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Genotoxic effects of estrogens in epithelial cells from the neonatal mouse uterine cervix: modifications by metabolic modifiers.

Epithelium from the neonatal mouse uterine cervix and uppermost part of vagina was cultured in vitro. The culture medium was supplemented with 17 beta-estradiol (E2; 10(-6)-10(-5) M) or diethylstilbestrol (DES; 10(-8)-10(-5) M) alone or in combination with different metabolic modifiers (alpha-naphthoflavone, beta-naphthoflavone, phenobarbital, metyrapone, indomethacin) with postulated activating or inhibitory effects on DES metabolizing enzymes (cytochrome P-448- and P-450-dependent microsomal monooxidases, prostaglandin cyclooxygenase). E2 at 10(-5) M and DES at 10(-6) and 10(-5) M concentrations increased the incidence of cells with a high number of sister chromatid exchanges (high-frequency chromatid exchange cells, HFCEC). Indomethacin partially depressed DES-induced HFCEC, whereas the incidence was increased by alpha-naphthoflavone, which may be a result of stimulation of the fetal type of P-448-dependent enzyme activity or of DES increasing the metabolic activation of alpha-naphthoflavone. Phenobarbital and beta-naphthoflavone did not affect the incidence of DES-induced HFCEC. Metyrapone alone induced the highest incidence of HFCEC observed in this study, and this effect was inactivated by phenobarbital and/or DES. The mechanisms behind these results are discussed. This study shows that E2 and DES have a genotoxic effect (sister chromatid exchanges) in vitro in epithelial cells from the same target organ as in which epithelial aberrations occur after in vivo estrogen treatment in the neonatal period. The difference in incidence of tetraploid cells between stroma and epithelium is stressed (less than 5% vs. 16-47% depending on experimental group).