Tumorigenic responses to lindane in mice: potentiation by a dominant mutation

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Abstract
Obese mottled yellow Avy/a, lean pseudoagouti Avy/a and lean black a/a (YS×VY) F-1 hybrid female mice were fed diet containing 160 p.p.m. lindane (γ-hexachlorocyclohexane) for 6, 12, 18 or 24 months. Clara cell hyperplasia was present in a majority of the mice after six months of lindane ingestion; however, more yellow mice (77%) than pseudoagouti (50%) or black (56%) mice had developed this lesion. Continued ingestion of lindane increased the incidence of Clara cell hyperplasia and resulted in similar prevalences in the three phenotypes. Lung tumors associated with lindane ingestion for 24 months were found only in yellow (19%) and pseudoagouti (14%) mice but not in the black mice. Prevalences of hepatocellular adenomas and carcinomas were very low (vy/a mice but not in the black a/a mice indicate, for the first time, that the Avy gene itself, in the absence of obesity, sensitizes cells to transformation. The greater prevalence of hepatocellular adenomas in obese yellow Avy/a than in lean pseudoagouti Avy/a mice implicates obesity-associated factors in tumor promotion. Similarly, the increased prevalence of hepatocellular carcinomas in untreated obese yellow Avy/a mice, as compared to lean pseudoagouti mice, implicates obesity-associated factors as favoring histiotypic progression of liver tumors. Thus, the Avy/a gene not only sensitizes cells to respond to tumorigenic stimuli but also, by the induction of obesity, enhances promotion and progression of transformed cells.