Estradiol Promotion of Size and Number of Hepatic Enzyme-Altered Foci in Rats in the Absence of Cell Proliferation
High-dose (95 μg/kg/day) 17β-estradiol (E2) administered as a promoter in a two-stage model of hepatocarcinogenesis significantly (p < 0.05) increases the number, size (mean volume and mean surface area) and volume density of enzyme-altered foci (EAF) larger than 0.003 mm2 in the livers of ovariectomized F344 rats when compared with diethylnitrosamine-initiated (150 mg/kg) controls. Changes observed at 9.5 μg E2/kg/day, which mimics serum E2 levels of intact animals, were limited to a qualitative increase in the number of EAF ≤ 0.003 mm2. At termination (days 39/40), the mean cumulative bromodeoxyuridine (BrdU) labeling indices for the E2-treated groups did not differ from the mean labeling index for initiated controls. E2’s failure to increase the cumulative BrdU-labeling index indicates that generalized hepatic growth stimulation (proliferation as measured by BrdU-labeling index) does not completely explain the increase in number and/or size of EAF observed. It is hypothesized that an alteration of the cell-cycle kinetics of initiated hepatic EAF may contribute to the promotion of hepatocarcinogenesis by E2.
KeywordsOral Contraceptive Relative Liver Weight Ethynyl Estradiol Hepatic Focus Hormonal Carcinogenesis
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