Scientific American Article On the Genetic Male Biological Clock Nails It

June 26, 2008

Fact or Fiction: Men Have a Biological Clock
Does male fertility have an expiration date?
By Anne Casselman


snipets


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 50developed 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."

We also note that schizophrenia and autism share certain risk factors such as advanced paternal age

: Behav Brain Sci. 2008 Jun;31(3):264-265.
Animal models may help fractionate shared and discrete pathways underpinning schizophrenia and autism.Burne TH, Eyles DW, McGrath JJ.
Queensland Centre for Mental Health Research, The Queensland Brain Institute, The University of Queensland, St Lucia, Brisbane, 4072, Australia. t.burne@uq.edu.au http://www.qbi.uq.edu.au eyles@uq.edu.au http://www.qbi.uq.edu.au john_mcgrath@qcmhr.uq.edu.au http://www.qbi.uq.edu.au.

Crespi & Badcock (C&B) present an appealing and parsimonious synthesis arguing that schizophrenia and autism are differentially regulated by maternal versus paternal genomic imprinting, respectively. We argue that animal models related to schizophrenia and autism provide a useful platform to explore the mechanisms outlined by C&B. We also note that schizophrenia and autism share certain risk factors such as advanced paternal age. Apart from genomic imprinting, copy number variants related to advanced paternal age may also contribute to the differential trajectory of brain development associated with autism and schizophrenia.
PMID: 18578908 [PubMed - as supplied by publisher]

The Fragile X Factor

The Fragile X Factor
Thursday, Jun. 26, 2008 By CLAUDIA WALLIS Enlarge Photo
Cari Wheeler, center, and her dad Gary Boyer, seated, did not know they carried the fragile X trait until Max, center, was born with fragile X syndrome.
Mikey Tnasuttimonkol for TIMEArticle ToolsPrintEmailReprintsSphereAddThisRSSYahoo! Buzz They called him "the singing baby." As a newborn, Maxwell Wheeler would lie in his crib, whistling shrilly as he breathed in and out. For Cari and Andrew Wheeler of Madera Ranchos, Calif., it was one of the first signs that all was not right with their second child--an infant who didn't like to be touched, refused to nurse and struggled to keep down formula. At 10 months, when Max was still spitting up more than sitting up, the Wheelers consulted an occupational therapist, who noticed an extra fold above his eyelids, prominent ears and other features she called "dysmorphic."



"I said, 'What do you mean dysmorphic?'" Cari recalls. "'I think he's cute!'" But she and Andy agreed to have their baby tested for genetic disorders. And so began a medical odyssey that would engulf three generations of the family.

I met the Wheelers at the MIND (for Medical Investigation of Neurodevelopmental Disorders) Institute at the University of California at Davis, where they arrived with Max, now 7, his brother Brockton, 10, and Cari's parents Mary and Gary Boyer. It was one of many visits for the Wheeler-Boyer clan. Max raced around a visitors' room, occasionally hugging his mom and trying to pull his beloved granddad up from his chair. Mildly autistic and mildly retarded, Max doesn't speak much, and he didn't respond to my overtures. In addition, Max suffers from hyperactivity, low muscle tone, gastrointestinal problems and a tendency to spike scorchingly high fevers. Though he's doing fine in kindergarten--with an aide--he only recently managed to pass potty-training.

Max wasn't the only one in the room struggling with a worrisome condition. His grandfather Gary, 70, sat stiffly in his chair, tuning in to and out of the conversation. An architect with a Ph.D. in urban engineering, he has developed a tremor in his left hand, and he's so unsteady on his feet that he's taken several falls. "My legs are gone," he says. "I'm very numb from the knees down." Perhaps more alarming are the changes in his personality. The first sign was hoarding household items. "Then I started noticing that he became antisocial," says his wife Mary. "He didn't want to go out. And he didn't want to talk when people came over. He would sit on the patio and smoke."

Cari has been just as stunned by the changes in her once outgoing father, but lately she has had some odd symptoms of her own. Though only 35, she has begun to experience hot flashes, and her menstrual periods have become brief and irregular.

Ten years ago, no one would have connected Max's autism and other symptoms with Gary's neurological decline or Cari's premature signs of menopause. Now, however, researchers realize that all three are caused by changes in the same gene, one that's related to a disorder called fragile X syndrome (FXS), perhaps the most complicated genetic condition you've never heard of. Max has full-blown FXS. The disorder, as its name implies, is the result of a defective gene on the X chromosome, one of the pair of chromosomes that determines gender. FXS affects roughly 1 in 2,500 boys, causing autism spectrum disorders in about half of them. That makes FXS the most common known cause of autism, responsible for roughly 5% of all cases. It is also the most common inherited cause of mental retardation. Though the FXS defect occurs just as frequently in girls, they tend to be less severely affected.

Fragile X has been known for decades, but an explosion of new research, prodded along by advocacy groups like the National Fragile X Foundation and FRAXA, is yielding insights that have implications for understanding and treating autism--and perhaps a number of other conditions too. "Fragile X is leading the autism field in terms of new treatments," says pediatrician Randi Hagerman, medical director of the MIND Institute. "We know the gene, we know a lot about the biology, and we know how to fix it. That's pretty exciting!"

In addition, new research has revealed that relatives who carry the fragile X trait, like Max's mother and grandfather, may themselves be affected by it. At the National Institutes of Health (NIH), a new panel has been charged by Congress to direct research into FXS and related conditions. "We hope to learn lessons that may be applicable to helping people with Huntington's disease, Alzheimer's and myotonic dystrophies too," says Tiina Urv, who heads the panel. Research on the FXS family of disorders may also yield clues to some forms of infertility.

Most of us move through our days with only a vague awareness of our genetic endowment, fretting perhaps over a familial tendency toward heart disease or beaky noses. But families affected by fragile X can discuss their genome with startling specificity. Their key concern is a small strip of DNA on the long arm of the X chromosome. Normally, humans have five to 55 repetitions of the nucleotides CGG (cytosine, guanine, guanine) in this region. But for unknown reasons, the number of CGG repeats can expand beyond normal as the DNA is copied from mother to child.

Cari, for instance, has one normal X chromosome (with 24 repeats), inherited from her mother, and another with an abnormal 85 repeats, inherited from her father, who has 89 repeats. Cari's son Max has 363. Any number greater than 200 causes full-blown fragile X syndrome (so named because, under a microscope, the expanded X chromosome may look bent to the point of breaking). The reason boys are more likely than girls to develop major symptoms is that girls carry a pair of X chromosomes, which means that if one is defective, the other can compensate. Boys, however, carry an X and a Y, so the damaged chromosome is on its own.

People like Cari and her father, with 55 to 200 repeats, are considered carriers of a fragile X "premutation." Carriers are relatively common: about 1 in 250 women and 1 in 800 men have the premutation, though some studies suggest the prevalence is higher. Until recently no one worried too much about those numbers, since carriers were thought to be unaffected.

