Studies have continued to determine the molecular forms and cellular targets of estrogenic chemicals and establish the mechanisms by which interactions of estrogens with developing genital tract target cells result in permanently altered differentiation, including dysmorphology and neoplasia. In the period covered by the report, experiments in vitro with the fetal anlage of reproductive tract tissues from mice, the Mullerian duct, have demonstrated that the fetal tract is imprinted by DES at the molecular level and becomes unresponsive to its normal tissue effector, Mullerian Inhibiting Factor. As a consequence, offspring of both sexes retain genital structures associated with the opposite sex (Mullerian retention in males was associated with epididymal cysts and mesonephric retention in females was associated with paraovarian cysts). An embryologically derived lesion in the male offspring of DES treated pregnancies was detected in the rete testis; lesions resembling rete testis carcinoma (a rare lesion in experimental animals or men) was seen in 5 percent of these treated mice. Furthermore, the response of the uterine epithelium to estrogen at puberty was altered by prenatal DES treatment. The alteration was determined at the molecular and morphological levels. Studies on the target-organ metabolism of DES have revealed uterine specific metabolites both in vitro and in vivo. Furthermore, one pathway in the metabolism of DES and other estrogens occurs via a peroxidase (prostaglandin synthetase) and results, in certain cases, in formation of free radicals and quinones. To study estrogen-induced differentiation defects in detail, serum-free cultures of genital tract epithelial cells have been established.
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