Maybe the public will believe Scientific American on the Genetic Male Biological Clock?

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.

Why DOESN'T the public know that Autism and Schizophrenia Are Found More Often in Offspring of Older Fathers?

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.




: Schizophr Bull. 2001;27(3):379-93. Links
Paternal factors and schizophrenia risk: de novo mutations and imprinting.Malaspina D.
Columbia University Department of Psychiatry, New York State Psychiatric Institute, NY 10032, USA. dm9@Columbia.edu
There is a strong genetic component for schizophrenia risk, but it is unclear how the illness is maintained in the population given the significantly reduced fertility of those with the disorder. One possibility is that new mutations occur in schizophrenia vulnerability genes. If so, then those with schizophrenia may have older fathers, because advancing paternal age is the major source of new mutations in humans. This review describes several neurodevelopmental disorders that have been associated with de novo mutations in the paternal germ line and reviews data linking increased schizophrenia risk with older fathers. Several genetic mechanisms that could explain this association are proposed, including paternal germ line mutations, trinucleotide repeat expansions, and alterations in genetic imprinting in one or several genes involved in neurodevelopment. Animal models may be useful in exploring these and other explanations for the paternal age effect and they may provide a novel approach for gene identification. Finally, it is proposed that environmental exposures of the father, as well as those of the mother and developing fetus, may be relevant to the etiology of schizophrenia.

Cook Calls Archuleta's Dad 'Caring'

Cook Calls Archuleta's Dad 'Caring'
PEOPLE
Posted: 2008-06-23 18:01:52
Filed Under: American Idol, Music News, TV News
(June 23) - Jeff Archuleta may have gotten a bad rep for micromanaging his son, American Idol runner-up David Archuleta, but Idol winner David Cook doesn't see it that way.

"I've never seen Jeff be anything but a caring, loving father, so for me it’s much ado about nothing," Cook, 25, told PEOPLE on Saturday.

In fact, Cook looks forward to David’s dad joining them on the bus for this summer’s American Idols Live! tour that kicks off July 1 in Glendale, Ariz., and runs to Sept. 13. Cook says he will be working on a record at the same time as the tour “So I've got a busy summer,” he says.

MEDICAL BIOLOGY: AGE OF FATHERS AND SPERM DEFECTS

MEDICAL BIOLOGY: AGE OF FATHERS AND SPERM DEFECTS

The following points are made by Paul D. Thacker (J. Am. Med. Assoc. 2004 291:1683):

1) Women approaching middle age have long been aware that the consequences of a ticking biological clock include not only decreased fertility but also a sharp increase in the odds of delivering a child with Down syndrome. Older men, seemingly untouched by such biological constraints, felt free to father children as they entered middle, and even old, age.

2) But now it is becoming increasingly clear that the biological clock ticks for men as well as women, as researchers turn up evidence that as would-be fathers get older, they have an increased chance of passing on genetic defects to their children. New point mutations in humans are introduced through the male line, and the number of mutations in sperm increases as men age. This has been known since the 1950s. What is intriguing is why society chooses to ignore this.

3) Nevertheless, society is starting to pay attention. With many couples now deferring childbearing until they are older, the issue of paternal age and increased risk for birth defects is gaining a higher profile. It is also possible, according to some experts, that if current trends of older fatherhood continue, it could someday become a public health problem as well as a personal one.

4) According to the latest birth statistics released in December 2003 by the Centers for Disease Control and Prevention (CDC), the average age of motherhood is at an all-time high of 25.1 years compared with 21.4 years in 1971. Although some of this increase can be explained by the drop in teen births, another reason was an increase in older women having children. Women in two age groups -- 35 to 39 years and 40 to 45 years -- now have children at the highest levels in 3 decades. Statisticians find that women tend to marry men of similar ages, so it can be surmised that the ages of fathers have also increased.

5) While news reports on the CDC figures by various news outlets have mentioned the link between increased female age and disease risk to infants, none have reported the vulnerabilities posed by aging fathers that researchers have turned up in recent years, such as the association between increased paternal age and genetic diseases such as Apert syndrome (a disorder characterized by craniofacial and limb abnormalities) and achondroplasia (a skeletal disorder that causes dwarfism). Furthermore, studies show that 2% of children born to men 50 years or older will have schizophrenia, three times the incidence of schizophrenia in offspring born to fathers in their early 20s.

J. Am. Med. Assoc. http://www.jama.com

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

Related Material:

ON THE VULNERABILITY OF THE HUMAN SPERMATOZOON

The following points are made by J. Aitken and J.A. Graves (Nature 2002 415:963):

1) The impact of environmental toxicants and the innate inadequacy of human spermatozoa are compounded by the advent of effective contraception and the introduction of assisted-conception technologies. This lifting of the selection pressure on fertility means that those endowed with genes for high fecundity have lost their advantage over those without. As a result, future generations are bound to experience a further decline in semen quality and, ultimately, human fertility.

