Hepatocarcinogenesis in BXH recombinant inbred strains of mice: analysis of diverse phenotypic effects of the hepatocarcinogen sensitivity loci.

The hepatocarcinogen sensitivity (Hcs) loci were originally identified as determinants of the approximately 50-fold higher susceptibility of male C3H/HeJ (C3H) mice to perinatally induced hepatocarcinogenesis relative to male C57BL/6J (B6) mice. These two inbred strains also differ in other phenotypes related to hepatocarcinogenesis, including their incidences of spontaneous liver tumors and the properties of neoplastic hepatic lesions. To test the hypothesis that the Hcs loci also influence these phenotypes, we characterized male mice from B6, C3H, and nine BXH recombinant inbred (RI) strains for spontaneous liver tumor development, the frequency of activating mutations in tumors, and the presence of cytoplasmic inclusions in preneoplastic lesions. By comparing these results to the relative susceptibilities of the parental and RI strains to N,N-diethylnitrosamine (DEN)- and N-ethyl-N-nitrosourea- induced hepatocarcinogenesis in preweanling male mice, we concluded that the C3H alleles of the Hcs loci also positively influence the spontaneous development of liver tumors in male animals. While strain-dependent differences in the frequency of Ha-ras-1 activation in DEN-initiated liver tumors were observed, this phenotype was not correlated with susceptibility to liver tumor induction. The formation of eosinophilic intracytoplasmic inclusion bodies observed specifically in B6 liver tumors, which has been suggested to be associated with the resistance of this strain to hepatocarcinogenesis, also segregated independently of the Hcs loci.