results are far from conclusive. "It could be that men with poorer social skills get married later in life, and therefore transmit this characteristic to their boys. But our studies attempted to control for this variable by looking at brothers from the same father," he explains.

He also suggests that older men shouldn't change their minds about having children since the statistical risk is relatively minor. "The effects of a father's age on the health of his son are quite small, and many of the most dramatic effects in this study are driven by dads in their 50s," says Dr. Weiser. "The difference in risk between someone who is 35 or 45 is so small that it's irrelevant."

Dr. Weiser continues, "But the findings are interesting for clinicians who are looking at the bigger picture of how parental age affects the mental functioning of offspring and what mechanisms are at play in that functioning." And Dr. Weiser doesn't rule out the possibility that older fathers may have better resources for getting their boys tested for autism when symptoms arise.

Published in Oxford Journal's Schizophrenia Bulletin, the study builds on Dr. Weiser's previous research on parental age, autism and IQ scores.

Source: American Friends of Tel Aviv University

The biological clock ticks for men too

2008-12-13T14:11:00.000-08:00

The biological clock ticks for men too

As Sri Lanka’s pioneering Reproductive Health Centre Vindana celebrates a 10-year success story, Dr. N. Pandiyan, Chief Consultant in Andrology and Reproductive Medicine of Chettinad Health City in India reveals some disturbing statistics on reproduction while pointing out the benefits of Assisted Reproductive Techniques. Kumudini Hettiarachchi reports, Pix by M.A. Pushpa Kumara
Women should not allow their biological clock to tick if they wish to conceive and have a healthy baby, is repeated over and over again. Put baby before career, for one can always go back to work and catch up on the career but if time passes having a baby may not be possible.

Now comes a strong message that the other vital partner in the making of a baby, the father, too should not leave it too late.
With disturbing statistics that 1 in 6 couples need help in achieving a pregnancy, the advice from Dr. N. Pandiyan, Chief Consultant in Andrology and Reproductive Medicine of Chettinad Health City in India, is indeed timely.

Dr. Pandiyan
“Infertility is an age-related disease of the reproductive system and it is a race against time,” he says, explaining that two factors independently influence the prognosis of infertility – the age of the couple, particularly the woman, but also of the man and the duration of infertility.

Dealing with the age of the father, he points out that men over 40 years old had a “negative effect” on pregnancy, while there was also an increase in the miscarriage rates.

The adverse effects of older fathers include a higher mortality in the offspring of those who are 45 years old or more, with that going into adulthood as well. “Advanced paternal age has been associated with a higher risk of spontaneous miscarriage, stillbirth, pre-term birth, congenital malformations, childhood cancer, epilepsy, autism and schizophrenia in the offspring,” says Dr. Pandiyan.

Producing data to prove his point, he says studies on age and incidence of infertility show that those in the age group 20-24 had a 6% incidence of infertility; 25 to 29 -- 9%; 30 to 34 – 15%; 35 to 39 – 30% and 40 to 44 – 64%.

The lifestyle of the father also plays a major role, The Sunday Times understands. Quoting research, Dr. Pandiyan says that obesity increases the risk of male sub-fertility. The use of laptop computers on the lap and cell phones and also stress, have been implicated as possible “causative factors” for male sub-fertility.

Smoking impairs semen parameters and fertility while alcohol abusers have poorer semen samples, according to further research. “Drugs, both medical and recreational, impair male fertility, as does exposure to gonadotoxins from the environment and occupation.”

In the Vindana laboratory: Blood samples taken for testing.
Leaving aside the father’s impact, Dr. Pandiyan goes back to the time, after conception when the baby boy is still a foetus in the mother’s womb.

“Prevention of male sub-fertility starts peri-conceptually,” he explains, adding that healthy mothers give birth to healthy children. “A mother’s micro and macro environment influences the child’s reproductive health. The in-utero environment influences adult life and may also influence the reproductive health of the children.”

Pointing an accusing finger at many environmental contaminants that can affect reproductive health, this expert on andrology zeroes in on “endocrine-disrupting chemicals” which could affect hormones in the human body.

Dr. Pandiyan picks on bisphenol A (BPA) found in hard plastic, water and baby bottles, food containers, the lining of metal, food and drink cans, pacifiers and baby toys and dental sealants. Phthalates, the other culprit according to him, are a family of chemicals utilized to soften plastics used in medical devices, food wrap, flooring, wall coverings, personal care products (perfumes, lotions, cosmetics, hair spray), lacquers, varnishes and wood finishes and coatings.

Environmental contaminants during any life stage can increase the risk of adverse health effects, he says, stressing however that exposure during “susceptible windows” can result in irreversible effects that can have either immediate, lifelong or even intergenerational impacts on health.

“Humans are exposed daily to a mixture of environmental contaminants in air, water, food and consumer products. Environmental tobacco smoke, lead, mercury and phthalates are detected in nearly all members of the population. Melamine has recently been implicated in reproductive and urinary disorders,” he says.

Smoking impairs semen parameters and fertility
In the case of fertility problems, the world has advanced and many couples have experienced the joy of parenthood through Assisted Reproductive Techniques. (ART).

Although as Dr.Pandiyan stresses conception in the privacy of the bedroom is any day better than high-tech ART centres, for some the only hope of holding a baby would come through such techniques which mimic nature or give a helping hand to nature.

Having a baby is an investment

Is having a baby a luxury or a basic necessity? If needy couples have fertility problems should their yearnings for a baby remain unfulfilled with additional heartache being faced due to the barbs of malicious relatives?

If a person wants to buy a car, banks give loans, why shouldn’t the same apply for a much more important life-time investment of having a baby who would grow up to be a person who contributes to society, asks Dr. Pandiyan.

He urges that an insurance or loan scheme be introduced, taking into consideration that fertility issues are similar to any other disease. “Otherwise countries need to follow the Brunei model where the couple pays for the IVF cycle and the government pays for the drugs.”

Assisted Reproductive Techniques are costly because of the high cost of medication, it is learnt. The parents of the first baby born at Vindana underwent ART free of charge, it is understood.

101 babies in 10 years

Ten years and 101 babies later, it was celebration time for the Vindana Reproductive Health Centre last weekend.

While Vindana had invited two of its major supporters during the initial stages, Prof. Ariff Bongso and Dr. N. Pandiyan, to be part of their celebrations, the major focus was in fact a series of workshops to share the knowledge of their multidisciplinary team.

Prof. Seneviratne
Considered one of the foremost scientists on infertility in Asia, Prof. Bongso is Research Professor and Leader of the Reproductive Stem Cell Sciences group in the Department of Obstetrics and Gynaecology and Co-Leader of the Regenerative Medicine group of the Yong Loo Lin School of Medicine, National University of Singapore.

Vindana can justifiably be proud of its achievements in the past 10 years. Starting with in-vitro fertilization (IVF) in 1998 it has expanded to setting up a state-of-the-art sperm bank, egg sharing and also donation programme, Intra Cytoplasmic Sperm Injection using Testicular Sperm Aspiration and pregnancies using frozen and later thawed embryos, to put a smile on the face of couples with fertility issues.

The first IVF pregnancy managed and facilitated by a totally local team, saw the birth of a bouncy baby girl on July 1, 2002. Now she is a pretty six-year-old.

As Vindana steps into its 11th year, its sights are set on expansion into and linkages with affiliated fields such as genetics, molecular biology and in-vitro tissue biology, says its Chairman Prof. Harsha Seneviratne, well-known Obstetrician and Gynaecologist, adding that they will also help any other programme which hopes to assist couples facing fertility issues.

New study backs parent age-autism link

2008-12-12T17:05:00.000-08:00

New study backs parent age-autism link

Last Updated: 2008-12-12 9:12:21 -0400 (Reuters Health)

By Anne Harding

NEW YORK (Reuters Health) - Advanced parental age does indeed appear to boost autism risk in children, and the risk is seen with both mothers and fathers, new research shows.

"What we found was that actually it's both parents age, and when you control for one parent's age you still see the effect of the other parent's age, and vice versa," Dr. Maureen Durkin of the University of Wisconsin School of Medicine and Public Health in Madison, the lead researcher of the study reported in the American Journal of Epidemiology, told Reuters Health.

The findings may offer clues to understanding the causes of autism and why it's on the rise, but they shouldn't be used to guide family planning decisions, Durkin said. Even though the oldest child born to two older parents is three times as likely to be autistic than a middle or youngest child with younger parents, she explained, there's still a 97 percent chance that the higher-risk child will be perfectly fine. "The vast majority of children don't develop autism," she emphasized.

Several studies have suggested links between a father's age or the age of both parents and a child's likelihood of having autism. The current study included twice as many autism cases as any other research on this issue to date, which made it possible to tease out the effects of both maternal and paternal age.

The researchers looked at 253,347 children born in 1994 at 10 sites included in the Centers for Disease Control and Prevention's Autism and Developmental Disabilities Monitoring Network. There were 1,251 children who met standard criteria for an autism spectrum disorder at age 8 for whom information on both parents' age was available.

After the researchers accounted for factors that might influence the results

Paternal age: are the risks of infecundity and miscarriage higher when the man is aged 40 years or over?

2008-12-01T10:38:00.001-08:00

Rev Epidemiol Sante Publique. 2005 Nov;53 Spec No 2:2S47-55.Related Articles, Links
Paternal age: are the risks of infecundity and miscarriage higher when the man is aged 40 years or over?

De La Rochebrochard E, Thonneau P.

Unité Inserm-Ined 569, Hôpital de Bicêtre, 82, rue du Général-Leclerc, 94276 Le Kremlin-Bicêtre. roche@ined.fr

BACKGROUND: Maternal age of 35 years or over is a well-known risk factor for human reproduction that has been extensively investigated by demographers and epidemiologists. However, the possibility of a paternal age effect has rarely been considered. We carried out review of the literature to investigate the effect of paternal age on the risks of infecundity and miscarriage. METHODS: We carried out a MEDLINE search and checked the exhaustiveness of our reference list. RESULTS: We identified 19 articles analysing the effect of paternal age. Epidemiological studies provided evidence that paternal age older than 35-40 years affects infecundity. However, the few studies based on data from assisted reproductive techniques (especially IVF with ovum donation) do not confirm this finding. All studies analysing the effect of paternal age on the risk of miscarriage showed an increased risk in men aged 35-40 years or over. Other studies have shown some evidence for a paternal age effect on late foetal deaths. CONCLUSION: The risks of infecundity and miscarriage increase with paternal age. Two main hypotheses can be considered. First, these risks increase after the age of 35-40 years. However, a later paternal age effect (after 45-50 years) cannot be excluded. Second, due to the interaction of the ages of the two partners, the risks of infecundity and miscarriage may be higher when both partners are older (woman aged 35 years or over and man aged 40 years or over).

Publication Types:
Review

PMID: 16471144 [PubMed - indexed for MEDLINE]

Sperm 2. DNA damage is significantly related to age

2008-11-25T06:28:00.000-08:00

Fertility News Useful Links Video Library

Sperm DNA Damage: Correlation To Severity Of Semen Abnormalities
Main Category: Fertility
Also Included In: Urology / Nephrology; Genetics
Article Date: 24 Nov 2008 - 1:00 PST

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SAN FRANCISCO, CA, USA (UroToday.com) - Evaluation of male fertility includes assessment of the standard semen parameters (SSP) and may include assessment of DNA damage. However, the relationship between DNA damage and SSP remains controversial. This study examined the the relationship of DNA damage to SSP in patients presenting for infertility evaluation.

The authors conducted an IRB approved retrospective review of semen samples from 2586 unselected non-azoospermic patients underwent computer-assisted semen analysis and flow cytometry based sperm DNA damage assessment expressed as the DNA Fragmentation Index (DFI). DFI was significantly negatively correlated to sperm concentration, motility, and normal morphology and positively correlated to age (P<0.001). DNA damage increased in relationship to the number of abnormalities in the SSP (P <0.001).

The authors concluded:

1. DNA damage is significantly related to standard parameters of semen analysis
2. DNA damage is significantly related to age
3. The degree of DNA damage increases with the number of abnormal parameters in a sample and is most severe in patients with oligo-astheno-teratospermia (OAT).

Editorial Comments:

The authors demonstrate the relationship between progressively more abnormal semen parameters and abnormal DFI. This is consistent with clinical observations and does not appear to demonstrate any incremental value to DFI assessment, in clinical practice, in the initial assessment of the infertile male.

Presented by S. I. Moskovtsev, J. Willis, and J. White, et al., at the 64th Annual Meeting of the American Society for Reproductive Medicine - November 8 - 12, 2008 - San Francisco, California

Reported by UroToday.com Contributing Editor Harris M. Nagler, MD

UroToday - the only urology website with original content written by global urology key opinion leaders actively engaged in clinical practice.

To access the latest urology news releases from UroToday, go to: www.urotoday.com

Copyright © 2008 - UroToday

Alzheimer's link to older fathers

2008-11-21T18:58:00.000-08:00

Alzheimer's link to older fathers
Independent, The (London), Sep 17, 1998 by Charles Arthur Technology Editor
E-mail Print Link CHILDREN BORN to fathers who are approaching middle age have a higher than average risk of developing Alzheimer's disease in later life, a study suggests.

A retrospective investigation of 206 people who have the degenerative illness, but no history of it occurring in the family, revealed a statistically significant link with the age of their father when they were born.

Some genes are known to contibute to the chance of developing Alzheimer's, but the new study, carried out by Lars Bertram at the Technical University of Munich, suggests that simply having an older father - average age 35.7 - can be a risk factor even in the absence of those genes. For those where there was a family history of Alzheimer's, the average age of the father was 31.3 years.

Though the sample is comparatively small, it is in line with the knowledge that ageing is associated with genetic damage to the sperm, which carry the father's genetic contribution to the child. That might eventually lead to Alzheimer's in the offspring. "There's an accumulation of environmental factors which somehow alter the genome of the father," Dr Bertram told New Scientist magazine.

