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PUBLIC HEALTH: ENVIRONMENTAL POLLUTION AND MALE FERTILITY

The following points are made by R.J. Aitken et al (Nature 2004 432:48):

1) During the past 50 years, the rapid expansion of the chemicals industry in both the developed and developing worlds has resulted in the release of a plethora of xenobiotics (molecules foreign to biological systems) into the environment[1,2]. These alien molecules have worked their way into our lives in a variety of forms, including pesticides, herbicides, cosmetics, preservatives, cleaning materials, municipal and private waste, pharmaceuticals, and industrial by-products. Awareness of the biological risks of chemical toxicity has increased considerably in recent years, but some of these chemicals have long half-lives and have been detected in environmental samples 10-20 years after they were banned for sale or use.

2) Analysis of the biological fallout from environmental pollution has generally centered on the risks for induction of certain kinds of cancer. But it is becoming increasingly apparent that another major target of this chemical barrage is the reproductive system, particularly in the male[2]. This was first recognized more than 30 years ago, when male workers exposed to 1,2-dibromo-3-chloropropane, an agricultural control agent used to kill nematodes, exhibited severe disruption of sperm development and infertility[3]. Since then, numerous independent studies[4] have associated occupational exposure to pesticides, herbicides, industrial agents and heavy metals with poor semen quality and impaired fertility. Although male reproduction can be affected by a variety of mechanisms that affect hormone balance and other metabolic systems, the disruption of germ-cell differentiation and sperm quality seems to involve two fundamentally different routes of exposure.

3) Xenobiotics and other environmental factors such as radiation can act directly on male germ cells within the mature testis. The highly effective proofreading and repair of DNA in the stem cells that produce sperm means that the male germ line has one of the lowest spontaneous mutation rates in the body[5]. But as these cells go through meiosis, the cell-division process that produces reproductive gametes, their capacity for DNA repair is reduced and their ability to respond to such damage by undergoing programmed cell death is progressively lost. Moreover, once they are released from the tissue that produces them, the germinal epithelium, male germ cells can no longer rely on the protection previously afforded by their nurse cells in the testes, the Sertoli cells.

4) Thus, as soon as sperm are released from the germinal epithelium, they are on their own. Bereft of the cytoplasm that houses protective enzymes such as catalase or superoxide dismutase in somatic (non-germ) cells, sperm are committed to a sojourn of about a week in the epididymis, the duct system in which they are remodelled in preparation for ejaculation. Subsequently, they must spend up to six days swimming around the female reproductive tract searching for an egg. During this long and perilous marathon, sperm are particularly vulnerable to DNA damage by a variety of environmental factors. All in all, the sperm is much more susceptible to damage than the egg because of its prolonged solitary existence and relative lack of protective, repair and self-destruct mechanisms.

5) The second route by which xenobiotics exert an influence on male reproduction is less direct, through exposure of women during pregnancy and subsequent disruption of reproductive tract development in male embryos. Such action is thought to affect both the germ cells and the somatic tissues of the male tract, and the consequences include a complex array of pathological changes collectively known as the "testicular dysgenesis syndrome", or TDS, in the offspring. The features of TDS include poor semen quality, hypospadias (defective development of the urinary tract), testicular cancer, and cryptorchidism (the failure of one or both testes to descend).

References (abridged):

1. Robaire, B. & Hales, B. F. Advances in Male Mediated Developmental Toxicity (Kluwer/Plenum, New York, 2003)

2. Klaassen, C. D. Casarett & Doull's Toxicology: The Basic Science of Poisons, 6th edn (McGraw-Hill, New York, 2001)

3. Whorton, D., Milby, T. H., Krauss, R. M. & Stubbs, H. A. J. Occup. Med. 21, 161-166 (1979)

4. Oliva, A., Spira, A. & Multigner, L. Hum. Reprod. 16, 1768-1776 (2001)

5. Hill, K. A. et al. Environ. Mol. Mutagen. 43, 110-120 (2004)

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

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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

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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

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