Schizophrenia & Father's Age

Schizophrenia & Father's Age
The Influence of Paternal Age on Schizophrenia: An Expert Interview With Dolores Malaspina, MD, MPH
Editor's Note:
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, MD, MPH, 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.



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

Dolores Malaspina, MD, MPH: 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 2 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 that 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 3 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 1 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 3 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%. That means that 97% 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 benefitted 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.

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




Dolores Malaspina, MD, 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, NY


Disclosure: Jessica Gould has disclosed no relevant financial relationships.

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


WebMD Medical Reference from Medscape

Paternal Age in Case 2?

1: Singapore Med J. 2008 Apr;49(4):e98-e100. Links
Two cases of deletion 5p syndrome: one with paternal involvement and another with atypical presentation.Azman BZ, Akhir SM, Zilfalil BA, Ankathil R.
Human Genome Centre, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kota Bharu 16150, Malaysia.

We report two cases of deletion 5p or cri du chat syndrome (CdCS) with different presentations and risks of transmission: one case with paternal chromosome 5 involvement and another, a de novo case with atypical clinical presentation. Cytogenetic analysis was performed on the two cases and their parents. GTG-banded karyotype analysis of Cases 1 and 2 revealed abnormal 46,XY,del(5)(p13-15) male karyotypes. For Case 1, the mother showed normal female karyotype while the father showed an abnormal karyotype involving a balanced translocation 46,XY,t(5;10)(p13;p15). For Case 2, however, both parents showed a normal karyotype pattern. In Case 1, the clinical features, particularly the distinct facial phenotype in combination with a characteristic cat-like cry and hypotonia, aided in the diagnosis at birth and the karyotype analysis was resolutive. The boy in Case 2 presented with atypical clinical features. Even though this patient had multiple syndromic features, the typical high pitched cat-like cry was not prominent. Instead, the patient manifested persistent stridor (from day three of life), which might have prevented the clinician from suspecting CdCS at birth. However, when this patient was presented at seven months of age for cytogenetic analysis, a confirmatory diagnosis of CdCS was established. For children with congenital abnormalities, an early clinical diagnosis confirmed through cytogenetic and molecular investigations, is important for providing personalised diagnostic and prognostic evaluation, and also for genetic counselling on the reproductive risk, particularly for patients with parental chromosome translocation involvement.

PMID: 18418516 [PubMed - indexed for MEDLINE]

Will Jonathan Sebal Discuss Paternal Age as a Probable Cause of Genome Copy Number Variation Sporadic, and Autism and Schizophrenia?

Analysis of Genome Copy Number Variation in Psychiatric Disease
Keynote Speaker: Jonathan Sebat
Dr. Jonathan Sebat will discuss the analysis of genome copy number variation in psychiatric disease. 4:30 PM
Genetics & Development Seminar
Jun 24, 2008
4:30 PM - 5:30 PM
Columbia University, Hammer Health Sciences Center, Room 301, 722 W. 168th St., between Haven Ave. and Fort Washington Ave.

Contact: Celia Morales
(212) 305-4011

Expert calls for vigilance on IVF technology

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.

As men age they do not lose their capacity to generate spermatozoa; however, the quality of these gametes deteriorates

Full Text
Expert Review of Obstetrics & Gynecology
May 2008, Vol. 3, No. 3, Pages 267-271
(doi:10.1586/17474108.3.3.267)


Just how safe is assisted reproductive technology for treating male factor infertility?
R John Aitken




Assisted reproductive technology (ART) has been responsible for the birth of over 3 million babies since the delivery of Louise Brown in the UK 28 years ago. Currently, one in 80–100 children born in the USA, one in 50 born in Sweden, one in 40 born in Australia and one in 24 born in Denmark are the product of this form of treatment. In 2003, more than 100,000 in vitro fertilization (IVF) cycles were reported from 399 clinics in the USA, resulting in the birth of more than 48,000 babies [1,101]. Worldwide, this figure has now exceeded 200,000 births per annum [2] and is continuing to rise. Indeed, it is a biological certainty that the more ART is used in one generation, the more it will be needed in the next. Given the cost of this form of treatment, and the fact that children born as a consequence of ART stand a 30–40% increased risk of birth defects [3], the current widespread use of assisted conception may constitute the beginnings of a serious public health problem.



There is general agreement that the two major reasons for patient referral to assisted conception programs are increased maternal age and male subfertility. The former can be easily reversed by public awareness and a change in social attitudes to family planning. However, the latter is a more intractable problem, as we have little or no understanding about the origins of this pathology. As a result, rational treatment or prevention of male infertility is all but impossible.
The importance of the male factor in human infertility has been highlighted by recent analyses of population trends in Denmark. This population has witnessed a steady decline in fertility rates in recent years, which is being addressed by increasing reliance on ART [4]. At the present time, 21% of young Danish men exhibit semen quality (in terms of sperm count and morphology) that falls below the internationally accepted thresholds of normality set by the WHO [5]. Moreover, it has been suggested that this situation is getting worse with the passage of time and, according to a recent publication [6]:
‘we may now have reached a level where semen quality of a significant segment of men in the population is so poor that it may contribute to the current widespread use of assisted reproduction’.
Although Denmark affords a particularly striking example of secular trends in male reproduction, semen quality in human males is notoriously poor. Indeed, it is a feature of the human condition, with at least one in 20 men in developed countries suffering from some level of infertility [7]. Most men produce sufficient numbers of spermatozoa to fertilize an egg in vivo; however, the gametes they generate have lost their biological potential for fertilization and the support of normal embryonic development. An important characteristic of these defective spermatozoa is a high level of DNA damage, which is, in turn, correlated with poor fertility, high rates of miscarriage and an increased incidence of disease in the offspring, including childhood cancer [8].
The use of such DNA-damaged spermatozoa in ART is thought to be a major contributor to the increased incidence of birth defects and other diseases seen in children conceived in vitro. Specifically, it has been proposed that the DNA damage brought into the fertilized egg by the spermatozoon may increase the mutational load carried by the embryo as a consequence of the aberrant or incomplete repair of this damage in the interval between fertilization and initiation of the first cleavage division [9,10]. Experimental verification of this relationship between DNA damage in the fertilizing sperm and embryo development has recently been secured in an animal model [11]. In these studies, intracytoplasmic sperm injection (ICSI) was performed in mice with fresh or DNA-damaged spermatozoa. Use of the latter was associated with poor preimplantation development and a reduction in the number of live births. Postnatal examination of the progeny revealed that the use of DNA-damaged spermatozoa in ICSI was associated with behavioral defects (increased anxiety, lack of habituation pattern, deficit in short-term spatial memory and age-dependent hypolocomotion in an open field test), the appearance of mesenchyme tumors, premature aging and a shortened lifespan. These results are supported by clinical data [8] and have profound implications for the safety of ICSI, which must frequently involve the use of DNA-damaged spermatozoa [12]. Currently, both the nature of this genetic damage and its origins are a matter of intense investigation. In terms of etiology, the ensuing paragraphs summarize data suggesting that paternal age, environmental toxicants, errors of endogenous metabolism and exposure to electromagnetic radiation are all potential contributors to DNA damage in the male germ line.