Similar effects are already known to occur in women, where mothers over 35 have a far higher chance of giving birth to babies with Down's syndrome, which is caused by a genetic defect in the embryo. People with Down's syndrome are also more likely eventually to develop Alzheimer's.

Copyright 1998 Newspaper Publishing PLC
Provided by ProQuest Information and Learning Company. All rights Reserved.

12Next »

Advanced Parental Age and the Risk of Autism Spectrum Disorder.

2008-10-24T21:41:00.000-07:00

Am J Epidemiol. 2008 Oct 21. [Epub ahead of print]
Advanced Parental Age and the Risk of Autism Spectrum Disorder.Durkin MS, Maenner MJ, Newschaffer CJ, Lee LC, Cunniff CM, Daniels JL, Kirby RS, Leavitt L, Miller L, Zahorodny W, Schieve LA.
This study evaluated independent effects of maternal and paternal age on risk of autism spectrum disorder. A case-cohort design was implemented using data from 10 US study sites participating in the Centers for Disease Control and Prevention's Autism and Developmental Disabilities Monitoring Network. The 1994 birth cohort included 253,347 study-site births with complete parental age information. Cases included 1,251 children aged 8 years with complete parental age information from the same birth cohort and identified as having an autism spectrum disorder based on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria. After adjustment for the other parent's age, birth order, maternal education, and other covariates, both maternal and paternal age were independently associated with autism (adjusted odds ratio for maternal age >/=35 vs. 25-29 years = 1.3, 95% confidence interval: 1.1, 1.6; adjusted odds ratio for paternal age >/=40 years vs. 25-29 years = 1.4, 95% confidence interval: 1.1, 1.8). Firstborn offspring of 2 older parents were 3 times more likely to develop autism than were third- or later-born offspring of mothers aged 20-34 years and fathers aged <40 years (odds ratio = 3.1, 95% confidence interval: 2.0, 4.7). The increase in autism risk with both maternal and paternal age has potential implications for public health planning and investigations of autism etiology.

PMID: 18945690 [PubMed - as supplied by publisher]

Men have their own biological clock

2008-10-23T08:24:00.000-07:00

Oct
23
2008
Men have their own biological clock
Published by Times of the Internet at 3:34 am under Top News

SYDNEY, Oct. 22 (UPI) —

An Australian study suggests men have a biological clock that signals a drop in fertility after the age of 35.

Researchers at Sydney IVF said sperm and DNA samples from more than 3,000 men shows DNA fragmentation of sperm increased with age, the Australian Broadcasting Corp. reported Wednesday.

The report said there was significant DNA damage to sperm in samples from men over the age of 35.

They cannot take fertility absolutely for granted, there is also an impact of male age on fertility, Mark Bowman of Sydney IVF said.

Copyright 2008 by United Press International
All Rights Reserved.

Overlap Found Between Autism, Schizophrenia-Spectrum Disorders

2008-10-03T12:31:00.000-07:00

Psychiatr News October 3, 2008
Volume 43, Number 19, page 20
© 2008 American Psychiatric Association

Articles by Arehart-Treichel, J.

--------------------------------------------------------------------------------

Clinical & Research News

Overlap Found Between Autism, Schizophrenia-Spectrum Disorders
Joan Arehart-Treichel
Some patients may have traits of both autism and schizophrenia because the autism-spectrum and schizophrenia-spectrum disorders share some of the same susceptibility genes.

Although autism and schizophrenia are now generally recognized as two separate illnesses, there is reason to believe that autistic traits and schizophrenia traits co-occur in some individuals.

For instance, some children with autism disorder have been found to develop schizophrenia later in life, the negative symptoms of schizophrenia have been found to co-vary with autistic traits in certain schizophrenia subjects, and a link between autistic traits and schizophrenia traits was found in a sample of college students.

Now certain individuals with schizotypal personality disorder—considered the mildest schizophrenia-spectrum illness—have been found to possess an unusual preponderance of autistic traits. The results of the study, which was led by Michelle Esterberg, M.P.H., of Emory University, were published in the September Schizophrenia Research.

The study included 121 adolescent subjects—35 with schizotypal personality disorder; 38 with other types of personality disorders (antisocial, avoidant, borderline, narcissistic, obsessive-compulsive, paranoid, or schizoid); and 48 with no personality disorders. The subjects were evaluated for various autistic characteristics, and the results for each group were then compared.

The schizotypal group scored significantly higher than the other two groups on a number of autistic traits. They included being socially anxious, having no close friends, using a limited number of facial expressions, not showing affection, being unaware of social cues, having circumscribed or unusual interests, and being resistant to change. Furthermore, the schizotypal group scored especially high on deficits in the social-functioning domain.

"The present findings indicate significant ... overlap between autism-spectrum and schizophrenia-spectrum disorders," Esterberg and her colleagues concluded.

Why might autistic traits and schizophrenia traits coexist in certain persons? Esterberg and her group suspect that it is because the autism-spectrum disorders and the schizophrenia-spectrum disorders share some of the same susceptibility genes or because some of the susceptibility genes contributing to each spectrum are occasionally inherited together.

For instance, individuals who lack genes on a particular stretch of chromosome 22—called the 22q11 chromosomal deletion—are known to be at heightened risk for both the autistic-spectrum and schizophrenia-spectrum disorders, they pointed out, suggesting that some genes located in this stretch are complicit in both disorders (Psychiatric News, September 19).

But one point they are quite sure about, as are many other investigators, is that autism and schizophrenia are not identical illnesses. One reason is because 10 of their schizotypal subjects, as well as two other subjects from the "other personality disorder" category, developed schizophrenia during a three-year follow-up period. Yet the researchers could find no link between having autistic traits and subsequently developing schizophrenia.

The study was funded by the National Institute of Mental Health.

An abstract of "Childhood and Current Autistic Features in Adolescents With Schizotypal Personality Disorder" can be accessed at by clicking on "Browse A-Z," "S," and then "Schizophrenia Research."

A small study of children with autism spectrum disorder, the umbrella term for a range of similar conditions, found they were more likely to have been

2008-09-30T17:03:00.000-07:00

fathered by men over the age of 33.

Father age link to autism in children
Older fathers are almost twice as likely to have autistic children as younger men, research has found.

By Rebecca Smith, Medical Editor
Last Updated: 12:31AM BST 01 Oct 2008

A small study of children with autism spectrum disorder, the umbrella term for a range of similar conditions, found they were more likely to have been fathered by men over the age of 33.

There was no link with the condition and the mother's age, the Japanese study found.

The research involved 84 children with high-functioning autism spectrum disorders, meaning they had the social impairments of the condition but had normal intelligence, and 208 children without the disorder.

Children whose fathers were over 33 were 1.8 times more likely to have autism than those fathers were under 29. Men who fathered children between the age of 29 and 32 were 30 per cent more likely to have an autistic child.

The research is published in the British Journal of Psychiatry.

This is the first study to explore the effect of paternal age on the risk of high-functioning autistic spectrum disorder. Its findings correspond with previous studies which have shown a link between older fathers and a low IQ in children.

Benet Middleton, director of communications at The National Autistic Society, said: "The causes of autism are still being investigated. Many experts believe that the pattern of behaviour from which autism is diagnosed may not result from a single cause. Autism affects around one in 100 people in the UK and does not solely affect children of older parents.

"Members of the NAS are made up of parents of children from a variety of ages and backgrounds; in addition there is evidence to suggest that complex genetic factors are responsible for some forms of autism."

Some experts have argued that the measles, mumps and rubella vaccination is linked to the development of autism but this has been widely discredited and other studies have failed to find any link.

The potential public health consequences of delayed parenting were emphasized.

2008-09-27T09:27:00.000-07:00

The Male Biological Clock - Does It Exist?
Main Category: Urology / Nephrology
Also Included In: Men's health; Endocrinology; Fertility
Article Date: 26 Sep 2008 - 4:00 PDT

BERLIN, GERMANY (UroToday.com) - Dr Harry Fisch, Professor of Clinical Urology Columbia University reviewed the controversial subject of decreasing sperm counts. His published analysis demonstrated that sperm counts have not decreased; the previously reported apparent decreases were the result of regional variations.

His comprehensive review was recently published in an article entitled "Declining Worldwide Sperm Counts: Disproving a Myth," in Male Infertility: Current Concepts and Controversies, edited by Harris M. Nagler, Urologic Clinics of North America (2008).

However, Dr Fisch presented data indicating the decline in male fertility is associated with age. Dr Fisch presented his data on the impact of paternal age on Down syndrome (Fisch et al., "The Influence of Paternal Age on Down Syndrome". J.Urol 2003) There are a large number of entities that have been reported to be associated with advanced paternal age. One potential explanation for the increased incidence of some of these entities may be a recognized increase in sperm acneuploidy with increasing age.

The incidence of schizophrenia has also been reported as having a correlation to increasing paternal age ("Advancing Paternal Age and the Risk of Schizophrenia," D. Malaspina, et al., Arch Gen Psychiatry.158:758, 2001).

The potential public health consequences of delayed parenting were emphasized.

Paternal age of 33, 34, 35 is when new genetic disorders begin to show up

2008-09-14T07:14:00.001-07:00

Am J Med Genet A. 2008 Sep 15;146A(18):2385-9. Links
The population-based prevalence of achondroplasia and thanatophoric dysplasia in selected regions of the US.Waller DK, Correa A, Vo TM, Wang Y, Hobbs C, Langlois PH, Pearson K, Romitti PA, Shaw GM, Hecht JT.
Houston Health Science Center, The University of Texas, Houston, Texas 77030, USA. kim.waller@uth.tmc.edu

There have been no large population-based studies of the prevalence of achondroplasia and thanatophroic dysplasia in the United States. This study compared data from seven population-based birth defects monitoring programs in the United States. We also present data on the association between older paternal age and these birth defects, which has been described in earlier studies. The prevalence of achondroplasia ranged from 0.36 to 0.60 per 10,000 livebirths (1/27,780-1/16,670 livebirths). The prevalence of thanatophoric dysplasia ranged from 0.21 to 0.30 per 10,000 livebirths (1/33,330-1/47,620 livebirths). In Texas, fathers that were 25-29, 30-34, 35-39, and > or =40 years of age had significantly increased rates of de novo achondroplasia among their offspring compared with younger fathers. The adjusted prevalence odds ratios were 2.8 (95% CI; 1.2, 6.7), 2.8 (95% CI; 1.0, 7.6), 4.9 (95% CI; 1.7, 14.3), and 5.0 (95% CI; 1.5, 16.1), respectively. Using the same age categories, the crude prevalence odds ratios for de novo cases of thanatophoric dysplasia in Texas were 5.8 (95% CI; 1.7, 9.8), 3.9 (95% CI; 1.1, 6.7), 6.1 (95% CI; 1.6, 10.6), and 10.2 (95% CI; 2.6, 17.8), respectively. These data suggest that thanatophoric dysplasia is one-third to one-half as frequent as achondroplasia. The differences in the prevalence of these conditions across monitoring programs were consistent with random fluctuation. Birth defects monitoring programs may be a good source of ascertainment for population-based studies of achondroplasia and thanatophoric dysplasia, provided that diagnoses are confirmed by review of medical records. Copyright 2008 Wiley-Liss, Inc.

PMID: 18698630 [PubMed - indexed for MEDLINE]

Related ArticlesEffect of paternal age in achondroplasia, thanatophoric dysplasia, and osteogenesis imperfecta. [Am J Med Genet. 1995] The birth prevalence rates for the skeletal dysplasias. [J Med Genet. 1986] Thanatophoric dysplasia: an autosomal dominant condition? [Am J Med Genet. 1988] Association of paternal age with prevalence of selected birth defects. [Birth Defects Res A Clin Mol Teratol. 2007] Prevalence of spina bifida at birth--United States, 1983-1990: a comparison of two surveillance systems. [MMWR CDC Surveill Summ. 1996] » See all Related Articles...

Bipolar risk rises with father's age

2008-09-01T08:56:00.000-07:00

Bipolar risk rises with father's age

Adam Cresswell, Health editor September 02, 2008
CHILDREN of older fathers are more likely to have bipolar disorder - a discovery that could explain the increasing numbers of people diagnosed with the condition.
Compared with the offspring of fathers aged 20 to 24, people whose fathers were aged 55 or over at the time of their birth are 37 per cent more likely to be diagnosed with bipolar disorder.
Children of fathers aged 30-34 had an 11 per cent increased risk of bipolar, while children of fathers aged 40-44 had a 15 per cent increased risk.
Having an older mother also increased the risk, but the effect was far less pronounced.
The research is based on nearly 13,500 Swedish people with bipolar disorder, a severe mood disorder that causes repeated peaks of euphoria and hyperactivity followed by troughs of depression.
The authors of the study, published in the US journal Archives of General Psychiatry, said paternal age was already known to be linked to other developmental disorders such as schizophrenia and autism. They suggested the findings might reflect the increased risk of DNA mutations in sperm cells, which, unlike a woman's eggs, undergo hundreds of replication cycles in which errors can occur.
Australian psychiatrist Gordon Parker, executive director of the Black Dog Institute, said the findings were important, and might explain why diagnoses of bipolar disorder had been rising.
In 1992, according to the Australian Bureau of Statistics, 35 per cent of fathers of children aged 0-14 were under 35. This fell to 26 per cent by 2003. The proportion of fathers aged 45 and over rose from 19 per cent in 1992 to 25 per cent in 2003.
However, Professor Parker said as the existing risk of bipolar disorder was thought to be between 4 and 6 per cent, the effect of the increases remained slight.
"I would hate to see any concern in the community that people shouldn't have babies because they have bipolar disorder in their family," he said.
"If you have bipolar disorder in your family, you are more likely to end up in Who's Who, because high intelligence and creativity is over-represented in families with bipolar disorder."

Older Dad Past 33 May Be Hazardous To Your Health

2008-08-30T17:15:00.001-07:00

The Fifty Foot Blogger: Caution: Dad may be hazardous to your health

Who Thinks About the Male Biological Clock Before Having Children?

