Comparative effects of dieldrin on hepatic ploidy, cell proliferation, andapoptosis in rodent liver

Dieldrin-induced hepatocarcinogenesis, which is seen only in the mouse, app arently occurs through a nongenotoxic mechanism. Previous studies have demo nstrated that dieldrin induces hepatic DNA synthesis in mouse, but not rat liver. A number of nongenotoxic hepatocarcinogens have been shown to increa se hepatocyte nuclear ploidy following acute and subchronic treatment in ro dents, suggesting that an induction of hepatocyte DNA synthesis may occur w ithout a concomitant increase in cell division. The current study examined the effects of dieldrin on changes in hepatocyte DNA synthesis, mitosis, ap optosis, and ploidy in mouse liver ( the sensitive strain and target tissue for dieldrin-induced carcinogenicity) and the rat liver ( an insensitive s pecies). Male F344 rats and B6C3F1 mice were treated with 0, 1, 3, or 10 mg dieldrin/kg diet and were sampled after 7, 14, 28, or 90 d on diet. Liver from mice fed 10 mg dieldrin/kg diet exhibited significantly increased DNA synthesis and mitosis at 14, 28, or 90 d on diet. In rats, no increase in D NA synthesis or mitotic index was observed. The apoptotic index in liver of mice and rats did not change over the 90-d study period. Exposure of mice to only the highest dose of dieldrin produced a significant increase in oct aploid (8N) hepatocytes and a decrease in diploid (2N) hepatocytes, which w ere restricted primarily to centrilobular hepatocytes, with the periportal region showing little or no change from control. No changes in hepatocyte n uclear ploidy were observed in the rat. This study demonstrates that exposu re to high concentrations of dieldrin is accompanied by increased nuclear p loidy and mitosis in mouse, but not rat, liver. It is proposed that the obs erved increase in nuclear ploidy in the mouse may reflect an adaptive respo nse to dieldrin exposure.