The objectives of this project are 1) to establish a model for transplacental carcinogenesis in the rat using diethylstilbestrol (DES) with comparisons to natural estrogens, and 2) to identify the mechanisms for this chemically induced carcinogenesis due to prenatal exposure. In the prenatally exposed DES Wistar rat population (0.1 to 50 mg/kg), 38% of the female progeny (120) and 74% of the male progeny (157) have demonstrated teratogenic, dysplastic, metaplastic, or neoplastic lesions. A 9-10% incidence of non-neoplastic lesions were observed in our control population (116). A dose-effect relationship was noted in the progeny when the diethylstilbestrol was administered on days 18-19-20 of gestation. Metabolism of DES by fetal rat tissues utilizing in vitro as well as in vivo technics has been demonstrated. Besides oxidative and glucuronide metabolites, 4-10% (depending upon the particular tissue studied) of the total tissue radioactivity originally associated with 14C-DES is covalently bound to cellular components. Under in vitro conditions, oxygen is required for this covalent binding of DES/metabolites and trichloropropene oxide (an inhibitor of epoxide hydrase and glutathione) increased the covalent binding. Metyrapone did not substantially decrease this binding while 4 degrees C incubation markedly inhibited binding. Thus, metabolism of DES to reactive intermediates, e.g., epoxides, quinones, are critical for this covalent binding in tissue sections both in the fetus and mother. Modification of the terato/tumorgenicity utilizing these biochemical observations are in progress.
NIH ExPorter
NIH ExPorter