2008-08-10T19:09:00.000-07:00

Tom Pastor thinks about the Male Biological Clock in relationship to his cousin

Saturday, August 09, 2008

MY TWO UNCLES: THE MALE BIOLOGICAL CLOCK
"Moses was one hundred twenty years old when he died; his sight was unimpaired and his vigor had not abated"* (Deuteronomy 34:7).Women know that they have a biological clock. By the time they are in their 30's the bio ticking gets louder and louder. There is a lot of psychology connected with the feminine biological clock.But, is there a male biological clock? Yes, but what guy is checking the time? Guys assume that they will always make sperm so, what is the hurry? What is important for guys to know is that, from a fertility and health perspective, having children is for the young. The biological material is just better. After 35 deterioration is beginning to set in. Men 40 and over are nearly 6 times more likely to have offspring with autism than men younger than 30.** By age 60, 85% of sperm is clinically abnormal. Increased age in the father increases the risk of schizophrenia in the children.I have 2 uncles in my family history, one on my dad's side and one on my mother's side. Both of these uncles did not marry until they were 40 years old. One uncle fathered 4 children who grew up to be responsible, well-functioning adults. The other uncle fathered 3 children, 2 of them grew up to be good citizens, Christians and parents. The oldest child of the second uncle developed normally. He was a good student and was dedicated as a Christian too. During his college years he developed schizophrenia. This mental illness led to his tragic death and was the cause of a great deal of anguish for the family too.Would this have happened had my second uncle fathered children earlier in life? We cannot know for sure, but if there is a question about the timing of having children, put the odds in your favor and do it sooner rather than later.Grace&Peace,Tom*James Michener said in "The Source" that the verse meant that Moses was good in bed at 120 years old. I doubt that he took any supplements either, but then all his food was organic.**Statistics came from an article in "Psychology Today" called "A Man's Shelf Life," by Mark Teich. I had read similar statistics in other publications on this subject so it seemed like they were credible.
Posted by Tom at 8:05 PM

Excellent Must See Video

2008-07-15T21:36:00.000-07:00

Male Biological clock

Dr. Sheena Lewis People often mistakenly assume they will be able to have children later in life

2008-07-14T20:10:00.000-07:00

Tuesday, July 15, 2008
Timing is key to fathering children
In this section »
Doctors say women's age remains the major factor
Can regular sex preserve potency?
THERESA JUDGE
New research suggests men's biological clocks are also ticking
FERTILITY EXPERTS have warned there is a growing body of evidence showing that the man's age is a significant factor affecting the chances of a couple conceiving and of having a healthy child.
A new study presented last week at the annual meeting of the European Society of Human Reproduction and Embryology in Barcelona found that miscarriage rates increased significantly when the man was older than 35, and that pregnancy rates dropped when the man was older than 40. The study was based on more than 12,000 couples attending a fertility clinic in Paris.
Professor of reproductive medicine at Queen's University Belfast, Sheena Lewis, who also presented a paper at the conference, said the Paris study "provided more data to add to an emerging picture" relating to the significance of the age of the father.
She said people needed to realise that they are taking a risk by waiting until they were 35 years or older to have children - as an increasing number of women and men are. "You cannot assume that it will happen, that it will not be a problem," she said.
Prof Lewis, who is a scientist at the Regional Fertility Centre at the Royal Victoria Hospital in Belfast, said there was a growing trend of people leaving it later to have children when their careers were established, and of people trying to start second families later in life. She said the clinic was seeing an increasing number of men in their 40s and 50s who wanted to have children, often in a second relationship.
People often mistakenly assume they will be able to have children later in life, she said. "What happens is that we are inclined to take anecdotal evidence and assume that it applies to the whole population - so people hear about Cherie Blair and Madonna having babies and assume that older mothers can have easy pregnancies.
"And they hear about Picasso fathering a child when he was 81, and they believe that every man can do it, and it becomes the accepted wisdom, but unfortunately it is not the case. We are perpetuating a myth and people often believe it until it is too late," Prof Lewis said.
She said there were now quite a number of studies showing that as a man ages, the likelihood of his sperm being damaged increases. "A sperm is a very specialised little cell - it is just DNA with a tail and it has one single function, to get the DNA to the egg to fertilise it. In order to do that, the cell gets rid of everything but DNA, so it gets rid of repair mechanisms that you find in other cells. So if it gets damaged it can't repair itself."
She said that after fertilisation, the DNA damage of the sperm becomes part of the genetic make-up of the embryo. "If a poor sperm fertilises an egg, and even if you get a pregnancy, there is quite often a miscarriage," Prof Lewis said. While one study had suggested that an egg could repair a damaged sperm, she said there was not a great deal of evidence to support this, and further research would be needed to test it. She said other studies had shown that when a man is older it takes longer for a couple to conceive.
Dr Stephanie Belloc, who led the study at the Eylau Centre for Assisted Reproduction in Paris, told the Barcelona conference: "Until now gynaecologists only focused on maternal age and the message was to get pregnant before the age of 35 or 38, because afterwards it would be difficult. But now gynaecologists must also focus on paternal age and give this information to the couple."
The study examined 12,236 couples who had decided to try intra-uterine insemination (IUI) after having difficulty conceiving. This procedure involves spinning sperm in a centrifuge to separate it from seminal fluid and then inserting it directly into the womb.
Pregnancy, miscarriage and delivery rates were recorded as were the quality, activity and shape of the men's sperm. The analysis separated out male and female factors.
As expected, women over the age of 35 were less likely to get pregnant but the man's age was also found to be a significant factor both in miscarriage rates and pregnancy rates.
For men aged 34, the miscarriage rate was 16.7 per cent, but for men aged between 35 and 39 it rose to 19.5 per cent, and by age 44 it had reached 32.4 per cent.
Pregnancy rates only began to change significantly when the men reached the age of 40. As the men's age rose from 39 to 44 the proportion of treatment cycles producing a pregnancy fell from 13.4 per cent to 10.9 per cent.
Dr Belloc said the study "proves for the first time that there is a strong paternal age-related effect on IUI outcomes" and she said the findings were relevant to all couples wishing to have children.
Prof Lewis and her colleagues in Belfast are currently conducting research into "lifestyle hazards" that affect male fertility. These include smoking, alcohol, sexually transmitted diseases, recreational drugs and substances that mimic oestrogens which are found in some products ranging from certain foods, aerosols and body creams, and plastic food coverings. Much of the research in this area was prompted by a Danish finding in 1992 that men's sperm count had declined by 50 per cent in 50 years.
Prof Lewis said a recent study in Denmark had also found that 40 per cent of young men had a low sperm count. "It appears to be a particular problem in northern Europe," she said.
The paper she presented at last week's Barcelona conference concerned the impact of cannabis use on male fertility. The study found that cannabis use decreased sperm motility - the pace at which sperm can swim. Other studies have also shown that cannabis use reduces sperm production.
She said that men who wanted to become fathers should be aware that it takes about 70 days for a sperm to be produced, so the "lifestyle hazards" such as smoking and recreational drugs should be avoided for at least three months if they want their sperm to be healthy.
She also pointed out that studies suggest that a father smoking, and the resulting damage to the sperm DNA, can lead to an increase in certain childhood illnesses, in particular some forms of cancer and more recently an association has been found with autism.
"When a mother smokes and damages the egg, the egg has the capacity to repair the damage, but the damage to the sperm becomes part of the embryo's genetic make-up," she said.
© 2008 The Irish Times
This article appears in the print edition of the Irish Times

------------------------------------------------------------------------------------------------

Professor Sheena E.M. Lewis, BSc PhD
School of MedicineObstetrics and GynaecologyQueen’s University BelfastInstitute of Clinical ScienceGrosvenor RoadBelfast BT12 6BJN Ireland
e: s.e.lewis@qub.ac.uk
t: +44-28-9063-3987
f: +44-28-9032-8247
I am Professor and Director of the Reproductive Medicine research group here in Queen's having previously been Reader in Obstetrics and Gynaecology at Queen's University since October 2000. I was also appointed as an Honorary Consultant in the Royal Group of Hospitals in Belfast in 2003.Services to the scientific communityNationally, I am a regular reviewer for 10 specialist journals and for research charities including The Wellcome Trust, Wellbeing, and BBSRC.I am a member of the Practice and Policy committee of the British Fertility Society and on the Research and Development Fellowship Committee and Northern Ireland Forum for Health and Social Care Research for Northern Ireland.RESEARCH PUBLICATIONS62 peer reviewed publications, 9 review articles, 6 invited chaptersincluding 23 since 2000 (First or final author on 20)RESEARCH GRANTS AWARDED£1,000,000 including three from The Wellcome Trust.PROFESSIONAL SOCIETIES• British Fertility Society• British Andrology Society• Society for the Study of Fertility• International Society of Andrology• Institute of Learning and Teaching in Higher Education• Research and Development Fellowship Committee, N.I• Ulster Obstetrical and Gynaecological Society• Vice Chairperson of the Ladies Committee, Royal Maternity Hospital• Association of University TeachersINVITED GUEST SPEAKER AT RECENT SCIENTIFIC CONFERENCES• First Mediterranean Congress of Reproductive Medicine, Taormina, Sicily• Opening Doors-scientific workshop organised by British and Spanish Councils, Spain,• GSRMC (Good Samaritan Regional Medical Centre Phoenix, Arizona, USA)• UKEMS (The United Kingdom Environmental Mutagen Society)• British Fertility Society• British Andrology Society• Biology of Spermatozoa Annual Meeting• Senior Staff Conference, Royal College of Obstetrics and Gynaecologists• Association of Clinical Biochemists in IrelandINVITED SPEAKER BY MEDIA• BBC Radios 1, 2, 4 and 5• BBC News• Sky news• Ulster Television; UTV LIFE – CHAPS UK Study• Radio Eireann – Donor Sperm• Radio Ulster – Comment on Health Minister’s proposal and comment on BFS in Belfast.• British Satellite News - for CNN news, Tokyo News, Mid Eastern broadcasting and others• Ulster Television The Family Show- Infertility and LifestyleCENTRAL UNIVERSITY ACTIVITIES• Member of Academic Council of Queens University, Belfast• Mentor and mentee in Gender Initiative in Queen’s University, BelfastRESEARCH INTERESTSOur research interest is in Andrology; the study of male reproductive function. Our twin aims are:i) to understand the endocrine, cellular and molecular reproductive dysfunctions in infertile men compared with a fertile baseline. Within this framework, we have focused on specific lifestyle, environmental and disease factors that may exacerbate infertilityii) to establish novel prognostic tests to enhance assisted conceptionOngoing projects:Lifestyle hazards: recreational drugsi) to determine the in vivo and in vitro effects of tetrahydrocannabinoid; THC the primary psychoactive cannabinoid in marijuana on human sperm functionii)the effects of Viagra on sperm function and early embryo development using human and animal modelsEnvironmental hazardsthe effects of dietary phytoestrogens on male reproductive healthDiseases exacerbating male infertilityEndocrine, cellular and molecular effects of diabetes and impotence treatments (first generation Viagra and second generation Tadalafil) on male fertilityDevelopment of novel male fertility tests with prognostic value in assisted conception• assessment of sperm nuclear and mitochondrial DNA iv)investigation of the failure of post-vasectomy testicular sperm to achieve pregnancies by ICSI• the regulation of spermatogenesis by apoptosis in fertile men and males with obstructive azoospermia- clinical implications• Ubiquitin tagging ( internal and surface) on sperm and its implications for male fertility (in collaboration with Dr Peter Sutovsky, Columbia-Missouri )Future Studies• Genetic and epigenetic alterations associated with spontaneous abortion achieved by assisted conception (in collaboration with Dr Ken McIlreavey, Pasteur Institute, Paris and Dr Colum Walsh, University of Ulster )
Obstetrics and Gynaecology at Queen's.

Among couples with fertility problems, those in which the man is over age 35 have lower pregnancy rates and increased chances of miscarriage,

2008-07-07T19:26:00.000-07:00

Father's Age a Factor in Infertility

MONDAY, July 7 (HealthDay News) -- Among couples with fertility problems, those in which the man is over age 35 have lower pregnancy rates and increased chances of miscarriage, a new study shows.
To come to this conclusion, French researchers looked at more than 12,000 couples who went to a fertility clinic in France.

In most of the cases, the couples were being treated due to the man's infertility. The couples underwent a total of 21,239 intrauterine inseminations (IUIs).

The researchers found that women over age 35 had a pregnancy rate of 8.9 percent, compared to 14.5 percent in younger women.

"But we also found that the age of the father was important in pregnancy rates -- men over 35 had a negative effect. And, perhaps more surprisingly, miscarriage rates increased where the father was over 35," study author Dr. Stephanie Belloc, of the Eylau Center for Assisted Reproduction in Paris, said in a prepared statement.

2008-07-06T22:37:00.000-07:00

The female biological clock—its tick-tock marking the decline of fertility that grows louder as a woman reaches middle age—is deeply ingrained in popular consciousness. Take this scene from the film Bridget Jones's Diary: Bridget's Uncle Geoffrey reminds her that as a career girl she "can't put it off forever," alluding to her declining fertility. His wife Una chimes in: "tick-tock, tick-tock," her finger wagging like a metronome.
The biological clock, although just a metaphor, refers to a real phenomenon: Women over 35 years of age are only half as likely to become pregnant in the most fertile part of their menstrual cycle than women younger than 26.

So do men suffer from the same thing?

"For women, a biological clock is a decline in fertility and an increased chance of having genetically abnormal babies as they age," says Harry Fisch, director of New York City's Male Reproductive Center and author of The Male Biological Clock: The Startling News About Aging, Sexuality, and Fertility in Men. "And that's exactly what's happening with men."

So how did Indian farmer Nanu Ram Jogi sire a healthy child at the age of 90 last year? Such a feat would be impossible for a woman, even in an age when Carmela Bousada, 67, gave birth to twins in January 2007 after lying about her age to the doctors who gave her in vitro fertilization. Whereas fertility declines along with testosterone levels as men age, it doesn't drop to zero.

