Chronic exposure of B6C3F1 mice to
phenobarbital (PB), subsequent to a single initiating dose of
diethylnitrosamine (DENA) at 15 d of age, has been previously shown to inhibit hepatic
tumorigenesis in male mice, while promoting hepatic
tumor formation in female mice (Weghorst & Klaunig, 1989). In the present study, the effects of another hepatic
tumor promoter,
alpha-hexachlorocyclohexane (
alpha-HCH), in similarly initiated B6C3F1 mice was investigated. Male and female mice received a single intraperitoneal (ip) injection of either DENA or saline at 15 d of age. Beginning at 28 d of age, the mice received either
alpha-HCH in the diet (250 ppm) or untreated basal diet. Like PB,
alpha-HCH inhibited hepatic
tumorigenesis in male mice, while promoting hepatic
tumor formation in female mice following chronic exposure. In an additional experiment, already formed preneoplastic hepatic foci in male and female B6C3F1 mice were examined for their responsiveness to the induction of
DNA synthesis by
alpha-HCH treatment. The mice received a single ip injection of DENA at 15 d of age to induce hepatocellular foci. Beginning at 24 wk of age, mice received either basal diet or diet containing 250 ppm
alpha-HCH for 7 consecutive d.
DNA synthesis was assessed by continuous [3H]
thymidine infusion via subcutaneously implanted osmotic minipumps. In female mice treated with
alpha-HCH,
DNA synthesis in hepatocellular foci was increased substantially compared to untreated females. In contrast, male mice receiving
alpha-HCH showed no increase in
DNA synthesis in hepatocellular foci from that seen in non-
alpha-HCH-treated males. Based on these results, we postulate that the gender-dependent differences in hepatic
tumorigenesis observed in B6C3F1 mice initiated during infancy may be related to chemical
tumor promoter modulation of the normal hormonal environment, or to differences in the ability of hepatocellular foci to respond to the induction of
DNA synthesis by the
tumor promoter.