As men age they do not lose their capacity to generate spermatozoa; however, the quality of these gametes deteriorates. This change can be visualized as an age-dependent increase in DNA fragmentation in spermatozoa [13,14]. Paternal age is also widely recognized as a key factor in the etiology of dominant genetic diseases, such as Apert syndrome or achondroplasia [15]. Furthermore, genetic damage to the spermatozoa of aging males is thought to contribute to the etiology of more complex polygenic conditions such as autism, spontaneous schizophrenia and epilepsy [8]. Since older men tend to be married to older women it is significant that as oocytes age in the ovary, they suffer the depletion of several key genes involved in protection against oxidative stress and the maintenance of DNA integrity, including genes with a probable role in DNA repair [16]. Thus, age-related changes to the integrity of DNA in the spermatozoa are compounded by age-related declines in the oocytes’ capacity for DNA stabilization and repair. In combination, these factors could well make a significant contribution to the elevated incidence of birth defects associated with assisted conception therapy. Whichever way you look at it, aging and reproduction are incompatible bedfellows.


Environmental pollution ChooseTop of pageINTRODUCTIONThe male factorParental ageEnvironmental pollution Errors of endogenous meta...Electromagnetic radiation...Epigenetic damageIs ART a dangerous form o...References
An impact of environmental pollutants on DNA integrity in spermatozoa has been known for some time. For example, men who smoke heavily produce spermatozoa suffering from high levels of oxidative DNA damage. This does not necessarily impair the capacity of these cells for fertilization, however, it does impact upon the subsequent ability of the fertilized egg to develop normally. As a result, the children of heavy smokers stand a four- to fivefold increased chance of developing childhood cancer: a fact that is not often appreciated in the antismoking debate [9].
Recently, exposure of mice to particulate air pollution in an urban/industrial location has also been shown to induce high levels of DNA damage in spermatozoa [17]. Analyses of young men exposed to high levels of air pollution as a result of excessive coal combustion during Eastern European winters have substantiated these results in a clinical context [18]. Similarly, toxicological studies have demonstrated elevated levels of DNA damage in human spermatozoa, which are linked to the presence of metabolites of insecticides or persistent organochlorine pollutants in blood or urine [19,20]. Exposure to environmental endocrine disruptors, such as nonylphenol [21], as well as heavy metals [22], have also been demonstrated to induce oxidative DNA damage in human spermatozoa. Further resolution of the kinds of environmental pollutant that might be damaging to human spermatozoa is clearly needed. Elucidation of the significance of enzyme polymorphisms in defining an individual’s susceptibility to toxicant exposure is also required, as exemplified by a recent study demonstrating that men who are homozygous null for glutathione-S-transferase M1 are more likely to respond to air pollution with high levels of DNA damage in their spermatozoa than men possessing this isoform [23].


Errors of endogenous metabolism ChooseTop of pageINTRODUCTIONThe male factorParental ageEnvironmental pollutionErrors of endogenous meta... Electromagnetic radiation...Epigenetic damageIs ART a dangerous form o...References

Induction of DNA fragmentation in human spermatozoa is not solely due to exposure to environmental toxins, it can also result from errors of endogenous metabolism. An extremely important observation in this context is a recent preliminary report indicating that young male patients suffering from diabetes mellitus exhibit high levels of DNA damage in their spermatozoa [24]. These results have been confirmed in animal studies demonstrating that the experimental induction of diabetes in male mice is associated with oxidative stress and a postmeiotic genotoxic effect reflected in high rates of embryonic resorption in mated females [25]. Our laboratory has also demonstrated that endogenously generated estrogens, particularly catechol estrogens, can have a profound effect on DNA integrity in human spermatozoa, as a consequence of their inherent redox cycling activity [26]. Such studies reinforce the generally held view that most endogenously generated DNA damage in human spermatozoa is a consequence of oxidative stress [8,28]. If this is the case, then any ion (lead or cadmium), organic compound (phthalate ester), enzyme (NADPH oxidase), organelle (mitochondria) or cell (neutrophil), capable of generating reactive oxygen species in the vicinity of human spermatozoa is potentially capable of contributing to DNA damage in the male germ line [8–10,22,28]. In addition to oxidative damage, it is possible that in some patient’s sperm DNA is cleaved by the sequential action of topoisomerase IIB and an uncharacterized nuclease in a process analogous to apoptosis in somatic cells [29]. The relative significance of nuclease- and free radical-mediated mechanisms in the cleavage of sperm DNA, is a key issue that awaits resolution.


Electromagnetic radiation ChooseTop of pageINTRODUCTIONThe male factorParental ageEnvironmental pollutionErrors of endogenous meta...Electromagnetic radiation... Epigenetic damageIs ART a dangerous form o...References

Various forms of electromagnetic radiation are also known to have a detrimental effect on DNA integrity in the male germ line. A classic example is heat. The scrotum is designed to maintain the testes and epididymis slightly below core body temperature. It has been known for some time that elevated testicular temperature impairs spematogenesis. However, recent data have also indicated the ability of mild scrotal heat stress (42°C for 30 min) to induce DNA damage in epididymal mouse spermatozoa [30]. Radiofrequency electromagnetic radiation has also been demonstrated to induce DNA damage in epididymal sperm in animal models [31] and there are some reports of mobile phone exposure having a detrimental effect on semen quality in men [32]. Thus, any practice that elevates testicular temperature, such as wearing clothes or a sedentary occupation, or exacerbated exposure to other forms of electromagnetic radiation, such as excessive mobile phone use, are possible contributors to DNA damage in human spermatozoa.


Epigenetic damage ChooseTop of pageINTRODUCTIONThe male factorParental ageEnvironmental pollutionErrors of endogenous meta...Electromagnetic radiation...Epigenetic damage Is ART a dangerous form o...References

In some couples, the damage brought into the oocyte by the fertilizing spermatozoon may be epigenetic rather than genetic. These epigenetic factors are reviewed in an article in this edition of Expert Review of Obstetrics and Gynecology [31] and include: a functional centrosome to regulate cell division in the embryo; an appropriate pattern of chromatin remodeling; an appropriate population of mRNA and miRNA species that are carried into the zygote by the fertilizing spermatozoon and may play a role in the regulation of early embryonic development; and an appropriate pattern of DNA methylation. There are several recent papers indicating that the DNA methylation profile is dramatically altered in the spermatozoa of infertile men and we already know that the incidence of imprinting defects is elevated in children born as a result of ART [31,32]. The importance of epigenetic defects in the male germ line has recently been highlighted by analyses of vinclozolin, a fungicide used in the wine-making industry [33]. Transient embryonic exposure to vinclozolin in utero resulted in the birth of male offspring exhibiting a spermatogenenic defect. This defect was epigenetic in origin and was vertically transmitted through at least four generations.