Still, Jogi is definitely the exception rather than the rule. One study found that the odds of fatherhood for those under the age of 30 was 32.1 percent compared with 20 percent over the age of 50, signifying a 38 percent drop in male fertility across that age gap.

One study examined 97 men between the ages of 22 and 80 and found that as they aged their semen volume decreased by 0.001 ounce (0.03 milliliter) per year from an average total of 0.09 ounce (2.7 milliliters) and their "total progressively motile sperm count"—a rough index for the fertility potential of one's sperm based on its movement—decreased about five percent with each year they aged.

Fisch and his colleagues have also found that the children of women over 35 whose babies' fathers were also of that age were more likely to have Down's syndrome than offspring whose fathers were younger.

In other studies, older men were more likely to father children with mental illness or other deficits. Roughly 11 children out of a thousand conceived by men over age 50 developed schizophrenia compared with under three children out of a thousand for fathers under 20 in one study from the Archives of General Psychiatry. And the children of men 40 years or older were nearly six times more likely to have autism spectrum disorders than kids begot by men under 30.

So do men's sperm get staler over time? To maintain sperm levels, cells known as germ cells must continue dividing. After all, men find ways to dispose of sperm—ahem—and once ejaculated they only survive for several days. By the age of 50, these germ cells will have divided 840 times. Each one of those divisions is an opportunity for something to go wrong. "There's more of a chance to have genetic abnormalities the more the cells divide," Fisch says. In sperm these mutations dot the genes with changes in the basic structure of the DNA—and can lead to problems in the resulting offspring.

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Men's fertility decreases after 35, study confirms

2008-07-06T11:04:00.000-07:00

Men's fertility decreases after 35, study confirms
Email Printer friendly version Normal font Large font Kate Benson Medical Reporter
July 7, 2008
IT HAS long been known that a woman's chance of reproducing declines once she hits 35, but now scientists have found that men who have some forms of fertility treatment in their 30s suffer the same fate.

A study by Laboratoire d'Eylau, a centre for assisted reproduction in Paris, followed more than 21,000 men who had intrauterine inseminations at fertility clinics. It found the process, where semen is washed to extract the sperm, resulted in a decrease in pregnancies and an increase in miscarriages.

All the men in the study, which will be presented today at the annual conference of the European Society for Human Reproduction and Embryology, were aged over 35.

"We already believed that couples where the man was older took longer to conceive," said the study's author, Stephanie Belloc.

"But how DNA damage in older men translates into clinical practice has not been shown up to now. Our research shows for the first time that there is a strong paternal age-related affect on [intrauterine insemination] outcomes and this information should be considered by both doctors and patients in assisted reproduction."

She said sperm with DNA damage, common in older men, could still enter the egg during intrauterine insemination, which could result in a failure to conceive or a miscarriage.

But during in vitro fertilisation, the zona pellucida, or outer membrane of the egg, was an efficient barrier in preventing the penetration of sperm with DNA damage.

"And in ICSI [intracytoplasmic sperm injection], the best sperm can be selected for use. These methods, although not in themselves a guarantee of success, may help couples where the man is older to achieve a pregnancy more quickly and reduce the risk of miscarriage," Dr Belloc said.

She followed 21,239 patients, and examined the sperm of each partner for count, motility and morphology. Pregnancy rates, miscarriage and delivery rates were also recorded.

"Some recent studies have established a relationship between the results of [intrauterine insemination] and DNA damage, which also correlated to a man's age, suggesting it might be an important factor, but until now there was no clinical proof. We have now found that the age of the father was important in pregnancy - men over 35 had a negative effect."

A Reason for the Rise in Schizophrenia, Autism, diabetes, Alzheimer

2008-06-15T08:35:00.001-07:00

You're never too old to be a dad
By Gazette Reporter

Pick up a copy of this week's Gazette to vote on your favourite picture of daddy
With new parents getting older and older, a pipe and slippers might be a fitting addition to the gift list for this Sunday's Father's Day.

Certainly, more than 75,000 British babies a year are born to fathers aged 40 and over - that's more than one in 10 of all births - and over 6,000 of these babies have dads aged over 50.

Such dads have very famous counterparts, of course - Rod Stewart was 60 when his youngest son, Alistair, was born, movie star Michael Douglas was 58 when his wife Catherine Zeta Jones gave birth to their daughter Carys, and Charlie Chaplin was 73 when his youngest son Christopher was born.

While not quite reaching daddy Chaplin's impressive years, the average age of men who father a child in the UK is certainly creeping up, and now stands at 32.

And while a new study this week found that men around this age enjoy being a father the most, it also concluded that becoming a father has the biggest effect on dads in their late 40s.

Of dads aged between 46-50 questioned in a study by Colief Infant Drops, 46% said fatherhood had changed their perspective on life.

advertisementAdrienne Burgess, research manager at think-tank The Fatherhood Institute, says this will be because older fathers have lived more of their lives and are ready for changes.

"In the 1970s when people got married and had babies younger, a lot of the dads weren't anywhere near ready, financially and in other ways,"

she says.

"Now that it's happening more when they're older, they're in a better place."

Burgess points out that while the age of fathers is increasing, plenty of them are second-time around dads because of family breakdown.

"Many of them are in a position to feel more confident financially, and they're also embracing the whole idea of being able to be closer to their children, which hadn't been acceptable before.

"They've been released and allowed to do it, in a way."

However, the Colief survey found older dads (aged 46-55) believed fatherhood had left them out of pocket, with 43% saying the expense was the worst thing about being a dad. In contrast, 37% of younger dads (aged 22-25) thought lack of sleep was the worst aspect.

Burgess admits: "The older dads who are becoming fathers for the first time in, say, their late 40s, are more likely to be financially worried.

"The younger men can see many years of good earning ahead of them, but the older dads aren't so sure and may be worried about how they're going to afford a teenager when they're 65, or older."

She points out that life expectancy is going up, and while there is an increased risk of older fathers dying when their children are still young, it's only a very small risk.

And she stresses: "There's clear evidence that for many men who become fathers later on, especially when they've got children from a previous relationship, it's a revelation and it's an absolutely wonderful experience having a child.

"It's because they're becoming fathers at a time when they're much more prepared and mentally involved. Often they are more financially secure, and they know who they are and where they're going.

"They've had a busy life and done a lot of things, and while they may not have as much energy as a man in his 20s, they're really happy to be at home and to be with this young child."

However, while older fathers may rejoice at becoming a dad, there are possible health implications for their babies.

A recent Danish study found that children whose fathers were over 45 when they were born were almost twice as likely to die before reaching adulthood as those fathered by men aged between 25 and 30.

The researchers believe the findings may be linked to the declining quality of sperm as men age.

Previous studies have also found that children of older fathers are more likely to have Down's syndrome, or suffer congenital defects such as heart and spine problems, as well as develop rare childhood cancers, and conditions including autism, schizophrenia and epilepsy.

It's an alarming catalogue of potential problems, but Burgess suggests that such negative outcomes are "very strongly" linked to lifestyle factors, and stresses: "An older dad who hasn't had a life of bad health behaviour is much more likely to have a child that's okay.

"The health messages need to get out there to dads - and men who want to be dads, whatever their age."

Dr Allan Pacey, senior lecturer in andrology - the study of male reproduction - at the University of Sheffield, says that while a bad lifestyle will certainly "make things worse", age alone can still have its own effects on reproduction.

He says: "It's not been studied in a controlled way, but it's certainly not the case that leading a healthy lifestyle will protect fathers from the effects of ageing."

He says that any man above the age of 40 would be considered an older father - 40 is the age at which men will no longer be accepted as sperm donors, for example.

"The list of problems which can result gets a lot longer after a man gets to the age of 40," he warns.

"We've known for a long time that the older a father is, the more likely his offspring are to have a number of health problems.

"They're not as common as those related to older mothers can be - you're still more likely to have Down's because your mum was older than because your dad was older - but the effect is still detectable statistically."

Pacey also warns that men above the age of 40 are thought to be about half as fertile as men aged under 25, explaining that although older men still have the same number of sperm, "clearly there's something happening at molecular level."

He adds: "The risks of having a baby with a problem when you're older are small, but they're detectable.

"What I would say is if you're delaying having children for no good reason, perhaps just because it never seems to be the right time, you should really think again."

11:38am today

Have Your Parents Young

2008-06-15T08:24:00.000-07:00

Have Your Parents Young
June 15th, 2008 · No Comments
Happy Father’s Day! When it comes to fatherly advice, I have none. Obviously. I am neither male, nor a parent. But I do have something I learned from my dad: he always says it’s better to have your children when you’re young. In other words, get on it. This article seems to agree, although the focus of the article confused me…it seems to be written for children, implying that, “For your sake, it’s better if your parents are young when they have you.”

Um…what is the point of warning someone about an event that is completely out of their control? Hello? What is a child supposed to be able to do about the age of its parents?

Ok, ok, I know that’s not really the point of the article. The real point is that a large study has shown that deaths of children fathered by men over the age of 45 occurred at almost twice the rate of those fathered by men aged between 25 and 30. Death by what, you ask? Congenital defects, autism, schizophrenia, and epilepsy.

Researchers believe the findings are linked to the declining quality of sperm as men age. Now there’s a sentence I never imagined myself writing.

Just in case you’re one of those children who couldn’t convince your parents to have you when they were younger, don’t get all worried. If you’re reading this, you’re fine; the majority of these premature deaths occurred when the offspring of the old men were less than a year old.

To my unborn child(ren),
Don’t get all anxious after reading this article and decide to show up before your alloted time. Daddy’s not that old yet!
Sincerely,
Mom

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"People shouldn't be too confident that just because the baby looks normal there is no damage there that won't appear later in life," he said.

2008-06-14T15:54:00.000-07:00

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Expert calls for vigilance on IVF technology
By Anna Salleh for ABC Science Online

Posted Sat Jun 14, 2008 10:46am AEST

A 3D ultrasound showing a foetus inside the womb. (Getty Images)
As humans become more dependent on reproductive technologies, an Australian reproductive biologist says we must remain vigilant to avoid the spread of genetic defects.

The warning comes in an editorial by Professor John Aitken, of the University of Newcastle, in the current issue of Expert Review of Obstetrics and Gynecology.

"People shouldn't be too confident that just because the baby looks normal there is no damage there that won't appear later in life," he said.

"People underestimate how much genetic damage they're passing onto the embryos."

Professor Aitkin says one in every 35 babies born in Australia are a result of IVF.

"In some countries it's more like one in 20 and there are models that predict it will be one in 10 before too long," he said.

Professor Aitken says because IVF allows infertile men to reproduce, the more we use it the more it will be needed in the future.

"So we better make sure it's safe because a large proportion of the population will be generated in this way," he said.

Ageing sperm

Professor Aitken says a number of factors are known, or suspected, to cause genetic damage to sperm that do not necessarily cause defects obvious at birth.

For example, Professor Aitken says the sperm of ageing males is thought to contribute to conditions such as autism, schizophrenia and epilepsy.

He says there is strong evidence linking sperm DNA damage to smoking, which can lead to the development of childhood cancers.

Epigenetic changes to sperm DNA that can affect fertility through several generations have also been reported.

For example, several recent papers have shown that infertile men have a dramatically altered DNA methylation profile.

Screening and monitoring

Professor Aitken says genetic problems mean it is important that reproductive clinics do a good job at screening sperm samples for genetic damage.

He is presenting the latest evidence on one screening technique he is developing with biotech company nuGEN at the Australian Research Council's Graeme Clark Research Outcomes Forum in Canberra next week.

But Professor Aitken says long-term monitoring of children born through IVF and other reproductive technologies is also essential, because such techniques can not pick up epigenetic damage.

"There are all kinds of things that can and could still go wrong," he said.

While he says IVF children are being monitored, he is concerned about complacency among clinics who celebrate their ability to produce normal looking babies from sperm with high levels of DNA damage.

IVF defended

Professor Michael Chapman of the Fertility Society of Australia, who also works for IVF Australia, says genetic damage is considered by IVF clinics.

"They're concerns that are shared within the IVF profession," he said.

Professor Chapman says one rare epigenetic disease has shown up in IVF children, at a rate of one in 1,500 versus one in 5,000 in the general population.

But he says Professor Aitken's "provocative" article overstates the problem since in the 20 years that IVF has been around, few long-term problems have arisen, despite thousands of children being monitored.

"I'm sure that if something starts to turn up, it will jump out at us," he said.

Sandra Hill, chief executive officer of ACCESS Australia, a group led by patients seeking IVF treatment, is confident that IVF is well-monitored, and she agrees this should continue.

But she says many of the concerns raised by Professor Aitken also apply to natural conception and she thinks the use of IVF should not be singled out.

She says it could be useful to educate men in general about the concerns raised by Professor Aitken - especially the need for men to have children before they get too old.

Professor Aitken says this may be so, but IVF still presents a unique challenge.

"With IVF you are facilitating the fertilisation of eggs with sperm that would otherwise be unsuccessful," he said.

Professor Aitken also says the rate of birth defects in IVF children are up to twice that of normally-conceived children, although he expects that to improve as techniques improve.

Low Birth Weight and Prematurity May Raise Baby’s Risk for Autism -- Especially Girls of Older Fathers

2008-06-03T07:07:00.000-07:00

Older age of fathers through mutations to sperm DNA causes genes controlling brain development to degrade. Low birth weight is found in daughters of older fathers and so is schizophrenia and autism.

Low Birth Weight and Prematurity May Raise Baby’s Risk for Autism
By Anna Boyd
12:20, June 3rd 2008 6 votes
Vote this story

Infants born before term and underweight, especially baby-girls are twice as likely to develop autism, a new study by the U.S. Centers for Disease Control and Prevention published in the June edition of the journal Pediatrics revealed.

Autism is a brain development disorder that appears before a child turns three years old; it has a serious impact on social interaction and communication. According to the CDC, one in 150 children in the U.S. now suffers from autism or related disorders that are known to belong to the autism spectrum.

