Lindane (gamma-hexachlorocyclohexane) has been shown to produce hepatomas in some strains of mice but not in others. Genetic factors and/or altered metabolism may play a role in the susceptibility to lindane-induced hepatomas. This study reports the effect of age and obesity on the comparative metabolism and disposition of lindane in obese yellow Avy/a and in lean pseudoagouti Avy/a and black a/a phenotypes of (YS x VY) F1 hybrid female mice at 8, 17, 30, 56, and 86 wk of age. At 24 h prior to sacrifice the mice were dosed p.o. with 18 mg lindane (containing 55 microCi [U-14C]lindane/kg). Aging altered the biotransformation of lindane such that while the excretion of lindane and its metabolites declined, the proportion of conjugated and polar metabolites increased. Tissue storage was elevated in older animals. In the yellow Avy/a mice, which are known to have a predisposition to the formation of hepatomas, there was accelerated and prolonged growth, reduced metabolite excretion, a greater proportion of conjugated metabolites, and higher dechlorinase activity compared to that of their pseudoagouti Avy/a and black a/a siblings.

Five different dose levels of 2-acetylaminofluorene (2-AAF) were fed to weanling mice of 4 different genotypes from three unrelated F1 hybrids for 13 wk to determine differences in susceptibility to induction of bladder hyperplasia. Differences in the prevalence of hyperplasia per se and in the average grade of hyperplasia were interpreted as indicating greater susceptibility. On this basis, males of all genotypes were more susceptible than females. Among the genotypes, (AEX YS)F1 mice (AY) were most susceptible, followed closely by yellow A vy/A(BALB/cXVY)F1 mice (CV). Agouti A/a(BALB/cXVY)F1 mice were less susceptible than their yellow siblings and similar to the (C57BL/6XC3H)F1 mice. Neither body weight gain nor any of the biochemical parameters measured appeared to be affected at any dose level of 2-AAF. However, quantitative differences in several biochemical characteristics were detected among the genotypes. Serum gamma-glutamyl transpeptidase activity was higher in the AY mice than in the other hybrids. Among the CV mice, the yellow animals had lower glutathione S-transferase (GST) activity than their agouti siblings. Hepatic GST activity was lower in CV mice than in either of the other hybrids. Hepatic cytochrome P-450 and bs activities were similar in all hybrids.

To assist in defining the mechanism(s) by which the activity of hepatic glutathione S-transferase (GST) is decreased in obese rodents, the cytosolic concentrations of individual GST isozymes were determined by high-performance liquid chromatography. For this purpose, liver cytosols from 8- and 16-week-old obese yellow Avy/a and lean black a/a male and female mice of the inbred VY/WffC3Hf/Nctr-Avy strain were assayed. Obese yellow males contained less hepatic GT-9.0 than lean black males; however, there were no differences between the obese and lean females. GT-9.0 concentration, which is induced by testosterone, was several-fold higher in males than in females, regardless of genotype or body weight. No differences in concentrations of other isozymes were detected. Hepatic GST activity towards 1-chloro-2,4-dinitrobenzene was significantly higher in lean males than in obese males; however, there were no differences between obese and lean females. Lean males had higher activity than lean females; but obese males and females had similar enzyme activities. These changes in enzyme activity can be accounted for by the changes in GT-9.0 concentration measured by HPLC. Lung and testes cytosols were also assayed for GST isozyme concentrations. No differences in any isozyme concentration were found between the sexes or the genotypes in the lung or between genotypes in the testes.

Genetic and hormonal factors and their interaction in the regulation of serum insulin level in mice have been examined. The inbred YS/ChWf and VY /Wf strains each segregate into two genotypes which düfer in their mean serum insulin level. YS/ChWf produces yellow AY/a and non-yellowa/a offspring; VY /Wf produces yellow A vy /a and non-yellow a/a young. Serum insulin levels in yellow YS males are lower than in their a/a brothers. However, in yellow VY males, these levels are higher than in a/a VY males. Response of serum insulin concentration to growth of an allogeneic tumor also differs between the two strains. Levels are increased in both VY genotypes while there is no change in the yellow YS mice and a decrease in the non-yellow YS mice. Castration had no effect on the serum insulin concentration in yellow YS males but reduced it to an extremely low value in the non-yellow YS males. Serum insulin levels and their response to growth of aJlogeneic tumor were also studied in several F 1 hybrids between these strains. The data indicate that the YS genome exerts a depressing effect on serum insulin concentration and that this effect is decreased when combined with the VY genome. The A vy /a ge no type seems to induce a higher serum insulin concentration and greater response to tumor growth than the AY /a genotype.Horm. Metab. Res. 2: 68-71 (1970) K e y -W 0 r d s Serum Insulin -Tumor GrowthCastration -Mouse Genotypes