SCIENTIFIC AMERICAN ARTICLE NAILS THE GENETIC MALE BIOLOGICAL CLOCK

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"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."

Paternal Age Explains Much Schizophrenia and Autism Risk

1: 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]

"Men around 40 ought to be thinking about the increased risk to their children, the same as women do," he said.

Biological clock ticks for dads too Grant McArthur

June 03, 2008 12:00am
CHILDREN born to older fathers are almost twice as likely to die before adulthood than those born to younger men, research shows.

Increased rates of birth defects, autism, schizophrenia, epilepsy and heart disease are believed to make children born to dads over 45 much less likely to live to 19 than those with fathers in their late 20s.

A Danish study of more than 100,000 children raises the prospect that biological clocks are ticking for men as sperm quality deteriorates with age.

Children born to teen fathers and over-45s are up to 88 per cent more likely to die before their 19th birthday than those born to men aged 25-29, researchers from the University of Aarhus found.

While deaths of children fathered by teens could be explained by their mothers also being young and often disadvantaged, the older men's children were only affected by their fathers' "underlying biological causes".

"The risks of older fatherhood can be very profound and it is not something that people are always aware of," said study author Jin Liang Zhu, from the Danish Epidemiology Science Centre.

The research, which tracked the children for up to the first 18 years, was published in the European Journal of Epidemiology.

Of 831 deaths, 601 were in the first year. Many were due to congenital defects.

Clinical geneticist Les Sheffield, of Melbourne's Murdoch Childrens Research Institute, said it was time fathers took responsibility for the risks.

Assoc Prof Sheffield said genetic errors in sperm increase by half a per cent when a man reaches 40, by 2 per cent when he is 50, by 5 per cent when he is 60 and by 20 per cent by the time he is 80.

"Men around 40 ought to be thinking about the increased risk to their children, the same as women do," he said.

"I speak to a lot of older parents and they talk about the women's risk, but when I talk about the father's risk they are just aghast because nobody has ever mentioned the father before," he said.

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

http://www.abc.net.au/news/stories/2008/06/14/2274718.htm

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

Posted 5 hours 36 minutes ago


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.

Tags: family-and-children, health, medical-procedures, medical-research, fertility-and-infertility, pregnancy-and-childbirth, reproductive-technology, science-and-technology, children, parenting, babies-newborns, australia, act, canberra-2600,

Genetic clock ticks for men

Genetic clock ticks for men 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

Fathers Can Harm Unborn

Fathers Can Harm Unborn
Posted on: Wednesday, 4 June 2008, 18:00 CDT

By BROWN, Tim

"There is no finer investment for any community than putting milk into babies," is one of Winston Churchill's less well-known quotes.

He was of course referring to the fact that the most important investment in our future is in our sons and daughters.

Even in the poor families of the Industrial Revolution priority was given to feeding children as well as possible. Parents would go hungry to do this.

In more recent times it has become clear that the health of the mother before and during pregnancy is paramount to the health of the newborn.

Abstinence from alcohol and cigarettes should be the starting point. Foetal alcohol syndrome is a now a well-established condition.

The next step is to check the mother is eating correctly and not lacking in any vitamins or minerals. This way most deficiencies, apart from those which may be genetically expressed, can be monitored and corrected.

Where does this leave poor Dad? Well probably quite happy that his metabolism does not seem to directly affect the health of the child. After all the sperms are constantly being freshly synthesised so what is the worry?

However there is now strong evidence that exposure of future fathers to chemicals, such as Agent Orange or dioxin, has had major detrimental effect on the foetus. This effect could not be via the mother who was not exposed.

Babies of fathers exposed to solvents are more likely to be still born, miscarried or develop later cancer. Teenage dads face premature births, low-birth weight and postnatal death. Seventy to 80-year- old dads stand a greater risk of passing on genetic abnormalities. They are likely to have babies with autism, schizophrenia and Down's syndrome. It is all a matter of numbers.

Since males make new sperm every 74 days it used to be believed that the slate was wiped clean. Each year after puberty sperm- producing cells divide 23 times. Each cell division provides risk of genetic error.

Consequently sperms produced when a man is 40 have gone through 610 replications. This is 610 chances of mutation and alteration of the DNA. Parents over 40 are six times more likely to have a child with Down's syndrome than are 25-year- old parents.