Unfortunately, there is no cure for autism, but proper guidance and prognosis can hugely affect the behavior. The bad news is that some three to six children out f every 1,000 will develop autism, according to the National Institute for Neurological Disorders and Stroke. Males are four times more likely to develop the disorder than girls.

For the study, researchers at the CDC compared data from 565 children in Atlanta born between 1986 and 1993 who were suffering from autism with a group of babies who served as control.

The analysis showed that baby girls weighing less than 5.5 pounds had 3.5 times increased risk of autism. Also, prematurity seemed to influence, as baby girls born more than seven weeks early had a 5.4 times increased risk of autism. For boys, the birth weight and prematurity didn’t have a significant difference in their risk of being autistic.

The findings suggest that, even though autism is partly genetic, partly caused by environment factors, boys and girls appear to have different risk factors for the disorder, said study author Diana Schendel of the National Center on Birth Defects and Developmental Disabilities at the CDC in Atlanta.

“What is new in this study is the in-depth look at the gender effect,” Xinhua quotes Schendel.

It has long been known that babies born before term have long-term disabilities, such as chronic lung disease, blindness, deafness, and neurodevelopmental problems or worse they are three times more likely to die during the first year of life, especially in the first month of life. Unfortunately, about one in eight births (totaling more than 520,000 babies) in the U.S. is premature.

The findings of the CDC study reinforce once again the importance of monitoring children who are born underweight or early for behavioral problems so they can get the necessary treatment at the right time, Schendel said.

Also, women are urged to seek prenatal care as early as possible and discuss everything with their doctor related to their pregnancy and the symptoms they have. They are urged not to smoke, have a balanced diet and exercise daily. And most important of all they should not worry, as stress is the worst enemy for their unborn baby.

The CDC study is not the first to link prematurity with major birth defects. Just last week, researchers from the CDC, the March of Dimes and the Albert Einstein College of Medicine released a report according to which the dramatic rise in preterm births is also due to the increase in C-section deliveries in the U.S. The analysis revealed that 92 percent of the increase in singleton premature birth is due to C-sections, which is pretty amazing, Dr. Alan Fleischman, medical director and senior vice president of the March of Dimes, said.

'The risks of older fatherhood can be very profound and it is not something that people are always aware of.'

2008-06-01T17:50:00.000-07:00

Children born to men in their 20s are nearly twice as likely to survive to the age of 19, the new study says

'The risks of older fatherhood can be very profound and it is not something that people are always aware of.'

Children of older fathers are almost twice as likely to die before adulthood, research shows.
A study of more than 100,000 children revealed those fathered by over-45s were much less likely to live to be 19 than those born to men in their late 20s.
It is thought increased rates of birth defects as well as autism, schizophrenia and epilepsy stack the odds against children of older fathers.

Scientists reveal dangers of older fathers

2008-05-31T17:29:00.000-07:00

Scientists reveal dangers of older fathers
By Laura Donnelly, Health Correspondent
Last Updated: 10:18PM BST 31/05/2008
Children are almost twice as likely to die before adulthood if they have a father over 45, research has shown.
A mass study found that deaths of children fathered by over-45s occurred at almost twice the rate of those fathered by men aged between 25 and 30.

Scientists believe that children of older fathers are more likely to suffer particular congenital defects as well as autism, schizophrenia and epilepsy. The study was the first of its kind of such magnitude in the West, and researchers believe the findings are linked to the declining quality of sperm as men age.

A total of 100,000 children born between 1980 and 1996 were examined, of whom 830 have so far died before they reached 18, the majority when they were less than a year old.

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The deaths of many of the children of the older fathers were related to congenital defects such as problems of the heart and spine, which increase the risk of infant mortality. But there were also higher rates of accidental death, which the researchers believe might be explained by the increased likelihood of suffering from autism, epilepsy or schizophrenia.

Most research into older parents has, until now, focused on the risks passed on by older mothers. But the new study, published in the European Journal of Epidemiology, was adjusted to take account of maternal age and socio-economic differences.

The research also found higher death rates among children of the youngest fathers, especially those below the age of 19. However, the study said these differences were explained by the risks of teenage motherhood and poorer diet and lifestyle.

Previous research using the same data found that older men were four times as likely to father a child with Down's syndrome, while other studies have found that the genetic quality of sperm deteriorates as men age.

More than 75,000 babies in Britain are born to fathers aged 40 and over each year, or more than one in 10 of all births. This includes more than 6,000 born to fathers aged 50 or over. The average age of fathering a child in this country is 32.

Dr Allan Pacey, senior lecturer in andrology – the medical specialty dealing with male reproduction – at the University of Sheffield, said: "A lot of people know that there are risks for the child that come from having an older mother, but children of older fathers also carry an increased risk. These sorts of results provide another good reason to have children early, when possible."

Dr Pacey, who is secretary of the British Fertility Society, said scientists were unsure exactly what impact the ageing process had on the quality of sperm, making it impossible to detect defects before conception.

Dr Jin Liang Zhu, from the Danish Epidemiology Science Centre, which carried out the research, said: "The risks of older fatherhood can be very profound, and it is not something that people are always aware of."
The mother's age still has the bigger impact on child health, however. About one in 900 babies born to women under 30 have Down's syndrome – a figure which reaches one in 100 by the age of 40. The number of over-40s giving birth in Britain each year has doubled in the past decade to 16,000. The risk of miscarriage rises sharply with age.

This adds to the cumulating evidence on adverse effects of advanced paternal age in procreation

2008-04-26T17:00:00.000-07:00

: Eur J Epidemiol. 2008 Apr 25 [Epub ahead of print]Paternal age and mortality in children.Zhu JL, Vestergaard M, Madsen KM, Olsen J.
The Danish Epidemiology Science Centre, University of Aarhus, Vennelyst Boulevard 6, 8000, Aarhus C, Denmark, zjl@soci.au.dk.

Background Since paternal age correlates with some diseases that have a high case-fatality, a paternal age effect on offspring's survival is expected but unsettled. We examined the association between paternal age and mortality in children in a large population-based cohort taking maternal age and socioeconomic factors into account. Methods From the Danish Fertility Database (1980-1996), we identified 102,879 couples and their firstborn singleton children. Information on childhood death (N = 831) was obtained by linking the cohort to the nationwide register on cause of death (1980-1998). Results We observed a U-shaped association between paternal age and the overall mortality rate in children up to 18 years of age. Adjustment for maternal age and other confounders reduced the mortality rate ratio (MRR) for children of younger fathers but not for children of older fathers. Compared with children of fathers aged between 25 and 29 years, the adjusted MRR was 1.77 (95% confidence interval 1.28-2.45) for children of fathers aged between 45 and 49 years and 1.59 (1.03-2.46) for children of fathers aged 50 years or more. The cause-specific MRRs were highest for congenital malformations [2.35 (1.42-3.88)] and injury or poisoning [3.43 (1.49-7.92)] for children of fathers aged 45 years or more. Conclusion Our data revealed a higher mortality in offspring of fathers aged 45 years or more that lasted into adulthood. This adds to the cumulating evidence on adverse effects of advanced paternal age in procreation.

PMID: 18437509 [PubMed - as supplied by publisher]

Children born to older fathers may have a higher risk of developing schizophrenia

2008-04-26T16:39:00.000-07:00

Friday, April 25, 2008
Oct. 21, 2004 --

Oct. 21, 2004 -- Children born to older fathers may have a higher risk of developing schizophrenia than those with younger dads, according to a new study.

Schizophrenia is a severe, disabling mental illness. Contrary to popular belief, it has nothing to do with multiple or split personalities. Instead, people with schizophrenia hear voices that others don't; they suffer from paranoia and live fearful and withdrawn lives. The first signs of the mental illness emerge around adolescence and early adulthood. The cause of schizophrenia is not known, and there is no cure.

The study is based on more than 750,000 Swedes born between 1973 and 1980, all of whom were still living in Sweden at age 16.

It was conducted by epidemiology professor Finn Rasmussen of Karolinska Institute in Stockholm, Sweden, and colleagues and appears in the Oct. 23 online edition of the journal BMJ Online First.

The researchers examined a variety of records, including Sweden's birth registry and data on Swedish hospital admissions for schizophrenia between 1989 and 2001. The study did not include undiagnosed or non-institutionalized cases.

The study conducted by Rasmussen shows that schizophrenia occurred more frequently among those born to dads older than 30.

The link was stronger in fathers with no family history of schizophrenia, and it remained important even after taking into account other factors that might increase the risk of schizophrenia.

The researchers found that for every 10-year increase in paternal age, there was an almost 50% increased risk of schizophrenia in the children.

Children born to older fathers have higher rates of several disorders including certain cancers, write the authors. They say that while several factors are operating to increase the risk of disorders in child born to older fathers, the higher rates of mutations in sperm cells seen in this age group is though to play a role.

Paternal age wasn't seen as a strong risk factor for other kinds of psychoses.

6:43 PM | Permalink

Dad's Hidden Influence

2008-04-20T17:48:00.000-07:00

ALL CONTENT FREELY
ACCESSIBLE UNTIL 4/15/08

Men younger than 20 and older than 30 make more abnormal sperm than men in their 20s. These damaged sperm could create an unhealthy embryo or pass on damage that could lead to birth defects or illness in offspring.

Week of March 29, 2008; Vol. 173, No. 13 , p. 200

Dad's Hidden Influence
A father's legacy to a child's health may start before conception and last generations
Tina Hesman Saey
Pregnant women know the drill. Don't drink. Don't smoke. Don't eat too much fish. Take vitamins. Mothers have long shouldered the responsibility, and the blame, for their children's health. Fathers don't usually face the same scrutiny.

How a man lives, where he works, or how old he is when his children are conceived doesn't affect their long-term health, scientists used to think. But growing evidence suggests that a father's age and his exposure to chemicals can leave a medical legacy that lasts generations.

Animal studies demonstrate that drugs, alcohol, radiation, pesticides, solvents, and other chemicals can lead to effects that are handed from father to son. Human studies are less clear, but some show that fathers play a role in fetal development and the health of their children.

Teenage dads face increased risk that their babies will be born prematurely, have low birth weight, or die at birth or shortly afterward, a new study in Human Reproduction shows.

Babies of firefighters, painters, woodworkers, janitors, and men exposed to solvents and other chemicals in the workplace are more likely to be miscarried, stillborn, or to develop cancer later in life, according to a review in the February Basic & Clinical Pharmacology & Toxicology.

Fathers who smoke or are exposed at work to chemicals called polycyclic aromatic hydrocarbons put their children at risk of developing brain tumors.

And, older fathers are more likely to have children with autism, schizophrenia, and Down syndrome and to have daughters who go on to develop breast cancer.

Though some of these observations are decades old, attitudes lag even further behind, says Cynthia Daniels, a political scientist at Rutgers University–New Brunswick in New Jersey. Dads aren't held accountable if something goes wrong during fetal development.

Matter of math
Since men make new sperm every 74 days, people used to reason, the genetic slate is wiped clean every couple of months. And even if a man makes defective sperm, the "all-or-nothing" view of reproduction holds that damaged sperm don't fertilize eggs. No harm. No foul.

So no one bothers to remind men to protect themselves against environmental toxins. There are no images of "crack dads" and "crack babies" in the media like those of women who harm developing fetuses with drug and alcohol use, Daniels said in February at a meeting of the American Association for the Advancement of Science held in Boston.

When someone does study fathers-to-be, the focus is usually on fertility, not on the consequences for children's health, she says.

Yet even fertility messages meet resistance from many men.

Harry Fisch, director of the Male Reproductive Center and a urologist at Columbia University Medical Center, found that out when he suggested that men, like women, have ticking biological clocks.

Men can produce sperm throughout life, but that doesn't mean their cells are forever young.

"Every cell in the body ages," says Fisch. "Every cell. The older you get, the more chance of an abnormality. The same thing goes for sperm."

Men younger than 20 and older than 30 make more abnormal sperm than men in their 20s. These damaged sperm could create an unhealthy embryo or pass on damage that could lead to birth defects or illness in offspring.

It is not a popular message.

"Men do not want to hear this," Fisch says. "When my book came out, I got e-mails. I got faxes saying, 'How dare you say this? How can you say this? We know that there are men in their 70s having healthy children.'"

Despite these anecdotal accounts of elderly dads, studies demonstrate that older men are at increased risk of passing on genetic abnormalities. It's a matter of math.

Women are born with all the eggs they will produce in their lifetime. The cells that give rise to eggs divide 24 times, all before birth. But the cells that produce sperm continue to divide throughout a man's lifetime. Each year after puberty, a man's sperm-producing cells replicate about 23 times. Every time the cells divide is another chance for error.

As a result, the sperm produced by a 40-year-old man have gone through about 610 rounds of replication. That's 610 chances of introducing a mutation in the DNA, or improperly divvying up genetic material.

Parents over age 40 are six times more likely to have children with Down syndrome than 25-year-old parents, Fisch and colleagues showed in a 2003 study in the Journal of Urology. An extra copy of chromosome 21 causes Down syndrome. This extra chromosome is just as likely to come from dad as mom in the older couples.

Older dads also have a higher risk of fathering children with rare mutations that cause dwarfism or a premature aging disease called Hutchinson-Gilford progeria syndrome.

But sometimes aging fathers pass along traits that can't be traced to only a single mutation. Fathers 40 and older have an increased chance that their children will develop complex disorders such as autism or schizophrenia. There is growing evidence that those disorders are caused by defects in many genes and the way genes are turned off and on.

Scientists don't yet understand the changes that age induces in sperm-making germ cells, and environmental exposure presents an even bigger mystery. People come in contact with a plethora of chemicals every day. But it is no easy task to sort out exactly which ones, or which combinations, cause heritable problems. The effects chemicals and radiation may have on offspring don't always follow predictable patterns either.

And when researchers do find a clear link between a father's lifestyle and his children's health, it's not always clear what the data mean.

