Environmental antiandrogens: developmental effects, molecular mechanisms, and clinical implications.
Industrial chemicals and environmental pollutants can disrupt reproductive development in wildlife and humans by mimicking or inhibiting the action of the gonadal steroid hormones, estradiol and testosterone. The toxicity of these so-called environmental endocrine disruptors is especially insidious during sex differentiation and development due to the crucial role of gonadal steroid hormones in regulating these processes. This review describes the mechanism of toxicity and clinical implications of a new class of environmental chemicals that inhibit androgen-mediated sex development. For several of these chemicals, including the agricultural fungicide vinclozolin and the ubiquitous and persistent 1,1,1-trichloro-2,2-bis (p-chlorophenyl)ethane metabolite, 1,1-dichloro-2,2-bis(p-chlorophenyl) ethylene, the molecular mechanism of action and the adverse developmental effects on male sex differentiation have been elucidated and are used as examples. Environmental chemicals with antiandrogenic activity offer profound implications with regard to recent clinical observations that suggest an increasing incidence of human male genital tract malformations, male infertility, and female breast cancer. Finally, in light of increasing concern over the potential endocrine disrupting effects of environmental pollutants, an in vitro/in vivo investigational strategy is presented which has proved useful in identifying chemicals with antiandrogen activity and their mechanism of action.
Kelce
W R
WR
Reproductive Toxicology Division, United States Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA.
Wilson
E M
EM
D000726:Androgen Antagonists / Q000633:toxicity*; D059002:Androgen Receptor Antagonists; D000728:Androgens; D003633:Dichlorodiphenyl Dichloroethylene / Q000633:toxicity; D004785:Environmental Pollutants / Q000633:toxicity*; D005786:Gene Expression Regulation; D006801:Humans; D007021:Hypospadias / Q000209:etiology; D008297:Male; D010080:Oxazoles / Q000633:toxicity; D010936:Plant Extracts / Q000633:toxicity; D028024:Serenoa; D012733:Sex Differentiation / Q000187:drug effects*
D000726:Androgen Antagonists; D059002:Androgen Receptor Antagonists; D000728:Androgens; D004785:Environmental Pollutants; D010080:Oxazoles; D010936:Plant Extracts; D003633:Dichlorodiphenyl Dichloroethylene; C040972:saw palmetto extract; C025643:vinclozolin