Rapid growth of preneoplastic lesions in hepatocarcinogen-sensitive C3H/HeJ male mice relative to C57BL/6J male mice

We have previously shown that C3H/HeJ male mice are ~ 20-fold more susceptible to the induction of liver tumors by iV-ethyl-A/-nitrosourea (ENU) than are C57BL/6J male mice and that this difference in sensitivity is largely deter-mined by a single genetic locus (Hcs, hepatocarcinogen sensi-tivity). In order to determine whether the Hcs locus affects initiation or promotion of hepatocarcinogenesis, we studied the development of putatively preneoplastic hepatic lesions that are deficient in glucose-6-phosphatase (G6Pase) in mice treated at 12 days of age with ENU. In ENU-treated male mice of both strains, the number and size of G6Pase-defkient hepatic foci increased over time between 12 and 24 weeks of age. However, the rate of growth of the lesions was 1.7 times faster for C3H/HeJ male mice (volume doubling time 2.0 ± 0.1 weeks) than for C57BL/6J mice (3.4 ± 0.4 weeks). Although the number and size of G6Pase-deficient foci in-duced by ENU treatment of female C3H/HeJ and C57BL/6J mice were smaller than for foci in similarly treated male mice, there was no significant difference between the growth rates of the foci in female C3H/HeJ and C57BL/6J mice. Thus, the phenotypic effect of the Hcs locus appears to be depen-dent on promotion of liver tumor induction by the male hor-monal environment. In agreement with studies on the growth rate of the foci in male mice, the [3H]thymidine labeling index of G6Pase-deficient hepatocytes in C3H/HeJ males (12%) was 1.5-fold higher than in C57BL/6J male mice (8.0%) at 20 weeks and 1.2-fold higher at 28 weeks (11 % versus 9.5%). The labeling index of histochemically normal hepato-cytes in C3H/HeJ male mice (0.38%) was 2.6-fold higher than in C57BL/6J mice (0.15%) The Hcs locus may affect the pro-motion phase of hepatocarcinogenesis in male mice by increas-ing the proliferative rate of both normal and preneoplastic hepatocytes