"What we can say is that we identified a group of fathers with adverse outcomes for their fetuses, but we don't have an idea of the mechanism," says Shi Wu Wen of the University of Ottawa in Canada and one of the lead authors of the study showing that babies of teenage fathers have a greater risk of birth problems.

Wen and his colleagues examined birth records for more than 2.6 million babies born between 1995 and 2000 to married, first-time, 20-something mothers in the United States. Looking at the husbands' ages, the team found that babies of teenage fathers, but not middle-age men, had an elevated risk of still birth, low birth weight, and other birth problems. The study was published online Feb. 6 in Human Reproduction.

'Preposterous' inheritance
Some animal studies showing paternal effects emerged years ago but were roundly dismissed, says Gladys Friedler, professor emeritus at Boston University.

OLDER AGE, HIGHER RISK. As men age, they stand a greater chance of fathering children who will develop schizophrenia by age 34. Paternal age is only one of many factors linked to schizophrenia.
E. Roell, (Source: D. Malaspina, et al., Arch. of Gen. Psychiatry, 2001)

Four decades ago, Friedler was studying tolerance to narcotics, one of the first steps of addiction. To find out if a mother rat could pass tolerance on to her offspring along with antibodies and other immune factors, as some scientists theorized, Friedler exposed female rats to morphine before pregnancy. Babies of exposed mothers were born much smaller than average. And those babies also went on to give birth to tiny babies, even though the offspring had never encountered the drug.

Friedler also gave male rats morphine before they bred. "To my total disbelief and bewilderment, paternal exposure also affected progeny," Friedler said at the AAAS meeting.

Her adviser dismissed the result. Morphine doesn't cause mutations, so the idea that males could hand down a trait without passing along a mutation seemed preposterous. The whole thing smacked of Lamarckism, the long-rejected idea that environmental influences can change an animal or plant's structure and offspring can inherit that change.

But in recent decades, scientists have discovered that chemical modifications to DNA and proteins can change the way genes are packaged and regulated without changing the genes themselves. Such modifications are known as epigenetic changes.

"What was Lamarckian is now epigenetic," Friedler says.

Epigenetic modifications act as a molecular scrapbook, preserving memories of events in parents' lives and handing them down to the next generation and beyond.

"There's a chromosomal memory," says Anne Ferguson-Smith, a developmental geneticist at Cambridge University in England. "The chromosomes remember whether they came from the mother or the father."

That memory is established in the form of a chemical mark called methylation. Methylation usually turns a gene off. At least 100 genes in humans are turned off only on the chromosome contributed by the mother or only on the chromosome that came from the father. Such genes are called imprinted genes because of the indelible impression parents leave on their offspring's DNA.

Several imprinted genes help build the placenta or encode growth factors that need to be tightly controlled so an embryo will develop correctly. "There's a contribution from both parents that is essential," Ferguson-Smith says. "One can't do without the other. They must work together to have a healthy offspring."

Imprints and other methylation marks are not encoded in the DNA. Instead the epigenetic modifications decorate chromosomes like ornaments on a Christmas tree. But these ornaments are heirlooms of a different type. It's as if a seedling grows straight from the ground already gussied up with tinsel and lights in the same places its parents were decorated. If a chemical or aging alters the epigenetic pattern on a man's chromosomes, his heirs could bequeath mismarked DNA to their children, too. Some mistakes may be as benign as exchanging a red bulb for a blue one. Other alterations, akin to placing the star on the lowest branch instead of the treetop, are likely to have more profound consequences.

Male mice exposed to cocaine, for example, pass memory problems on to their pups, a 2006 study in Neurotoxicology and Teratology shows. The male mice inhaled cocaine in long daily sessions akin to crack binges. When they mated with females never given coke, they had pups that had trouble learning and remembering where to find food in simple mazes. The problem was especially severe for female offspring. The researchers couldn't find any obvious DNA damage in coke-smoking males' sperm, but did find altered levels of two enzymes involved in the methylation of DNA in sperm-producing tissue in the father mice. The result suggests that epigenetic changes may be responsible for the offspring's behavior problems.

Fungicide legacy
Matthew Anway doesn't know whether the rats in his lab at the University of Idaho in Moscow have methylation problems. Some studies suggest they do, but Anway doesn't yet have definitive proof.

He can prove that male rats exposed to a fungicide in the womb can pass tumors and diseases of the prostate and kidney down for at least three generations. The rats could provide the first model for how prostate disease is inherited, he says.

Male babies born to mothers that had been injected with fungicide had prostate problems that mimic those seen during human aging. The second-generation rats also had more tumors, kidney defects, and higher rates of abscesses, cysts, and other infections than unexposed control rats. Germ cells in the testes of exposed rats also died more quickly than those in the control rats.

Subsequent generations of male rats also had the prostate and testes defects, and both male and female offspring developed kidney problems and tumors.

But only male rats could pass along the defects. The exposed rats bequeathed their fungicide legacy to their sons, grandsons, and great-grandsons even though none of the later generations were exposed to the chemical.

Exposed animals decrease production of enzymes that methylate DNA, Anway says. But he hasn't yet found consistent changes in the methylation patterns in exposed rats.

It's not clear whether Anway's results have any implication for human health. The rats were exposed to extremely high doses of fungicide through the completely unnatural route of injection.

What's important is that the male shares experiences with descendants for years to come. Further research could give new insights, Anway says, into how alterations in early development could lead to adult disease in humans.

--------------------------------------------------------------------------------

If you have a comment on this article that you would like considered for publication in Science News, send it to editors@sciencenews.org. Please include your name and location.

References:

Anway, M.D., A.S. Cupp, M. Uzumcu, and M.K. Skinner. 2005. Epigenetic transgenerational actions of endocrine disruptors and male fertility. Science 308(June 3):1466-1469. Abstract available at http://dx.doi.org/10.1126/science.1108190.

Anway, M.D., S.S. Rekow, and M.K. Skinner. 2008. Transgenerational epigenetic programming of the embryonic testis transcriptome. Genomics 91(January):30-40. Abstract available at http://dx.doi.org/10.1016/j.ygeno.2007.10.002.

Anway, M.D., and M.K. Skinner. 2008. Transgenerational effects of the endocrine disruptor vinclozolin on the prostate transcriptome and adult onset disease. The Prostate 68(April 1):517-529. Abstract available at http://dx.doi.org/10.1002/pros.20724.

Chen, X.K., S.W. Wen, et al. In press. Paternal age and adverse birth outcomes: Teenager or 40+, who is at risk? Human Reproduction. Available at http://dx.doi.org/10.1093/humrep/dem403.

Choi, J.-Y., et al. 2005. Association of paternal age at birth and the risk of breast cancer in offspring: A case control study. BMC Cancer 5(Oct. 31):143. Available at http://dx.doi.org/10.1186/1471-2407-5-143.

Cordier, S. 2008. Evidence for a role of paternal exposures in developmental toxicity. Basic & Clinical Pharmacology & Toxicology 102(February):176-181. Abstract available at http://www.blackwell-synergy.com/doi/
abs/10.1111/j.1742-7843.2007.00162.x.

Cordier, S., et al. 2004. Parental exposure to polycyclic aromatic hydrocarbons and the risk of childhood brain tumors. American Journal of Epidemiology 159(June 15):1109-1116. Available at http://aje.oxfordjournals.org/cgi/content/full/159/12/1109.

Croen, L.A., et al. 2007. Maternal and paternal age and risk of autism spectrum disorders. Archives of Pediatric and Adolescent Medicine 161(April):334-340. Available at http://archpedi.ama-assn.org/cgi/content/full/161/4/334.

El-Saadi, O., et al. 2004. Paternal and maternal age as risk factors for psychosis: Findings from Denmark, Sweden and Australia. Schizophrenia Research 67(April 1):227-236. Abstract available at http://dx.doi.org/10.1016/S0920-9964(03)00100-2.

Fisch, H., et al. 2003. The influence of paternal age on Down syndrome. Journal of Urology 169(June):2275–2278. Abstract available at http://dx.doi.org/10.1097/01.ju.0000067958.36077.d8.

He, F., I.A. Lidow, and M.S. Lidow. 2006. Consequences of paternal cocaine exposure in mice. Neurotoxicology and Teratology 28(March-April):198–209. Abstract available at http://dx.doi.org/10.1016/j.ntt.2005.12.003.

Lewis, B.H., M. Legato, and H. Fisch. 2006. Medical implications of the male biological clock. Journal of the American Medical Association 296(Nov. 15):2369-2371. Abstract available at http://jama.ama-assn.org/cgi/content/short/296/19/2369.

Thacker, P.D. 2004. Biological clock ticks for men, too. Journal of the American Medical Association 291(April 14):1683-1685. Extract available at http://jama.ama-assn.org/cgi/content/extract/291/14/1683.

Further Readings:

Skinner, M.K. 2008. What is an epigenetic transgenerational phenotype? F3 or F2. Reproductive Toxicology 25(January):2–6. Abstract available at http://dx.doi.org/10.1016/j.reprotox.2007.09.001.

Frequently asked questions from the Epigenome Network of Excellence can be found at http://www.epigenome-noe.net/consulting/webconsulting.php.

Sources:

Matthew Anway
University of Idaho
Department of Biological Sciences
Gibb Hall 239
P.O. Box 443051
Moscow, ID 83844-3051

Sylvaine Cordier
INSERM U625,
GERHM, IFR140,
University of Rennes I,
Campus de Beaulieu
Rennes cedex F-35042
France

Cynthia Daniels
Department of Political Science
Rutgers, the State University of New Jersey
Hickman Hall
89 George Street
Douglass College
New Brunswick, NJ 08901

Anne C. Ferguson-Smith
Department of Physiology, Development and Neuroscience
University of Cambridge
Physiology Building, G-floor Downing Street
Cambridge CB2 3EG
United Kingdom

Harry Fisch
Columbia University
College of Physicians and Surgeons
Department of Urology
944 Park Avenue
New York, NY 10028

Gladys Friedler
4 Newport Road #4
Cambridge, MA 02140

Shi Wu Wen
OMNI Research Group
Department of Obstetrics and Gynecology
University of Ottowa
501 Smyth Road, Box 241
Ottowa, Ontario K1H 8L6
Canada

From Science News, Vol. 173, No. 13, March 29, 2008, p. 200.

Rates of rare mutations soar 3 to 4 times higher in schizophrenia-autism is the new name for early childhood schizophrenia

2008-03-27T14:41:00.000-07:00

Multiple genetic glitches disrupt pathways critical for brain development
People with schizophrenia have high rates of rare genetic deletions and duplications that likely disrupt the developing brain, according to studies funded in part by the National Institutes of Health.

These tiny anomalies were found in 15 percent of adult onset schizophrenia patients and 20 percent of child and adolescent onset patients, compared with only 5 percent of healthy participants. Collectively, the mutations carried by patients were significantly more likely than those in healthy participants to disrupt genes involved in brain development -- potentially implicating hundreds of genes in the illness.

"If anything, our findings may indicate that it's even more complex than what we suspected because there may be literally thousands and thousands of different mutations in many different number of genes," McClellan said.

-----------------------------------------------------------------------

Discovery of role of rare gene mutations in schizophrenia

Published: Monday, 31-Mar-2008

Medical Research News
Using an important new method that can be applied in the study of other psychiatric illnesses, scientists at Cold Spring Harbor Laboratory (CSHL) in collaboration with colleagues at the University of Washington (UW) and the National Institute of Mental Health (NIMH), have identified multiple, individually rare gene mutations in people with schizophrenia that may help explain how that devastating illness is caused.
The team screened for novel deletions and duplications in the genome -- what are called gene copy-number variations, or CNVs. They found that deletions, disruptions and duplications of normal genes, most of them rare, were three to four times more frequent in people with schizophrenia than in controls.
CSHL's contribution to the research effort was led by Assistant Professor Jonathan Sebat, Ph.D., and Shane E. McCarthy, Ph.D. Drs. Tom Walsh, Jon McClellan and Mary-Claire King led the UW team, while Drs. Anjene Addington and Judith Rapoport led the researchers at NIMH.
A New Method of Finding Candidate Genes
The researchers used a novel method to study their two-cohort sample, which included 418 individuals, 150 of whom had schizophrenia or schizoaffective disorder. Instead of trying to show a statistical correspondence between a large group of people with schizophrenia and irregularities in common versions of genes, the team began by looking for "glitches" or changes in DNA that are likely to disrupt gene function. Then they compared which genes -- with what kinds of functions -- were impaired, both in the healthy subjects and those with schizophrenia.
The results were striking. Rare mutations showed up in only 5 percent of the healthy controls versus 15 percent of those with schizophrenia. The rate of rare mutation was higher still -- 20 percent -- among an "early-onset" subset of patients, who had developed schizophrenia before age 19.
"This part of our findings indicates something we didn't know before: that rare structural mutations in genes, while present in both healthy people and people with schizophrenia, are much more likely to occur among people with the illness. This suggests a previously unknown role for rare mutations in the causation of schizophrenia," said Dr. Sebat.
Rare Mutations and What They Do
The second part of the research aimed to answer a key question about the genes discovered to be irregular: What were their functions? Were their functions similar or different in healthy people versus those with schizophrenia?
Here, too, the results were striking. "In people with schizophrenia, almost half the time the disrupted genes were involved in pathways important in brain development," Dr. Sebat said. "By contrast, when we looked at the set of genes that were disrupted in healthy people, we found that they were not overrepresented in any particular pathway."
In a paper that will first appear March 27 in the online edition of Science, the team notes that of 24 rare mutations seen in the schizophrenia group, 11, or 45 percent, affect cellular signaling pathways critical to neuronal cell growth, migration, proliferation, differentiation, apoptosis and synapse formation. Some of the affected pathways have turned up in past studies of schizophrenia, notably those involving signaling in neuregulin, a growth factor, and glutamate, a neurotransmitter.
Implications and Future Studies
While the study, as the scientists directly concede in their paper, "does not prove the involvement with the illness of any specific variant, or even the involvement of any specific gene," it does, however, indicate a role for rare mutations that disrupt genes in pathways of neuronal development and regulation.
The results are powerful because they link specific structural variation in genes with specific functions known to be important in the early years of life, during which schizophrenia develops in many patients.
This important result leads the scientists to advocate broad use of the method they employed in the study. Gene discovery in complex psychiatric illnesses "should focus on methods that allow detection of structural mutations" across the genome in affected individuals, the team urges.
"Although each mutation discovered may be individually rare," they maintain, "collectively the total number of disease-causing variants in a gene [found to be] relevant to the disorder may explain a substantial number of cases."
Dr. Sebat is currently applying the mutation-screening method in studies involving a greater number of patients and in other illnesses. Among other things, he seeks to determine whether spontaneous mutations play as significant a role in schizophrenia as they do in autism, as revealed by a study he co-authored a year ago with CSHL Professor Michael Wigler. (See: http://www.cshl.edu/public/releases/07_autism.html.)
http://www.cshl.org/

Guys Should Be Aware of Their Part In Having Healthy Offsping

2008-02-11T19:23:00.000-08:00

http://coolmrsoftie.wordpress.com/2007/12/01/want-healthy-offspring-guys-should-chip-in-too/

Daily Herald chicago---- Should Older Men Become Dads? http://www.dailyherald.com/story/?id=106959

2008-02-07T17:58:00.000-08:00

Should older men become dads?
How old is too old to father a child?
Dad's age links strongly to problems in offspring, including autism, schizophrenia and cancer
By Mark Teich Published in Psychology Today on 1/7/08: "....a virtual tidal wave of recent research has made it irrefutable: Not only does male fertility decrease, especially after age 35, but aging sperm can be a significant and sometimes the only cause of severe health and developmental problems in offspring, including autism, schizophrenia and cancer.