Given the evidence that both IVF and ICSI are associated with a significant increase in birth defects, should ART be regarded as safe? On one hand, there is no denying that ART, and particularly ICSI, is an effective form of treatment for infertility. After 12 months approximately 90% of couples submitting to this form of therapy walk away with a baby. Furthermore, even though the risk of birth defects is significantly elevated following ART, the incidence is still relatively rare and should decrease as the field moves towards single-embryo transfers, thereby eliminating complications created by multiple births. Moreover, several clinical groups have trumpeted their ability to successfully perform ART in couples where the male partner’s spermatozoa exhibit high levels of DNA damage, without any obvious consequences as far as the health and wellbeing of the offspring are concerned [34]. These and other data tell us that even if DNA-damaged spermatozoa are used for assisted human conception, the risk of generating a visible phenotypic change in the offspring is extremely low.
However, we should also recognize that the absence of a pathological phenotype in the vast majority of children born as a result of ART, does not mean that the genome has not been damaged, or that the damage will not emerge in some future generation, as a result of mechanisms such as haploid insufficiency, the expression of X-linked defects in male offspring or the future creation of double-recessive combinations. It also does not mean that we will not find defects if we look hard enough. The controversial discovery of fertility-threatening Y-chromosome deletions in the offspring of genotypically normal males as a consequence of ART, is an example of a condition that may take 25–30 years to surface even though the mutation was probably created shortly after fertilization [35].
Clearly, we must continue to be vigilant in our long-term monitoring of the health and wellbeing of children produced by ART. Given recent advances in our understanding of epigenetic defects in the spermatozoa of infertile male patients, we should also extend this surveillance to the DNA methylation profiles of children born as a result of assisted conception. It is also incumbent upon embryologists to optimize the quality of the gametes that are used for ART, particularly where ICSI is involved. The development of prophylactic antioxidant therapies [36], improved culture conditions [37], novel gamete selection technologies [38] and noninvasive methods for the assessment of embryo quality [39] will all contribute to the future evolution of ART as a safe, effective means of treating human infertility.
Financial & competing interests disclosure
Aitken is a Consultant for NuSep. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.


References ChooseTop of pageINTRODUCTIONThe male factorParental ageEnvironmental pollutionErrors of endogenous meta...Electromagnetic radiation...Epigenetic damageIs ART a dangerous form o...References

