From malformations to molecular mechanisms in the male: three decades of research on endocrine disrupters

For three decades, we have known that estrogens alter the development of th e mammalian reproductive system in predictable ways. In mice exposed prenat ally to diethylstilbestrol (DES) or other estrogens, the male offspring exh ibit structural malformations including cryptorchidism, epididymal cysts an d retained Mullerian ducts. The estrogen-associated alterations in the geni tal tract phenotype can be usefully considered as a model called Developmen tal Estrogenization Syndrome. While estrogen treatment during critical peri ods of morphogenesis of the male reproductive system has been associated wi th these changes, the mechanisms at the molecular level are still being dis covered. Parallel findings on the hormones involved in Mullerian duct regre ssion and testicular descent have helped guide research on the mechanisms o f developmental estrogenization of the male. Cellular localization of molec ular signals associated with key steps in genital tract development, use of mice with gene disruption, and knowledge of the mechanisms underlying pers istent changes in gene expression are beginning to provide a blue print for both the physiological role and pathological effects of estrogens in repro ductive tract development. Since many of the same biological principles und erlie genital tract morphogenesis in mammals, one may expect some of the sa me changes in males of other species exposed to estrogen during the appropr iate developmental periods.