The older the father, the higher the risk.

"Men thought they were getting off scot-free, and they weren't. The birth defects caused by male aging are significant conditions that can cause a burden to families and society," says Ethylin Wang Jabs, professor of pediatric genetics at Johns Hopkins University in Baltimore and leader of a recent study showing the link between aging paternity and certain facial deformities in offspring.

"We now know that men and women alike could be increasing the risk of infertility or birth defects by waiting too long to have children," Jabs said.

In the past several years, studies worldwide have found that with each passing decade of their lives and with each insult they inflict on their bodies, men's fertility decreases, while genetic risk to offspring slowly mounts. The range of findings is staggering: Several studies have shown that the older the man, the more fragmented the DNA in his ejaculated sperm, resulting in greater risk for infertility, miscarriage or birth defects.

Investigations in Israel, Europe and the United States have shown that nonverbal intelligence might decline exclusively due to greater paternal age; that up to a third of all cases of schizophrenia are linked to increasing paternal age; and that men 40 and older are nearly six times more likely to have offspring with autism than men under age 30. Other research shows that the risk of breast and prostate cancer in offspring increases with paternal age.

Fisch has found that when both parents are over 35, paternal aging might be responsible for as many as half of all cases of Down syndrome, formerly thought to be inherited from the mother. And recent studies show that half a dozen or more rare but serious birth defects appear to be inherited exclusively from the father, including Apert syndrome, Crouzon syndrome and Pfeiffer syndrome (all characterized by facial abnormalities and the premature fusion of skull bones) as well as achondroplasia (the most common form of dwarfism).

Male mutations

Scientists have long known that advanced paternal age (like increased maternal age) played some role in fertility problems and birth defects.

Yet because the reports mainly involved children who died before birth or who had extremely rare disorders, no one really rang the alarm. Now, with new studies linking the father's age to relatively frequent, serious conditions like autism, schizophrenia and Down syndrome, the landscape is shifting.

Women have borne the brunt of the blame for birth defects. When the conditions were passed on through chromosomal lineage, women were somehow widely believed culpable, even though such defects can be traced to either partner. "But what we're finding now is that in humans as well as in other mammals, when there's a new genetic change -- called 'de novo' or 'sporadic point mutation' -- it almost always happens in the male parent," says Dolores Malaspina, chair of psychiatry at New York University Medical Center. And these de novo mutations increase in frequency with the age of the male parent.

These mutations could reflect the differences in male and female reproduction, notes Jabs. By the time females reach their teen years, their eggs have already been formed -- just one new egg matures each month. Men, on the other hand, produce millions of sperm cells every time they ejaculate. After each ejaculation, they must literally replicate those cells, and each replication multiplies the chance for a DNA "copy error" -- a genetic chink in the sperm DNA. The more ejaculations a man produces, the greater the chance for chinks to arise, leading to increased point mutation and thus increased infertility and birth defects.

While a woman's reproductive capacity halts more or less abruptly after all her eggs have been used up somewhere in her 40s or 50s, men experience a longer, more gradual winnowing and disintegration. "We believe that something in men's DNA replication machinery keeps becoming less efficient and less accurate with age, and the problems accumulate," says Jabs.

A chilling finding

The biggest news -- the father's role in brain disorders -- has come to light largely because of research from Israel, where birth records routinely include the age of the male parent. The first unsettling finding linked paternal age and schizophrenia.

"In our first study, looking at every pregnancy in Jerusalem from 1964 to 1976, we found that increased age in the father predicted increased cases of schizophrenia in the children," explains Malaspina, who was on the team doing the work. "In our second study, we found that when the cases arose from new mutations -- not familial inheritance -- it almost always could be traced to the genetics of the father. Somewhere between a quarter and a third of the cases could be explained only by the age of the father -- a threefold risk linked to fathers older than 50 compared with those in their 20s." Studies in Sweden and California produced almost identical results.

The autism findings are even more disturbing: Men 40 and older in the Israeli study were almost six times as likely to have offspring with autism as men under 30. Some researchers believe that older fathers might hold a clue to the vast upsurge in autism cases in the past decade.

"With older and older couples having children -- in the past two years, for the first time, more babies are being born to women over age 30 than under age 30, and on average, male partners tend to be older than female partners -- it's very feasible that paternal age is a major predictor of autism," asserts Fisch.

Invisible damage

Perhaps the creepiest aspect of the new findings is that a little genetic damage in men's sperm might actually be worse than a lot of damage.

The greater threat to offspring is the less flagrant DNA damage that gets passed on, declares Charles Muller, lab director of the Male Fertility Clinic at the University of Washington in Seattle.

Resulting defects may not show up until offspring are adults and it's too late to trace the cause. Damage can then be passed from one generation to the next.

"In short, the biggest genetic threat to society may not be infertility but fertile old men," says University of Wisconsin in Madison geneticist James F. Crow.

The new findings have profound implications for any potential parent. Older women, focused though they are on their own reproductive timetable, might increasingly view their partner's age with a wary eye. When both parents are aging, the risks to offspring multiply.

For men, the findings might be, above all, a clarion call to take better care of themselves. "This should make men reconsider their role and responsibility in childbearing," says Barbara Willet, of the Best Start childhood resource center in Ontario, Canada. "It's as if we're suddenly aware that men who want to be fathers need to be healthy, too."

Men typically don't think about their health, and we need to get them to. If you're drinking or smoking, if you're working in toxic environments with pesticides, X-rays, solvents or ionizing radiation, these things affect you as well as women, and will ultimately affect the children you conceive.

Alarming though the findings might be to some, researchers have a clear directive: "Don't panic."

"The research is still fresh," says Crow, "and more needs to be done before we start making sweeping recommendations like urging people to have children younger, or telling men to freeze their sperm after their 20s. I don't advocate asking the general public to change at this point, because while some of these mutations cause very severe effects, in the totality of things that can go wrong, this is not that large a part of the picture."

Freezing sperm might sometimes be the way to go. While frozen sperm may not be quite as potent as when it is fresh, it is not a proven problem. Since the turn of the last century, sperm of domestic animals has been frozen safely for as long as 75 years, Muller says. And frozen sperm is used routinely in humans for artificial insemination. Pregnancy rates and childbirth are right up there with regularly conceived birth, and there is no substantial DNA breakdown. If you're going to get a vasectomy, join the Army or go through cancer therapy, "I'd advise you to freeze your sperm beforehand," Muller says.

Most men can steer a gentler course just by watching their health. "Chances of problems increase as the years pass, but some men have significant DNA damage at 35, while others go on forever -- their sperm is fine in their 70s," Muller said.

Men can't rewind their biological clocks, but they can slow them down, Fisch agrees. Just remember, once you're in your 40s, you're past your maintenance-free years -- you have to take care of yourself. "If you want children from then on," he advises, "get into the best shape of your life."

The male biological clock

20s: Men have the maximum amount of mature sperm cells and the least DNA damage. The risk of producing birth defects in offspring is as low as it ever will be.

30s: The mid-30s bring a significant increase in sperm DNA damage and thus an increased risk of producing birth defects. One in 99 fathers ages 30-35 sires a child with schizophrenia vs. one in 141 for fathers under age 25.

40s: The risk of schizophrenia doubles in children of fathers in their late 40s compared with children of fathers under age 25. Men 40 and older are nearly six times more likely to have offspring with autism than men younger than 30.

50s: The DNA cells that create sperm have gone through more than 800 rounds of division and replication, vastly increasing the chances of mutation and birth defects. The risk of schizophrenia almost triples for children of fathers 50 and older; one in 47 fathers sires a child with the condition.

60s: 85 percent of sperm is clinically abnormal.

Please Pass This Information On If You Care About Healthy Children

2007-12-09T14:10:00.000-08:00

Male Health: The Long ShotFrom puberty on, reproductive health and the viability of sperm continue to evolve.
By:Mark Teich

At the age of 60, 85 percent of sperm is clinically abnormal, something researchers attribute to normal aging.

20s
These are prime years for male reproduction. Men have the maximum amount of mature sperm cells and the least DNA damage. The risk of producing birth defects or causing other problems in offspring is as low as it ever will be.
30s
Testosterone levels start to decline at age 30, bringing a decrease in potency. By 32-34, fertility begins to fall. Men who are 35 or older are twice as likely to be infertile as men under age 25. The mid-thirties also bring a significant increase in sperm DNA damage and thus an increased risk of producing birth defects. One in 99 fathers ages 30-35 sire children with schizophrenia versus one in 141 for fathers under age 25.
40s
Type 2 diabetes and metabolic syndrome, involving pre-diabetes symptoms and cardiovascular risk factors, start to occur more often in men. Both disorders are strongly associated with below-normal levels of testosterone, lowering potency. Erectile dysfunction (ED) starts to be a problem in a number of men. The risk of schizophrenia doubles in children of fathers in their late forties compared with children of fathers under age 25. Men 40 and older are nearly six times more likely to have offspring with autism than men younger than 30.
50s
Erectile dysfunction increases for many men. By age 50, the DNA cells that create sperm have gone through more than 800 rounds of division and replication, vastly decreasing the quality of sperm and increasing the chances of mutation and birth defects. The risk of schizophrenia almost triples for children of fathers 50 and older; one in 47 fathers sires a child with the condition.

DNA in Sperm Mutated in Men Who Smoke- Children Could Inherit Damaged Genes

2007-06-07T17:59:00.000-07:00

DNA In Sperm Altered By Cigarette Smoke, Genetic Damage Could Pass To Offspring

The science has long been clear that smoking causes cancer, but new research shows that children could inherit genetic damage from a father who smokes.

Canadian researchers have demonstrated in mice that smoking can cause changes in the DNA sequence of sperm cells, alterations that could potentially be inherited by offspring. The results of their study are published in the June 1 issue of Cancer Research, a journal of the American Association for Cancer Research.

"Here we are looking at male germline mutations, which are mutations in the DNA of sperm. If inherited, these mutations persist as irreversible changes in the genetic composition of off-spring." said Carole Yauk, Ph.D., lead author of the study and research scientist in the Mutagenesis Section of Health Canada's Environmental and Occupational Toxicology Division. "We have known that mothers who smoke can harm their fetuses, and here we show evidence that fathers can potentially damage offspring long before they may even meet their future mate."

Males, whether they are mouse or man, generate a constant supply of new sperm from self-renewing spermatogonial stem cells. Yauk, along with colleagues at Health Canada and McMaster University, studied the spermatogonial stem cells of mature mice that had been exposed to cigarette smoke for either six or 12 weeks to look for alterations in a specific stretch of repeated portions of DNA, called Ms6-hm, which does not contain any known genes. The "smoking" mice were exposed to two cigarettes per day, the equivalent - based on blood levels of tobacco by-products - of an average human smoker, according to research previously published by one of the study's co-authors.

Yauk and her colleagues found that the rate of Ms6-hm mutations in the smoking mice were 1.4 times higher than that of non-smoking mice at six weeks, and 1.7 times that of non-smoking mice at 12 weeks. "This suggests that damage is related to the duration of exposure, so the longer you smoke the more mutations accumulate and the more likely a potential effect may arise in the offspring," Yauk said.

According to Yauk, previous studies have shown that Ms6-hm and similar locations of non-coding DNA are sensitive to damage from radiation, mutagenic chemicals and intense industrial air particulate pollution. While the researchers did not specifically study the protein-coding regions of DNA where genes reside, Yauk notes that previous studies correlate mutations in non-coding regions with those in coding regions, and that some repetitive regions of DNA (not exam-ined in this study) are associated with genes.

"It stands to reason that mutations could also interfere with genes, but our ongoing research looks to clarify the severity of DNA damage throughout the genome," said Yauk. "So, while some men say they'll quit smoking after their child is born, this represents a good reason to quit well in advance of trying to conceive."

Among the next steps in gaining a better understanding of the germline genetic health conse-quences of smoking, Yauk and her colleagues plan to study how altered DNA manifests itself in the children and grandchildren of male mice that are exposed to firsthand smoke. They also plan to study the effects of secondhand smoke on male mice as well the possibility that the eggs of females are affected by smoke.

###

Yauk's colleagues include fellow researchers from Health Canada and Martin Stämpfli, Ph.D., and his laboratory team at McMaster University. Funding for this research was provided by grants from the Canadian Regulatory System for Biotechnology and the Canadian Institutes of Health Research.