Papers of special note have been highlighted as: • of interest •• of considerable interest
1 Van Voorhis‌ BJ. Clinical practice. in vitro fertilization. N. Engl. J. Med. 356, 379–386 (2007). [CrossRef] [Medline]
2 Adamson‌ GD, de Mouzon J, Lancaster P, Nygren KG, Sullivan E, Zegers-Hochschild F; International Committee for Monitoring Assisted Reproductive Technology. World collaborative report on in vitro fertilization, 2000. Fertil. Steril. 85, 1586–1622 (2006). [CrossRef] [Medline]
3 Hansen‌ M, Bower C, Milne E, de Klerk N, Kurinczuk JJ. Assisted reproductive technologies and the risk of birth defects – a systematic review. Hum. Reprod. 20, 328–338 (2005)
•• Meta-analysis suggesting a 30–40% increased risk of birth defects associated with assisted reproductive technology (ART).
[CrossRef] [Medline]
4 Jensen‌ TK, Sobotka T, Hansen MA, Pedersen AT, Lutz W, Skakkebæk NE. Declining trends in conception rates in recent birth cohorts of native Danish women: a possible role of deteriorating male reproductive health. Int. J. Androl. 31(2), 81–92 (2007).
• Recent review highlighting the declining fertility rates typical of the Danish population.
[CrossRef] [Medline]
5 Jorgensen‌ N, Carlsen E, Nermoen I et al. East–West gradient in semen quality in the Nordic–Baltic area: a study of men from the general population in Denmark, Norway, Estonia and Finland. Hum. Reprod. 17, 2199–2208 (2002). [CrossRef] [Medline]
6 Andersen‌ AN, Erb K. Register data on assisted reproductive technology (ART) in Europe including a detailed description of ART in Denmark. Int. J. Androl. 29, 12–16 (2006). [CrossRef]
7 McLachlan‌ RI, de Kretser DM. Male infertility: the case for continued research. Med. J. Aust. 174, 116–117 (2001). [Medline]
8 Aitken‌ RJ, De Iuliis GN. Origins and consequences of DNA damage in male germ cells. Reprod. Biomed. Online 14, 727–733 (2007)
•• Recent review of the causes and consequences of DNA damage in the male germ line.
[Medline]
9 Aitken‌ RJ, Koopman P, Lewis SE. Seeds of concern. Nature 432, 48–52 (2004).
• Review of potential environmental impacts on DNA damage in the germ line.
[CrossRef] [Medline]
10 Aitken‌ RJ, Krausz C. Oxidative stress, DNA damage and the Y chromosome. Reproduction 122, 497–506 (2001). [CrossRef] [Medline]
11 Fernández-Gonzalez‌ R, Moreira P, Pérez-Crespo M et al. Long-term effects of mouse intracytoplasmic sperm injection with DNA-fragmented sperm on health and behavior of adult offspring. Biol. Reprod. 78(4), 761–72 (2008).
•• Important recent paper providing experimental evidence that the performance of intracytoplasmic sperm injection (ICSI) with DNA-damaged spermatozoa can have long-lasting impacts on the health and wellbeing of the offspring.
[CrossRef] [Medline]
12 Irvine‌ DS, Twigg JP, Gordon EL, Fulton N, Milne PA, Aitken RJ. DNA integrity in human spermatozoa: relationships with semen quality. J. Androl. 21, 33–44 (2000). [Medline]
13 Schmid‌ TE, Eskenazi B, Baumgartner A et al. The effects of male age on sperm DNA damage in healthy non-smokers. Hum. Reprod. 22, 180–187 (2007). [CrossRef] [Medline]
14 Singh‌ NP, Muller CH, Berger RE. Effects of age on DNA double-strand breaks and apoptosis in human sperm. Fertil. Steril. 80, 1420–1430 (2003). [CrossRef] [Medline]
15 Crow‌ JF. The origins, patterns and implications of human spontaneous mutation. Nat. Rev. Genet. 1, 40–47 (2000). [CrossRef] [Medline]
16 Hamatani‌ T, Falco G, Carter MG et al. Age-associated alteration of gene expression patterns in mouse oocytes. Hum. Mol. Genet. 13, 2263–2278 (2004). [CrossRef] [Medline]
17 Yauk‌ C, Polyzos A, Rowan-Carroll A et al. Germ-line mutations, DNA damage, and global hypermethylation in mice exposed to particulate air pollution in an urban/industrial location. Proc. Natl Acad. Sci. USA 105, 605–610 (2008).
•• Important recent paper clearly demonstrating the impact that air pollution has on the epigenetic programming and integrity of sperm DNA.
[CrossRef] [Medline]
18 Rubes‌ J, Selevan SG, Evenson DP et al. Episodic air pollution is associated with increased DNA fragmentation in human sperm without other changes in semen quality. Hum. Reprod. 20, 2776–2783 (2005). [CrossRef] [Medline]
19 Rignell-Hydbom‌ A, Rylander L, Giwercman A et al. Exposure to PCBs and p,p´-DDE and human sperm chromatin integrity. Environ. Health Perspect. 113, 175–179 (2005). [Medline]
20 Meeker‌ JD, Singh NP, Ryan L et al. Urinary levels of insecticide metabolites and DNA damage in human sperm. Hum. Reprod. 19, 2573–2580 (2004). [CrossRef] [Medline]
21 Anderson‌ D, Schmid TE, Baumgartner A, Cemeli-Carratala E, Brinkworth MH, Wood JM. Oestrogenic compounds and oxidative stress (in human sperm and lymphocytes in the COMET assay). Mutat. Res. 544, 173–178 (2003). [CrossRef] [Medline]
22 Xu‌ DX, Shen HM, Zhu QX et al. The associations among semen quality, oxidative DNA damage in human spermatozoa and concentrations of cadmium, lead and selenium in seminal plasma. Mutat. Res. 534, 155–163 (2003). [Medline]
23 Rubes‌ J, Selevan SG, Sram RJ, Evenson DP, Perreault SD. GSTM1 genotype influences the susceptibility of men to sperm DNA damage associated with exposure to air pollution. Mutat. Res. 625, 20–28 (2007). [Medline]
24 Agbaje‌ IM, Rogers DA, McVicar CM et al. Insulin dependant diabetes mellitus: implications for male reproductive function. Hum. Reprod. 22, 1871–1877 (2007).
• Sentinel paper indicating that diabetic patients possess high levels of DNA damage in their spermatozoa.
[CrossRef] [Medline]
25 Shrilatha‌ B, Muralidhara. Early oxidative stress in testis and epididymal sperm in streptozotocin-induced diabetic mice: its progression and genotoxic consequences. Reprod. Toxicol. 23, 578–587 (2007). [CrossRef] [Medline]
26 Bennetts‌ LE, De Iuliis GN, Nixon B et al. Analysis of the impact of estrogenic compounds on DNA integrity in the male germ line. Mutat. Res. (2007) (In Press).
27 Wang‌ X, Sharma RK, Sikka SC, Thomas AJ Jr, Falcone T, Agarwal A. Oxidative stress is associated with increased apoptosis leading to spermatozoa DNA damage in patients with male factor infertility. Fertil. Steril. 80, 531–535 (2003). [CrossRef] [Medline]
28 Aitken‌ RJ, Baker HW. Seminal leukocytes: passengers, terrorists or good samaritans? Hum. Reprod. 10, 1736–1739 (1995).
•• Discussion of the significance of leukocytic infiltration in the origins of oxidative stress in the male reproductive tract.
[Medline]
29 Shaman‌ JA, Yamauchi Y, Ward WS. Sperm DNA fragmentation: awakening the sleeping genome. Biochem. Soc. Trans. 35, 626–628 (2007). [CrossRef] [Medline]
30 Banks‌ S, King SA, Irvine DS, Saunders PT. Impact of a mild scrotal heat stress on DNA integrity in murine spermatozoa. Reproduction 129, 505–514 (2005). [CrossRef] [Medline]
31 Carrell‌ DT. Paternal genetic and epigenetic influences on IVF outcome. Expert Rev. Obstet. Gynecol. 3(3), 359–367 (2008). [Abstract]
32 Houshdaran‌ S, Cortessis VK, Siegmund K, Yang A, Laird PW, Sokol RZ. Widespread epigenetic abnormalities suggest a broad DNA methylation erasure defect in abnormal human sperm. PLoS ONE 2, e1289 (2007). [CrossRef]
33 Anway‌ MD, Cupp AS, Uzumcu M, Skinner MK. Epigenetic transgenerational actions of endocrine disruptors and male fertility. Science 308, 1466–1469 (2005). [CrossRef] [Medline]
34 Gandini‌ L, Lombardo F, Paoli D et al. Full-term pregnancies achieved with ICSI despite high levels of sperm chromatin damage. Hum. Reprod. 19, 1409–1417 (2004). [CrossRef] [Medline]
35 Feng‌ C, Wang LQ, Dong MY, Huang HF. Assisted reproductive technology may increase clinical mutation detection in male offspring. Fertil. Steril. (2008) (Epub ahead of print).
• Recent publication indicating that the treatment of male infertility patients with ART is associated with the de novo appearance of Y chromosome deletions in the offspring.
36 Greco‌ E, Iacobelli M, Rienzi L, Ubaldi F, Ferrero S, Tesarik J. Reduction of the incidence of sperm DNA fragmentation by oral antioxidant treatment. J. Androl. 26, 349–353 (2005). [CrossRef] [Medline]
37 Friedler‌ S, Schachter M, Strassburger D, Esther K, Ron El R, Raziel A. A randomized clinical trial comparing recombinant hyaluronan/recombinant albumin versus human tubal fluid for cleavage stage embryo transfer in patients with multiple IVF-embryo transfer failure. Hum. Reprod. 22, 2444–2448 (2007). [CrossRef] [Medline]
38 Ainsworth‌ C, Nixon B, Jansen RP, Aitken RJ. First recorded pregnancy and normal birth after ICSI using electrophoretically isolated spermatozoa. Hum. Reprod. 22, 197–200 (2007). [CrossRef] [Medline]
39 Patrizio‌ P, Fragouli E, Bianchi V, Borini A, Wells D. Molecular methods for selection of the ideal oocyte. Reprod. Biomed. Online 15, 346–353 (2007). [Medline]
Website 101 Australian Babies. 4102.0. Australian Social Trends. Australian Bureau of Statistics (2007). www.abs.gov.au/AUSSTATS

Affiliations
R John Aitken
Laureate Professor of Biological Sciences, Faculty of Science and IT, University of Newcastle, Callaghan, NSW 2308, Australia. john.aitken@newcastle.edu.au
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Genetic clock ticks for men By Les Sheffield Clinical Geneticist

A great article from a concerned clinical geneticist and professor of clinical genetics!!!!


Genetic clock ticks for men article: Les Sheffield

June 12, 2008 12:00am
MOST men would have been surprised to read that overseas researchers had found the death rate of young adults was higher if they had been born to older fathers.

This is no surprise to me. It has been scientifically established that genetic changes occur more often in the sperm of older fathers than younger fathers.

As men age there is a higher chance of changes in the genes in the sperm.

These changes can cause genetic conditions in their offspring, such as birth defects, autism and schizophrenia.

Their partners can also have an increased risk of miscarriages.

The presumed reason for the increase occurrence of all of these conditions is that they are all due to a new genetic change in the sperm of the older father.