2) The authors consider the mechanisms responsible for the poor fertilizing potential and genetic damage shown by human spermatozoa. Two main causes of germ-cell dysfunction have recently been discovered: gene deletions on the long arm of the male sex-determining Y chromosome, and oxidative stress. The authors suggest these etiologies may be associated. The Y chromosome is particularly vulnerable to gene deletions because it is not a matching partner for the X chromosome, so it cannot retrieve lost genetic information by homologous recombination. Over the past 300 million years, the mammalian Y chromosome has been reduced from a pairing partner to the X chromosome to a shadow of its former self, rescued only by a large addition from a non-sex-determining chromosome in "placental" mammals. Many of the remaining genes have acquired functions essential for sex determination and spermatogenesis.

3) The original Y chromosome contained approximately 1500 genes, but during the ensuing 300 million years all but about 50 were inactivated or lost. Overall, this gives an inactivation rate of five genes per million years. The presence of many genes that have lost their function (pseudogenes) on the Y chromosome indicates that this process of attrition is continuing, so that even these key genes will be lost. At the present rate of decay, the Y chromosome will self-destruct in approximately 10 million years. This has already occurred in the mole vole, in which the Y chromosome (together with all of its genes) has been completely lost from the genome.

References (abridged):

1. Aitken, R. J. J. Reprod. Fertil. 115, 1 7 (1999).

2. Marshall Graves, J. A. Biol. Reprod. 63, 667 676 (2000).

3. Just, W. et al. Nature Genet. 11, 117 118 (1995).

4. Kuroda-Kawaguchi, T. et al. Nature Genet. 29, 279 286 (2001).

5. Kamp, C. et al. Mol. Hum. Reprod. 7, 987 994 (2001).

Nature http://www.nature.com/nature

ScienceWeek http://scienceweek.com

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.

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
Sections: ChooseINTRODUCTIONThe male factorParental ageEnvironmental pollutionErrors of endogenous meta...Electromagnetic radiation...Epigenetic damageIs ART a dangerous form o...References





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

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.


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

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.



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

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.



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

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]
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• 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]
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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]
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• Review of potential environmental impacts on DNA damage in the germ line.

[CrossRef] [Medline]
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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]
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•• Important recent paper clearly demonstrating the impact that air pollution has on the epigenetic programming and integrity of sperm DNA.

[CrossRef] [Medline]
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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]
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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.

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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

As humans become more dependent on reproductive technologies, an Australian reproductive biologist says we must remain vigilant to avoid the spread of

genetic defects.

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.

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

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

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.

Child death rate autism rate schizophrenia rate cancer rate higher with older dads

Child death rate higher with older dads
Published: June 2, 2008 at 5:15 PM
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AARHUS, Denmark, June 2 (UPI) -- Danish researchers say they found a higher mortality in children of fathers age 45 years or older that lasted until the children were age 18. Liang Zhu of The Danish Epidemiology Science Center, University of Aarhus, in Denmark, says the findings add to the accumulating evidence on adverse effects of advanced paternal age in procreation.Using data from Danish Fertility Database from 1980 to 1996, the researchers identified 102,879 couples and their firstborn children. Information on childhood death was obtained by linking the data to to the nationwide register on cause of deathThe study, published in the European Journal of Epidemiology, found that the researchers observed a U-shaped association between paternal age and the overall mortality rate in children up to 18 years of age. Compared with children of fathers ages 25 and 29 years, the adjusted mortality rate ratio was double with fathers over the age of 45. The children's mortality was highest for congenital malformations and injury. The study also found higher death rates higher among children of the youngest fathers, below the age of 19, however, these differences were explained by the risks of teen motherhood, poorer diet and lifestyle.
© 2008 United Press International. All Rights Reserved.This material may not be reproduced, redistributed, or manipulated in any form

Advanced paternal age and risk of fetal death: a cohort study

1: Am J Epidemiol. 2004 Dec 15;160(12):1214-22. Links
Advanced paternal age and risk of fetal death: a cohort study.Nybo Andersen AM, Hansen KD, Andersen PK, Davey Smith G.
Department of Social Medicine, University of Copenhagen, Copenhagen, Denmark. ana@niph.dk

A possible detrimental paternal age effect on offspring health due to mutations of paternal origin should be reflected in an association between paternal age and fetal loss. The authors used data from a prospective study of 23,821 pregnant women recruited consecutively to the Danish National Birth Cohort from 1997 to 1999 to assess the association between paternal age and fetal death. Fathers of the pregnancies were identified by record linkage to population registers. The paternal age-related risks of fetal death and its components, early and late fetal loss, were estimated using survival analysis. Pregnancies fathered by a man aged 50 or more years (n = 124) had almost twice the risk of ending in a fetal loss compared with pregnancies with younger fathers (hazard ratio = 1.88, 95% confidence interval: 0.93, 3.82), after adjustment for maternal age, reproductive history, and maternal lifestyle during pregnancy. Various approaches to adjustment for potential residual confounding of the relation by maternal age did not affect the relative risk estimates. The paternal age-related risk of late fetal death was higher than the risk of early fetal death and started to increase from the age of 45 years. It should, however, be interpreted cautiously because of the restricted number of fetal deaths.