title: Gender-dependent differences in hepatic tumor promotion in diethylnitrosamine initiated infant B6C3F1 mice by alpha-hexachlorocyclohexane.
abstract: 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.
authors.affiliation: Department of Pathology, Medical College of Ohio, Toledo.
authors.forename: J C
authors.initials: JC
authors.lastname: Siglin
authors.forename: C M
authors.initials: CM
authors.lastname: Weghorst
authors.forename: D E
authors.initials: DE
authors.lastname: Rodwell
authors.forename: J E
authors.initials: JE
authors.lastname: Klaunig
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002273:Carcinogens / Q000633:toxicity*; D004273:DNA, Neoplasm / Q000096:biosynthesis; D004052:Diethylnitrosamine / Q000633:toxicity*; D004347:Drug Interactions; D005260:Female; D001556:Hexachlorocyclohexane / Q000633:toxicity*; D007274:Injections, Intraperitoneal; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D009929:Organ Size / Q000187:drug effects; D012737:Sex Factors
chemical_list: D002273:Carcinogens; D004273:DNA, Neoplasm; C040534:alpha-hexachlorocyclohexane; D004052:Diethylnitrosamine; D001556:Hexachlorocyclohexane