ARE ESTROGENS CARCINOGENIC DURING DEVELOPMENT OF THE TESTES

Many chemicals in the environment mimic the female sex hormone, estrog en. Exposure to environmental estrogens during early fetal development was proposed by Sharpe & Skakkebaek as a potential risk factor for su bsequent testicular disease, including neoplasia and poor semen qualit y. To understand the mechanisms of action of estrogenic chemicals duri ng differentiation of the male genital tract. we have studied developm ental exposure to the synthetic estrogen, diethylstilboestrol (DES). W hile DES is a much more potent estrogen than most environmental chemic als examined, several of these compounds share some of the same proper ties as DES? such as a relative lack of binding to serum estrogen carr ying proteins. Prenatal exposure to DES is associated with poor semen quality, prostatic disease, cryptorchidism and testicular neoplasia in mice. A rare form of testicular cancer, rete testis carcinoma, was ob served in five percent of male mice treated in utero, with DES. We als o demonstrated altered regulation of an estrogen responsive gene, lact otransferrin (LTF) in the seminal vesicles of treated mice, but not th e controls. Likewise, LTF was irreversibly altered in the uteri of dev elopmentally treated females; at the molecular level altered methylati on of the gene appears to be involved, thus, providing a potential mar ker for hormonal effects during development. The induction of permanen t or ''imprinted'' responses during the development of a relatively es trogen-free reproductive tract cell suggests that undifferentiated tar gets for estrogen action may be sites for subsequent growth and differ entiation defects associated with neoplasia.