Gladys Friedlander, Boston University, United States, found what appeared to be Lamarckism - that is, the inheritance of acquired characters - discredited long ago. Experiments with rats and narcotic tolerance showed that paternal exposure affected progeny.

More recently it have been discovered that chemical modifications of the DNA and proteins can change the gene packaging without changing the genes themselves. These epigenetic changes form a memory of whether the genes come from mother or father. This label is not encoded in the DNA.

Matthew Anway, University of Idaho, has shown that male rats exposed to fungicide in the womb can pass this on for at least three generations. Male rats born to mothers exposed to fungicide had prostate problems akin to those in aging human males. Subsequent generations of males and females showed kidney and tumour problems and the males testis and prostate problems. What was clear and unequivocal was that only the males could pass on these problems even though later generations were not exposed to the chemical.

The take home message from these observations is that the male, as well as the female, shares experiences with descendants for years to come. So maybe the sins of human fathers have been vested in the offspring for much longer than previously thought?

(c) 2008 Evening Standard; Palmerston North, New Zealand. Provided by ProQuest Information and Learning. All rights Reserved.

Kids Born To Old Fathers More Likely To Die Early

Kids Born To Old Fathers More Likely To Die Early
Posted June 4th, 2008 by Piyush Diwan
Featured
Health Update
Europe
A new study carried out by European researchers revealed that becoming a father after the age of 45 increases the mortality risk of the child due to the declining sperm quality as men age.
The researchers said that children of older fathers were twice as likely to die before they entered adulthood as compared to kids born to younger fathers.
The researchers added that the children of older fathers are more likely to suffer from particular inborn deficiencies despite autism, schizophrenia and epilepsy.
Lead researcher Jin Liang Zhu of Danish Epidemiology Science Centre, stated, “The risks of older fatherhood can be very profound, and it is not something that people are always aware of.”
The researchers analyzed 100,000 kids born between 1980 and 1996. Until now around 830 of kids have died before 13 years.
Most of the deaths of the children of the older fathers were due to congenital defects like problems of the heart and spine that increases the risk of infant mortality.
The study was published in the European Journal of ‘Epidemiology.’
Consumers must be cognizant that the mother's age has always been linked with problems like Down's syndrome. The above study provides proof that a father's age may also have a say in child’s lifespan.

This study confirms that paternal age contributes to the risk of preterm birth.

Epidemiology. 2006 Mar;17(2):218-21. Links

Comment in:
Epidemiology. 2006 Sep;17(5):593; author reply 593-4.
Paternal age and preterm birth in Italy, 1990 to 1998.Astolfi P, De Pasquale A, Zonta LA.
Department of Genetics and Microbiology, A. Buzzati-Traverso, University of Pavia, Pavia, Italy. astolfi@ipvgen.unipv.it

BACKGROUND: Advanced paternal age has been reported to impair pregnancy outcome. Here, we investigated the association of advanced paternal age with preterm birth by using a very large national data set. METHODS: We analyzed data from 1990 to 1998 on Italian firstborn singletons to mothers 20-24 and 25-29 years of age (n = 1,510,823). Odds ratios for overall preterm (<37 weeks' gestation), very preterm (<32 weeks), and moderate preterm (32-36 weeks) births were evaluated through logistic regression models in paternal age classes (20-24, 25-29, 30-34, 35-39, 40-44, 45-49, 50+ years) after adjustment for confounders. Nonparametric regression models were used to fit the effect of paternal ageing on the incidence of very preterm births. RESULTS: Odds ratios increased with paternal age more rapidly for very preterm than for moderate preterm births; among 45- to 49-year-old fathers, odds ratios for very preterm births reached 1.91 (95% confidence interval = 1.08-3.38) and 1.72 (1.25-2.36), respectively, in 20- to 24- and 25- to 29-year-old mothers. CONCLUSIONS: This study confirms that paternal age contributes to the risk of preterm birth. The effect is stronger on very preterm births but also influences moderate preterm births.

PMID: 16477263 [PubMed - indexed for MEDLINE]

Paternal Age as a Risk Factor for Low Birthweight

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


Socioeconomic Factors

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.