The mission of the American Association for Cancer Research is to prevent and cure cancer. Founded in 1907, AACR is the world's oldest and largest professional organization dedicated to advancing cancer research. The membership includes nearly 26,000 basic, translational, and clinical researchers; health care professionals; and cancer survivors and advocates in the United States and more than 70 other countries. AACR marshals the full spectrum of expertise from the cancer community to accelerate progress in the prevention, diagnosis and treatment of cancer through high-quality scientific and educational programs. It funds innovative, meritorious research grants. The AACR Annual Meeting attracts more than 17,000 participants who share the latest discoveries and developments in the field. Special Conferences throughout the year present novel data across a wide variety of topics in cancer research, treatment, and patient care. AACR publishes five major peer-reviewed journals: Cancer Research; Clinical Cancer Research; Molecular Cancer Therapeutics; Molecular Cancer Research; and Cancer Epidemiology, Biomarkers & Prevention. Its most recent publication, CR, is a magazine for cancer survivors, patient advocates, their families, physicians, and scientists. It provides a forum for sharing essential, evidence-based information and perspectives on progress in cancer research, survivorship, and advocacy.

Contact: Greg Lester

Paternal age equal or greater than 50 years and a 320% increase in congenital malformations in offspring compared to 20-29

2007-05-29T20:40:00.001-07:00

1: Hum Reprod. 2005 Nov;20(11):3173-7. Epub 2005 Jul 8. Links
Paternal age and congenital malformations.Zhu JL, Madsen KM, Vestergaard M, Olesen AV, Basso O, Olsen J.
The Danish Epidemiology Science Centre, University of Aarhus, Denmark.

BACKGROUND: Spontaneous mutations in germ cells increase with male age, but an association between paternal age and congenital malformations is not well established. We conducted a population-based cohort study to estimate this association. METHODS: A study population of couples and their firstborn children were identified in the Danish Fertility Database between 1980 and 1996 (n = 71937). Diagnoses of congenital malformations in children were obtained by linkage to the nationwide hospital register (1980-1999). RESULTS: Overall, there were no differences in the prevalence of malformations as a function of paternal age. However, the prevalence of malformations of extremities and syndromes of multiple systems, as well as Down's syndrome, increased with increasing paternal age. For example, in comparison with fathers age 20-29 years, adjusted hazard ratio of syndromes of multiple systems was 1.15 [95% confidence interval (CI) 0.81-1.65] for age 35-39 years, 1.33 (95% CI 0.79-2.25) for age 40-44 years, 1.73 (95% CI 0.82-3.65) for age 45-49 years, and 3.20 (95% CI 1.37-7.48) for age > or = 50 years (test for trend P = 0.01). CONCLUSIONS: Our data suggest that advanced paternal age may be associated with an excess occurrence of some specific malformations. The association could be caused by mutations of the gametes in men induced by biological or environmental factors.

PMID: 16006461 [PubMed - indexed for MEDLINE]

MOREOVER IN ANIMAL AND IN MAN, PATERNAL AGEING SEEMS RESPONSIBLE FOR A GRADUAL LOWERING IN THE LEVEL OF PROGENY CEREBRAL FUNCTIONS

2007-05-12T18:03:00.000-07:00

1: Contracept Fertil Sex. 1993 May;21(5):382-5. Links
[Age of the father and development][Article in French]
Auroux M.
Biologie de la Reproduction et du Developpement, CHU Bicetre.

Testicular ageing affects at the same time the individual and his lineage. In the individual, vascular, endocrine, blood testis barrier and Sertoli cells changes because of age lead a decrease of spermatozoa number and an alteration in their form and motility. These changes lead a gradual decrease of fertility. In the progeny, paternal ageing is responsible for new dominant autosomic mutations which themselves cause different malformations, as achondroplasia, Apert or Recklinghausen disease, Marfan Syndrome etc. and perhaps for certain chromosome X linked recessive mutations as Duchenne myopathy or hemophily A. Moreover, in animal and man, paternal ageing seems responsible for a gradual lowering in the level of progeny cerebral functions. In man, very youthful age is also related to these effects. Thus, the curve corresponding to this phenomenon presents an inverted U-Shape, of which the top corresponds to about thirty years of paternal age. Maternal age does not appear to play a part in this event. On the whole, these results pose the problem of the optimum age for fatherhood.

PMID: 7920923 [PubMed - indexed for MEDLINE

Do we know or act on the risks of age, toxins more than 3 cups of coffee per day on sperm DNA? Not usually

2007-05-09T22:20:00.000-07:00

Reprod Toxicol. 1992;6(4):289-92. Links
Male-mediated teratogenesis and other reproductive effects: biologic and epidemiologic findings and a plea for clinical research.Davis DL, Friedler G, Mattison D, Morris R.
This paper reviews biologic and epidemiologic evidence that prefertilization and perifertilization exposures to fathers influence a variety of reproductive outcomes, including fertilization, miscarriage, low birth weight, congenital anomalies, cancer, and neurodevelopmental and other childhood health problems. Males and females bring an equal number of chromosomes to their progeny, but their genomes may affect different aspects of reproduction. While the key male role principally ends at fertilization, there is growing experimental and human evidence that factors relating both to prefertilization and perifertilization exposure also play a role post fertilization. Some negative human epidemiologic findings reflect the fact that routinely gathered information usually generates detailed descriptions of maternal exposures and does not collect records regarding prefertilization paternal exposures. The absence of extensive human evidence should be interpreted as a deficiency in research rather than an absence of male-mediated adverse reproductive outcomes. More than 60 different compounds or industrial processes have been identified as increasing defects in human sperm and possibly increasing the risk to offspring from male-mediated exposures. Further research needs to include better characterizations of both maternal and paternal prefertilization and perifertilization exposures, in order to assess more accurately their relative effects. Pediatricians confronted with adverse pregnancy and antenatal health outcomes should obtain detailed information on relevant prefertilization exposures of both parents.

FATHERS 34 AND OVER WERE 90% MORE LIKELY THAN FATHERS AGE 20 TO 34 YEARS TO HAVE LOW-BIRTHWEIGHT BABIES

2007-05-08T23:21:00.000-07:00

May 2006, Vol 96, No. 5 | American Journal of Public Health 862-866
© 2006 American Public Health Association
DOI: 10.2105/AJPH.2005.066324

--------------------------------------------------------------------------------

RESEARCH AND PRACTICE
Paternal Age as a Risk Factor for Low Birthweight
Nancy E. Reichman, PhD and Julien O. Teitler, PhD

Nancy E. Reichman is with the Department of Pediatrics, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, New Brunswick. Julien O. Teitler is with the School of Social Work, Columbia University, New York, NY.

Correspondence: Requests for reprints should be sent to Nancy E. Reichman, PhD, Department of Pediatrics, Robert Wood Johnson Medical School, 97 Paterson St, Room 435, New Brunswick, NJ 08903 (e-mail: nancy.reichman@umdnj.edu).

Objectives. We examined associations between paternal age and low birth-weight in the US urban population.

Methods. Using a population-based sample of 4621 births, we used multiple logistic regression analysis to estimate associations between paternal age and low birthweight, controlling for maternal age, other demographic factors, and the child’s gender.

Results. When the child’s gender and the mother’s race/ethnicity, birthplace, parity, marital status, and health insurance type were controlled, teenaged fathers were 20% less likely and fathers older than 34 years were 90% more likely than fathers aged 20 to 34 years to have low-birthweight babies. The associations were significant when maternal age was also controlled. No racial/ethnic differences in associations between paternal age and low birthweight were found.

Conclusions. We identified paternal age as an independent risk factor for low birthweight in the US urban population, suggesting that more attention needs to be paid to paternal influences on birth outcomes and to the interactive effects of urban environments and individual risk factors on health.

But there is a growing body of evidence that the fruit of aging loins is burdened with increased risk of a wide variety of gene-influenced illnesses

2007-04-29T21:02:00.000-07:00

Ideas & Trends: Reproductive Gerontology; Ask Not for Whom the Clock Ticks
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By TAMAR LEWIN
Published: April 15, 2001
MEN, take note: you, too, have a biological clock.
True, it does not tick toward the absolute deadline that ends women's childbearing years. As notables like Tony Randall, Yasir Arafat, George Plimpton, Anthony Quinn, Clint Eastwood, Strom Thurmond and so, so many more have demonstrated, men can father babies no matter how old they get.

But there is a growing body of evidence that the fruit of aging loins is burdened with increased risk of a wide variety of gene-influenced illnesses

c. A study released last week raised the intriguing -- if skeptically viewed -- possibility that some cases of schizophrenia fall into that category.

The study found that older fathers are more likely to have children with schizophrenia. Fathers over 50 have three times the risk of having a child who develops schizophrenia as fathers under 25, the study found. Earlier studies linked advanced paternal age to a variety of conditions, including the most common type of dwarfism, neural tube defects, nervous system cancer, prostate cancer, neurofibromatosis, Apert syndrome (a malformation of the skull, hands and feet) and Marfan syndrome, which involves defects of the eyes, bones, heart and blood vessels. The study does not address what it is about the father that could cause schizophrenia. But Dr. Dolores Malaspina, a researcher at Columbia University and the lead author of the schizophrenia study, said that scientists have been seeing signs of a male biological clock for some time. ''While scientists have known for years that older fathers are a major source of gene mutations,'' she said, ''the public doesn't seem to have absorbed it, which may have something to do with a culture that sees older fathers as triumphantly virile.''

As research continues, her team suggested, it may be that the father's sperm will turn out to play as big a part in children's genetic problems as the mother's eggs.

While women are born with all the eggs they will ever have, the cells that become sperm divide and reproduce throughout a man's life -- with each division introducing a slight risk of error in the genetic material the new sperm passes on to the children. For men in their 40's and 50's, who assumed they could defer parenthood to their later, quieter years, the possibility of a male biological clock is not a happy concept.

''This is a new idea to me, and it doesn't make my day,'' said Gregory Mosher, a New York director and producer. ''But science is so mind-boggling that there always are new discoveries that make you rethink all your assumptions. This is just another thing to talk about with whoever you're making the decision with.''

And some men reacted by pointing out that, if they do have such clocks, they tick quietly. ''I know that the problem women face with their biological clock is something I'll never experience or fully understand,'' said Richard Orloff, a playwright. ''For men, even if there's some higher risk of having a child with a problem, there's still the possibility of being a father.''

If, as the new study suggests, one-fourth of all schizophrenics have older fathers, it may seem puzzling that the correlation was not noticed long ago. But what scientists find depends on what they look for, as women angered by the lack of female-specific data on problems like heart disease have long pointed out.

''We've known since the 1960's that schizophrenia is associated with last-born kids and older parents,'' said Dr. Malaspina. ''But most people choose spouses about their age, and if you didn't look specifically at the father's age, you would think there was a powerful link between maternal age and schizophrenia. It's only when we separated it out that we saw that paternal age mattered, and maternal age didn't.''

There is a particular irony in the finding that the devastating mental illness once thought to be caused by a type of bad mother -- the ''schizophrenogenic'' mother, a staple of 60's psychiatry -- may have something to do with the father.

THE BEST TIME FOR A MAN TO FATHER A HEALTHY CHILD IS 25 OR SO THE SAME AS FOR A WOMAN

2007-04-16T12:05:00.000-07:00

Like eggs, sperm have a "best by" date?

http://seattletimes.nwsource.com/html/health/2003303295_carnalknowledge15.html

By Faye Flam

By the time I'd reached my early 30s and was still not married, someone offered me this bit of advice: Just pick somebody.

Women are relentlessly reminded of the dreaded biological clock and the risks of having children after 35. But recent science suggests men, too, should be worried.

"The term 'biological clock' has always referred to females, but now there's evidence men are also ticking off some of their healthy children," says Jay Schinfeld, a fertility specialist.

The latest finding, published last month: Older fathers are more likely to have children with autism. Researchers tracked 387,000 people born in Israel and concluded the odds of fathering an autistic child are about 6 in 1,000 for men under 20. When a man reaches 50, those odds shoot up to about 52 in 1,000.

"The optimal time for a man to father a healthy child is the same as for a woman — 25 or so," says Dolores Malaspina, a psychiatry professor at New York University and coauthor of the study.

Malaspina led an earlier study showing a connection between paternal age and schizophrenia. She found children born to fathers over 50 carried about three times the risk of developing schizophrenia as those born to fathers in their 20s.

Autism and schizophrenia both arise from a little-understood combination of genetic and environmental triggers. Both disorders tend to run in families, suggesting that genetic risk factors can be inherited.

But you don't have to carry a genetic disease to pass one on — the trouble can start in your testicles. There, sperm-generating cells divide about 23 times a year, in the process slowly accumulating copying errors.

Older fathers are more likely to have children with achondroplasia (dwarfism) and several other conditions caused by spelling errors in the DNA. So for a man, the older you get, the less your child's genetic endowment will resemble your own.

For women, aging isn't as likely to lead to spelling errors because we make no new eggs after we're born. But that leads to other problems. The million or so we begin life with die at a rate of about 30 a day, and as the remaining eggs age, they get less adept at one of their critical jobs — dividing their 46 chromosomes in half. Eggs don't do this until after they're penetrated by a sperm.

If they get it wrong, some will get extra chromosomes, others will miss one, leading to Down syndrome (an extra chromosome 21), Turner's syndrome (a missing X chromosome in a girl), and Klinefelter's syndrome (an extra X chromosome in a boy).

Menopause creates a natural cutoff for women's fertility around 50, while an increasing number of men much older than that are becoming fathers, or trying to, says Abington's Schinfeld. "We get some as old as 70 coming here to try to make babies," he says.

Some get married a second time to a younger woman and others find love late in life. Schinfeld said one of his patients, a Vietnam veteran in his 60s, came to him with a wife in her 30s. The man explained that during the war he'd rescued a group of villagers, including a little girl, and that girl tracked him down after she grew up. Despite the age difference, they fell in love and got married.

It's hard to say whether men will now be subject to pressure the way women are, or accused of "wanting it all."