The disruption of the reproductive system of male and female animals in the wild has been attributed to environmental chemicals (xenobiotics). The effects seen mirror alterations one might anticipate if the steroid hormone-dependent processes that regulate these systems were impaired. To determine whether xenobiotics (present at a concentration of 100 microM) exert their action through steroid-mediated pathways, we examined their ability to inhibit the binding of [3H]physiological ligands (present at a concentration of 7 nM) to the androgen and estrogen receptors, rat androgen-binding protein (ABP), and human sex hormone-binding globulin (hSHBG). The gamma- and delta-isomers of hexachlorocyclohexane, congeners of dichlorodiphenyl-trichloroethane (DDT; p,p'-DDT; p,p'-DDE; o,p'-DDT), dieldrin, atrazine, and pentachlorophenol, caused a statistically significant inhibition of specific binding of [3H]5 alpha-DHT to the androgen receptor that ranged from 100% (p,p'-DDE) to 25% (dieldrin). Methoxychlor, o,p'-DDT1, pentachlorophenol, and nonylphenol significantly reduced [3H]17 beta-estradiol binding to the estrogen receptor by 10, 60, 20, and 75%, respectively. The binding of [3H]5 alpha-DHT to ABP was inhibited 70% by the delta-isomer of hexachlorocyclohexane, but the gamma-isomer did not reduce binding significantly. Methoxychlor, p,p'-DDT, atrazine, and nonylphenol reduced [3H]5 alpha-DHT binding to ABP by approximately 40%. Nonylphenol reduced the binding of [3H]5 alpha-DHT to hSHBG by 70%. Hexachlorocyclohexane reduced [3H]5 alpha-DHT binding to hSHBG by 20%, but the stereospecific effects observed with ABP did not occur. o,p'-DDT and pentachlorophenol resulted in a statistically significant 20% inhibition of [3H]5 alpha-DHT binding to hSHBG. Some xenobiotics resulted in dissociation of [3H]ligands from their binding proteins that was statistically identical to that caused by the unlabeled natural ligand, whereas others resulted in slower or more rapid dissociation rates.Imagesp294-aFigure 1.Figure 2.Figure 3.Figure 4. AFigure 4. BFigure 5.Figure 6.Figure 7.Figure 8.

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Considerable attention has been given in the past few years to the possibility that man-made chemicals (xenobiotics) in the environment may pose a hazard to human reproductive health. The endocrine-disrupting effects of many xenobiotics can be interpreted as interference with the normal regulation of reproductive processes by steroid hormones. Evidence reviewed here indicates that xenobiotics bind to androgen and oestrogen receptors in target tissues, and to androgen-binding protein and to sex hormone-binding globulin. Although environmental chemicals have weak hormonal activity, their ability to interact with more than one steroid-sensitive pathway provides a mechanism by which their hazardous nature can be augmented. A given toxicant may be present in low concentration in the environment and, therefore, harmless. However, we are not exposed to one toxicant at a time, but, rather, to all of the xenobiotics present in the environment. Therefore, numerous potential agonists/antagonists working together through several steroid-dependent signalling pathways could prove to be hazardous to human reproductive health.

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