GENDER-DEPENDENT DIFFERENCES IN HEPATIC TUMOR PROMOTION IN DIETHYLNITROSAMINE-INITIATED INFANT B6C3F(1) MICE BY ALPHA-HEXACHLOROCYCLOHEXANE

Chronic exposure of B6C3F1 mice to phenobarbital (PB), subsequent to a single initiating dose of diethylnitrosamine (DENA) at 15 d of age, h as been previously shown to inhibit hepatic tumorigenesis in male mice , while promoting hepatic tumor formation in female mice (Weghorst and 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-HC H in the diet (250 ppm) or untreated basal diet. Like PB, alpha-HCH in hibited hepatic tumorigenesis in male mice, while promoting hepatic tu mor formation in female mice following chronic exposure. In an additio nal experiment, already formed preneoplastic hepatic loci in male and female B6C3F1 mice were examined for their responsiveness to the induc tion of DNA synthesis by alpha-HCH treatment. The mice received a sing le ip injection of DENA at 15 d of age to induce hepatocellular loci. Beginning at 24 wk of age, mice received either basal diet or diet con taining 250 ppm alpha-HCH for 7 consecutive d. DNA synthesis was asses sed by continuous [H-3]thymidine infusion via subcutaneously implanted osmotic minipumps. In female mice treated with alpha-HCH, DNA synthes is in hepatocellular foci was increased substantially compared to untr eated females. In contrast, male mice receiving alpha-HCH showed no in crease in DNA synthesis in hepatocellular foci from that seen in non-a lpha-HCH-treated males. Based on these results, we postulate that the gender-dependent differences in hepatic tumorigenesis observed in B6C3 F1 mice initiated during infancy may be related to chemical tumor prom oter modulation of the normal hormonal environment, or to differences in the ability of hepatocellular loci to respond to the induction of D NA synthesis by the tumor promoter.