Genetic changes are occurring all the time. Sometimes they have a beneficial effect, such as making the individual stronger, taller or smarter.

This is part of the concept of "survival of the fittest".

Sometimes, when the gene change is in a non-coding part of the genome, they have no effect. At other times, they can be harmful.

The problem is that these harmful effects are extremely varied because they can affect any one of the 20,000 or so human genes.

For example, they often change the structure of the body. One example is dwarfism, where the arms and legs are short due to a genetic change. The commonest type of dwarfism is achondroplasia.

An individual with this condition will have a 50 per cent risk of having an affected child themselves.

Indeed, about 20 per cent of the parents of achondroplastic babies have one of the parents with this condition, but the remaining 80 per cent do not.

If you look at the parents of babies with achondroplasia, who do not have the condition themselves, you find their average age is older than other people having babies in the population.

Significantly, statistics show it is the father's age which is important and not the mother's.

Achondroplasia is rare and it is only one of the many genes that can go wrong. Collectively, any of the 20,000 genes can change and this causes an increase in risk from about the age of 40.

The risk in men for any single gene change is one in 200 at age of 40, 20 at age 50 and rises steeply after that.

This increase in risk with paternal age is no surprise to me, but it is a surprise to practically everyone else.

The increase risk for older mothers for Down syndrome is well-known.

As part of my work as a clinical geneticist, I see couples every week who come to ask about the risk of having babies because of the age of the mother.

We talk about this and often, as the male partner is also older, we talk about the risk of his age. Most of the partners are quite surprised and even taken aback with this news.

In today's society, delaying pregnancy until later is often done for career and other purposes but usually only the age of the mother is taken into account in planning when to start a family. Why is the increased risk in relation to a father's age not widely known?

There are many possible reasons. Some of the information - such as increased death rates of adults - is new.

But information about single gene changes, such as achondroplasia, has been around for many years.

I think the real reason for the lack of knowledge is the conditions that can be caused are varied and can't really be prevented by a screening program like the one offered for Down syndrome.

In fact, most of the conditions, such as achondroplasia, can't even be picked up by the normal ultrasound scan for abnormalities done at 18-20 weeks of a pregnancy.

So, if you're a male, the only way not to be exposed to this increased risk of genetic defects in your offspring is to plan your children early and regard the increasing risks of the woman in her late 30s and early 40s as also applying to you.

In other words, stop your child bearing at the same sort of age that women stop child bearing. This may not be what older men want to hear, but they need to seek information about what the risks actually are before making child-bearing decisions.

We hear about the positive sides of parenthood in some older celebrity fathers but the story last week about the increase in death rates of the offspring brings out the hidden risks associated with fathering children at an older age.

Associate Professor Les Sheffield is a clinical geneticist with the Victorian Clinical Genetics Services

Brainpower May Lie in Complexity of Synapses

VERY IMPORTANT ARTICLE "The roots of several mental disorders lie in defects in the synaptic proteins, more than 50 of which have been linked to diseases like schizophrenia, Dr. Grant said."


Brainpower May Lie in Complexity of Synapses



By NICHOLAS WADE
Published: June 10, 2008
Evolution’s recipe for making a brain more complex has long seemed simple enough. Just increase the number of nerve cells, or neurons, and the interconnections between them. A human brain, for instance, is three times the volume of a chimpanzee’s.


Get Health News From The New York Times » A whole new dimension of evolutionary complexity has now emerged from a cross-species study led by Dr. Seth Grant at the Sanger Institute in England.

Dr. Grant looked at the interconnections between neurons, known as synapses, which until now have been regarded as a standard feature of neurons.

But in fact the synapses get considerably more complex going up the evolutionary scale, Dr. Grant and colleagues reported online Sunday in Nature Neuroscience. In worms and flies, the synapses mediate simple forms of learning, but in higher animals they are built from a much richer array of protein components and conduct complex learning and pattern recognition, Dr. Grant said.

The finding may open a new window into how the brain operates. “One of the biggest questions in neuroscience is to answer what are the design principles by which the human brain is constructed, and this is one of those principles,” Dr. Grant said.

If the synapses are thought of as the chips in a computer, then brainpower is shaped by the sophistication of each chip, as well as by their numbers. “From the evolutionary perspective, the big brains of vertebrates not only have more synapses and neurons, but each of these synapses is more powerful — vertebrates have big Internets with big computers and invertebrates have small Internets with small computers,” Dr. Grant said.

He included yeast cells in his cross-species survey and found that they contain many proteins equivalent to those in human synapses, even though yeast is a single-celled microbe with no nervous system. The yeast proteins, used for sensing changes in the environment, suggest that the origin of the nervous system, or at least of synapses, began in this way.

The computing capabilities of the human brain may lie not so much in its neuronal network as in the complex calculations that its synapses perform, Dr. Grant said. Vertebrate synapses have about 1,000 different proteins, assembled into 13 molecular machines, one of which is built from 183 different proteins.

These synapses are not standard throughout the brain, Dr. Grant’s group has found; each region uses different combinations of the 1,000 proteins to fashion its own custom-made synapses.

Each synapse can presumably make sophisticated calculations based on messages reaching it from other neurons. The human brain has about 100 billion neurons, interconnected at 100 trillion synapses.

The roots of several mental disorders lie in defects in the synaptic proteins, more than 50 of which have been linked to diseases like schizophrenia, Dr. Grant said......

Paternal age and epilepsy in the offspring

1: Eur J Epidemiol. 2005;20(12):1003-5. Links
Paternal age and epilepsy in the offspring.Vestergaard M, Mork A, Madsen KM, Olsen J.
The Danish Epidemiology Science Centre, Institute of Public Health, Department of Epidemiology, University of Aarhus, DK-8000, Aarhus C, Denmark. mv@soci.au.dk

Advanced paternal age is associated with a higher rate of de novo mutation in sperm cells and mental disorders in the offspring. In a population based cohort study of 96,654 children, we found that fathers aged 35 years or more were slightly more likely to have a child diagnosed with epilepsy compared to fathers aged 25-29 years. Our data suggest a modest paternal effect on the aetiology of epilepsy.

Late paternity and stillbirth risk.

