On environmental threats to male infertility.

The possibility that environmental pollutants damage human fertility is a topic of both public concern and scientific interest. The effect of environmental factors on male fertility (semen parameters) has been a special focus, stimulated in part by the dramatic damage inflicted by the pesticide DBCP on testicular function. Extensive searches for testicular toxicants (in particular, the proposed effects of endocrine-disrupting compounds through fetal exposure) have produced little hard evidence of impairment in humans. This scarcity of evidence may reflect the difficulties of studying human fertility. Future fertility studies should consider the wide spectrum of environmental exposures that plausibly affect reproduction. The idea that human fertility might be damaged by environmental contaminants has captured the imagination of such eminent writers as PD James (The Children of Men) and Margaret Atwood (A Handmaid’s Tale). These novelists provide stark and dystopian visions of societies coping with fertility decline. It is no wonder that the scientific question of environmental damage to human fertility continues to attract public attention—even as the question itself remains stubbornly difficult to address. It was the late 1970s when environmental toxicants first became widely recognized as a threat to human fertility. Industrial and agricultural workers who were exposed to the pesticide dibromo-chloropropane (DBCP) were discovered to be azoospermic. This evidence of testicular damage, supported by toxicological research in rodents, led to swift scientific consensus that DBCP was a human reproductive toxicant. DBCP production was suspended. This discovery raised a further question: was DBCP a special case, or is testicular function broadly sensitive to industrial pollutants? The question prompted a wave of studies in the United States and Europe to explore diverse chemical exposures for possible testicular toxicity. These studies were largely negative, or with subtle findings that were seldom corroborated (for reviews, see Refs. 4–6). As a workplace exposure, DBCP appears to be atypical in its strong testicular effects, rather than the tip of an iceberg. Scientific attention to testis toxicology faded, only to be revived in 1992 by publication of a review of sperm-quality data by Carlsen and colleagues. Their summary of semen analyses across six decades suggested a disturbing decline of human sperm count. Limitations of these retrospective data prompted vigorous criticism of the paper and the paper might have had less impact were it not for a provocative hypothesis that emerged to explain it— the ‘estrogen hypothesis’. Toxicological research had already shown that many environmental chemicals are weakly estrogenic. The estrogen hypothesis proposed that environmental estrogens might be able to reduce the number of Sertoli cells in the male fetus through negative feedback of pituitary FSH secretion, thus impairing subsequent fertility. In pursuing this hypothesis, researchers found that the direct estrogenic activity of environmental contaminants is generally too weak to damage human fetal testicular development. Nonetheless, there is ample evidence that various environmental chemicals at extremely low levels (and perhaps in concert with one another) might interfere with hormone signalling, especially during critical phases of fetal and childhood development. While the estrogen hypothesis faded, the more general hypothesis of ‘endocrine disruption’ has emerged as highly influential in environmental toxicology and epidemiology. Since the mid-1990s, nearly 4000 scientific papers have been published on aspects of environmental endocrine disruptors and their possible consequences for a broad spectrum of health effects. The specific relevance of endocrine-disrupting compounds to male fertility in humans, however, remains to be established. Damage by endocrine disruptors to the male reproductive tract of laboratory animals is difficult to extrapolate to humans, given species-specific differences in key biological mechanisms. The assessment of fertility in men presents its own problems, and findings have been mixed. For example, studies of persistent environmental pollutants and impaired testicular function in humans have been mostly negative, but this does not rule out possible effects from exposures earlier in development. One observational study (from Seveso, Italy) has been able to examine sperm counts in relation to direct measures of early-life exposure to an endocrine disruptor. Sperm counts were lower in the sons of mothers who had been exposed to dioxin and who breastfed their sons. These findings are of great interest, but with no opportunities for replication. The fact that such studies have proven so difficult points to the complexity of the biology—but perhaps also to the elusiveness of the effect being sought. Can so elusive an effect have important public health consequences? At present, there is no scientific consensus. The endocrine disruption hypothesis has been extended to male reproductive end points beyond fertility. Exposures to endocrine disruptors in fetal life have been proposed to affect a range of male reproductive disorders including testicular cancer, cryptorchidism and hypospadias. There are tantalizing clues in support of this hypothesis: testicular cancer is one of the few types of cancer to have increased over the past 50 years, and factors operating in utero have been linked to lower sperm concentration and cryptorchidisminhumans. Thepossibility of a generalized ‘testicular dysgenesis syndrome’ has been supported by some experimental work ifnot all. Even so, epidemiologic data do notsupport the presence of sharedendocrineEpidemiology Branch, National Institute of Environmental Health Sciences, Durham, NC 27709-2233, USA and Department of Occupational and Environmental Medicine, University Hospital of Copenhagen, Copenhagen, NV DK-2400, Denmark Correspondence: Dr AJ Wilcox ([email protected]) Received: 30 November 2012; Accepted: 30 November 2012; Published online: 21 January 2013 Asian Journal of Andrology (2013) 15, 199–20