Hum Reprod. 2004 Nov;19(11):2497-501. Epub 2004 Aug 19. Links
Late paternity and stillbirth risk.Astolfi P, De Pasquale A, Zonta LA.
Department of Genetics and Microbiology 'A. Buzzati Traverso', University of Pavia, Via Ferrata 1, 27100 Pavia, Italy. astolfi@ipvgen.unipv.it

BACKGROUND: The role of paternal ageing on the incidence of some genetic diseases in offspring depends on the hypothesis that spontaneous mutations accumulate due to continuous cell divisions during spermatogenesis. We examined the effect of paternal age on the complex multifactorial character, stillbirth. METHODS: In 3,619,647 Italian singletons born in 1990-1996 we evaluated stillbirth risk as a function of paternal ageing by means of multiple logistic regression models, which included maternal age and family education, as categorical covariates and interactions. The categorical risk was estimated for mothers and fathers beyond threshold ages of 35 and 40 years, respectively. RESULTS: Stillbirth risk increases with paternal ageing in mothers > or =30 years old, and maternal age and family education modify the impact. In families with low education, the risk accounts for odds ratio (OR) 1.015 [95% confidence interval (CI) 1.01-1.02] in mothers aged 30-34 years, and for OR 1.032 (95% CI 1.02-1.04) in mothers aged > or =35 years; in families with higher education the risk accounts for OR 1.008 (95% CI 1.00-1.02) and OR 1.025 (95% CI 1.01-1.04), respectively, in mothers aged 30-34 and > or =35 years. In these latter families, for mothers aged <35 and fathers > or =40 years the risk accounts for OR 1.12 (95% CI 1.00-1.25). CONCLUSIONS: The effect of paternal ageing on stillbirth risk is revealed in mothers aged > or =30 years and is modified by family education. In mothers aged 30-34 years from families with high education, the increase imputable to paternal ageing might be indicative of a genetic component.

PMID: 15319387 [PubMed - indexed for MEDLINE]

Daughers of older fathers live shorter lives

Incidence of U. S. pediatric cancer varies with region and sex--Also Paternal age see below

General Health : Diseases Last Updated: Jun 2, 2008 - 8:48:32 AM

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Incidence of U. S. pediatric cancer varies with region and sex
By Ben Wasserman
Jun 2, 2008 - 8:42:00 AM

E.mail t.his a.rticle
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Monday June 2, 2008 (foodconsumer.org) -- Age, sex, race and region all make a difference in incidence of pediatric cancers in the United States, according to a new government study in the June, 2008 issue of Pediatrics.

White children (173 per million) had the highest incidence of all cancers while American Indians and Alaska Natives had the lowest. Children in the Northeast (179 per million) were most likely to be diagnosed with cancer than children in other regions of the country.

Boys were at higher risk of a pediatric malignancy (174 per million) than girls (157 per million) and those aged 15 to 19 (210 per million) had a slightly higher prevalence of cancer than children under 15 (151 per million).

The study was based on data from 39 National Program of Cancer Registries and five Surveillance, Epidemiology and End Results (SEER) databases involving 36,446 cases of childhood cancer from 2001 through 2003. The data represented more than 90 percent of the U.S. population.

Leukemia, central nervous system tumors and lymphomas are the three most common cancers found in children, accounting for 26 percent, 17.6 percent and 14.6 percent of pediatric cancers respectively. They accounted for about 60 percent of all childhood malignancies.

Boys were more susceptible to development of lymphoid leukemia, non-Hodgkin lymphoma, Burkitt lymphoma, osteosarcomas, hepatoblastoma and others while girls were more prone to kidney cancer, thyroid cancer and melanomas.

White children had the highest incidence of cancer at 173 per million compared to 118 for black children, 131 for Asian/Pacific Islanders and 164 for Hispanics. The lowest incidence was found in American Indians and Alaska Natives.

Northeast had the highest rate of pediatric cancer at 179 per million compared to 166 for the Midwest, 159 for the South and 165 for the West.

Dr. Jun Li, an epidemic intelligence office for the U.S. Centers for Disease Control and Prevention (CDC) in Atlanta and colleagues conducted the study.

It is unknown why there were the differences found in the study.

For more information on pediatric cancers, read http://www.cancer.gov/cancertopics/types/childhoodcancers

Source

PEDIATRICS Vol. 121 No. 6 June 2008, pp. e1470-e1477
Cancer Incidence Among Children and Adolescents in the United States, 2001–2003
Jun Li, MD, PhD, MPHa,b, Trevor D. Thompson, BSa, Jacqueline W. Miller, MDa, Lori A. Pollack, MD, MPHa and Sherri L. Stewart, PhDa
a Division of Cancer Prevention and Control, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, Atlanta, Georgia
b Epidemic Intelligence Service, Office of Workforce and Career Development, Atlanta, Georgia




IJE Advance Access originally published online on September 28, 2006
International Journal of Epidemiology 2006 35(6):1495-1503; doi:10.1093/ije/dyl177

Published by Oxford University Press on behalf of the International Epidemiological Association © The Author 2006; all rights reserved.

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Cancer


Parental age and risk of childhood cancers: a population-based cohort study from Sweden
Benjamin H Yip, Yudi Pawitan and Kamila Czene*
Department of Medical Epidemiology and Biostatistics, Karolinska Institute, 171 77 Stockholm, Sweden.

* Corresponding author. E-mail: kamila.czene@meb.ki.se


Abstract


Background Frequent germ line cells mutations were previously demonstrated to be associated with aging. This suggests a higher incidence of childhood cancer among children of older parents. A population-based cohort study of parental ages and other prenatal risk factors for five main childhood cancers was performed with the use of a linkage between several national-based registries.

Methods In total, about 4.3 million children with their parents, born between 1961 and 2000, were included in the study. Multivariate Poisson regression was used to obtain the incidence rate ratios (IRR) and 95% confidence interval (CI). Children <5 years of age and children 5–14 years of age were analysed independently.

Results There was no significant result for children 5–14 years of age. For children <5 years of age, maternal age were associated with elevated risk of retinoblastoma (oldest age group's IRR = 2.39, 95%CI = 1.17–4.85) and leukaemia (oldest age group's IRR = 1.44, 95%CI = 1.01–2.05). Paternal age was significantly associated with leukaemia (oldest age group's IRR = 1.31, 95%CI = 1.04–1.66). For central nervous system cancer, the effect of paternal age was found to be significant (oldest age group's IRR = 1.69, 95%CI = 1.21–2.35) when maternal age was included in the analysis.

Conclusion Our findings indicate that advanced parental age might be associated with an increased risk of early childhood cancers.



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Keywords childhood cancer, relative risk, paternal age, maternal age, incidence
Accepted 10 July 2006

Older dads and death of children

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Monday June 2 2008

Older dads and death of children
Children born to fathers over 45 years had a higher death rate
“Children of older fathers ‘more likely to die early’” is the headline in the Daily Mail today. Children of older fathers “are almost twice as likely to die before adulthood” warns the newspaper, reporting the results of a study in more than 100,000 children that showed that those born to fathers over 45 years old were less likely to live to be 19 than those born to men in their late 20s.

The newspaper story is based on a study of children born to parents of different ages. The study suggests a link between the age of the father and death due to some causes but not others, though the overall number of deaths recorded is small. As with all cohort studies, the question is whether the researchers have taken into account all other factors that could be responsible for any association seen. In this particular study, no adjustment was made for the health of the mother, and this could have had a large effect on child mortality.

Where did the story come from?
Dr Jin Liang Zhu and colleagues from the University of Aarhus in Denmark and the School of Public Health at the University of California in Los Angeles carried out this research. The study was funded by grants from the Danish National Research Foundation and was published in the (peer-reviewed) medical journal: European Journal of Epidemiology.

What kind of scientific study was this?
The study was a retrospective cohort study of couples with their first child, in which researchers were investigating the link between the age of the father and child mortality while adjusting for other factors that may have an effect, such as the age of the mother and socioeconomic factors.

The researchers used the Danish Fertility database (which holds data for all individuals in Denmark aged over 11 years old) to identify four different groups of couples with their first child. The first group consisted of all families recorded in the database where both members of the couple were aged over 35 at the time their child was born; the second group was all couples where fathers were over 35 years but with mothers younger than 30; the third group was of all mothers over 35 with fathers younger than 30; and the fourth group was a random sample from the database of parents who were both under 30 years old when their child was born.
"Our data revealed a higher mortality in offspring of fathers aged 45 years or more that lasted into adulthood." Jin Liang Zhu, lead author The researchers collected data about death of the children by linking them to the Register of Causes of Death. This was possible because all children in Denmark are assigned a unique registration number when they are born. For the purposes of this study, causes of death were recorded as perinatal (around the time of birth), due to congenital malformation, ill-defined, due to injury or poisoning, or due to other diseases. The researchers assessed the link between paternal age category (15–24 years, 25–29 years, 35–39 years, 40–44 years, 45+ years) and risk of death using the parental age group 25–29 years as the reference point (i.e. comparing rates of death in other groups to this one). They also analysed the data according to age at death. They took into account other factors that may have played a part, including maternal age, how many other children there were, maternal and paternal education, income, country of origin and year. To investigate the cause of death after birth, the researchers excluded children with congenital malformations, and only included those who had a healthy birthweight (2,500g or more), or those that were born at or after 37 weeks.

What were the results of the study?
The researchers followed up 102,879 children for up to 18 years. During this time, 831 children died (601 of them under one year old). When taking into account other factors, children born to older fathers (over 45 years) had a higher rate of death than children born to fathers aged between 25 and 29 years old.

This pattern did not change depending on the age of the child’s death (i.e. before one year old or between one and 18 years old). When the researchers explored this association by cause of death, they found that paternal age was linked to death due to congenital malformations (physical abnormalities in children at birth), and death due to injury or poisoning.

What interpretations did the researchers draw from these results?
The researchers conclude that they have found an association between advanced paternal age and death due to congenital malformation, and due to injury or poisoning. They are cautious to point out that the results may be due to unmeasured factors that they have not adjusted for. They say that the findings should be weighed up against socioeconomic advantages for children born to older fathers.

What does the NHS Knowledge Service make of this study?
The researchers conclude that the association between older age of fathers and death of offspring “may be related to differences in unadjusted lifestyle factors”. The researchers say that it is unlikely that the differences were related to different levels of healthcare, as the healthcare system is free for all residents. There may have been other factors to explain this pattern, that have not been considered.
The researchers discuss that reduced fertility may be confounding the association seen, as older couples are generally less fertile than younger ones. No information was collected on fertility, so it is not possible to estimate the contribution of fertility.
It is worth noting that deaths in children in this cohort were quite rare during the 18 years of follow up. Less than 1% of children died and the majority of those died when they were under the age of one year. This also means that when the researchers analysed deaths by the different paternal age groups, they were working with small sample sizes and outcome numbers (small numbers of deaths). This may have affected the accuracy of their results.
For the majority of causes of death, the age of the father had no effect. The researchers say that the link between injury and poisoning and death may be due to social and behavioural factors that have not been controlled for, or it could indicate that older fathers may be more accident prone (due to impaired functioning or for behavioural reasons). More research would be needed to explore this.
As with all cohort studies, the problem comes when controlling for other factors that may affect the outcome. The researchers have taken into account some of the factors, but others have not been considered, such as maternal health, which may have a large effect on the risk of death, particularly before the age of one year. The researchers say that their findings add to a growing body of evidence that advanced paternal age has negative effects during reproduction.
Links to the headlines
Children of older fathers 'more likely to die early'. Daily Mail, June 2 2008

Scientists reveal dangers of older fathers. The Daily Telegraph, June 2 2008
Links to the science
Zhu JL, Vestergaard M, Madsen KM, Olsen J. Paternal age and mortality in children. Eur J Epidemiol 2008; Apr 28 [Epub ahead of print]

Low Birth Weight May Increase Autism Risk in Girls

Low Birthweight and Advancing Paternal Age

Research and Practice
Paternal Age as a Risk Factor for Low Birthweight
Nancy E. Reichman 1* Julien O. Teitler 2


AJPH First Look, published online ahead of print March 29, 2006


©
American Journal of Public Health, 10.2105/AJPH.2005.066324


1 Robert Wood Johnson Medical School
2 Columbia University


Objectives. We examined associations between paternal age and low birthweight 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.

Key Words: Birth Outcomes, Socioeconomic Factors
Labels: advancing paternal age, autism, low birth weight, schizophrenia








Low Birth Weight May Increase Autism Risk in Girls (Update1)

By Elizabeth Lopatto

June 2 (Bloomberg) -- Autism strikes low birth weight baby girls at a higher rate than similar-sized boys when the infants are compared with larger children, according to a study that suggests risk factors for the disorder vary by sex.

Baby girls weighing less than 2.5 kilograms, or about 5.5 pounds, had 3.5 times increased risk of autism and baby girls born more than seven weeks early had a 5.4 times increased risk. Boys born small or early didn't have a significant difference in their risk of being autistic, the according to a report in the journal Pediatrics.

Doctors aren't sure what causes autism, though genetics and the environment probably both play roles, according to the National Institutes of Health. This research indicates that boys and girls have different risk factors for the disorder, said study author Diana Schendel.

``This suggests there may be sex differences in genetic factors leading to autism,'' said Schendel, a researcher for the Centers for Disease Control and Prevention, in a May 30 telephone interview. ``Girls may need an additional insult'' before birth that could include reduced growth or premature birth.

Autism and related disorders, some of them less severe, affect about 1 in 150 U.S. children. There is no cure for the malady, in which children may refuse to engage with other people, echo words and phrases, or repeat actions many times. Risk factors include older fathers and environmental toxins.

About 1 in 13 babies in the U.S. has low birth weight, according to the March of Dimes. Babies may weigh less than 5 pounds 8 ounces because they're premature, because the mother has heart problems, because of infections or because of cigarette, drug, or alcohol use.

`Biggest Risk Factors'

``We know that low birth weight and pre-term birth are among the biggest risk factors for developmental disabilities,'' Schendel said. ``The higher prevalence of autism supports monitoring these children carefully for behavioral problems.''

Babies born with low birth weights are likelier to have bleeding in the brain, lungs that are more likely to collapse, heart problems, and vision loss.

The study was of children born from 1981 to 1993 in Atlanta, who lived to 3 years of age, and were still living in Atlanta at ages 3 to 10. Over 550 children with autism were paired to normal children born in the same year.

To contact the reporter on this story: Elizabeth Lopatto in New York at elopatto@bloomberg.net.

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

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.'