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Comparative effects of dieldrin on hepatic ploidy, cell proliferation, and apoptosis in rodent liver
L M Kamendulis1, K L Kolaja, D E Stevenson
1Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis 46202, USA.
Abstract:
Dieldrin-induced hepatocarcinogenesis, which is seen only in the mouse, apparently occurs through a nongenotoxic mechanism. Previous studies have demonstrated that dieldrin induces hepatic DNA synthesis in mouse, but not rat liver. A number of nongenotoxic hepatocarcinogens have been shown to increase hepatocyte nuclear ploidy following acute and subchronic treatment in rodents, suggesting that an induction of hepatocyte DNA synthesis may occur without a concomitant increase in cell division. The current study examined the effects of dieldrin on changes in hepatocyte DNA synthesis, mitosis, apoptosis, and ploidy in mouse liver (the sensitive strain and target tissue for dieldrin-induced carcinogenicity) and the rat liver (an insensitive species). 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 DNA 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 octaploid (8N) hepatocytes and a decrease in diploid (2N) hepatocytes, which were restricted primarily to centrilobular hepatocytes, with the periportal region showing little or no change from control. No changes in hepatocyte nuclear ploidy were observed in the rat. This study demonstrates that exposure to high concentrations of dieldrin is accompanied by increased nuclear ploidy and mitosis in mouse, but not rat, liver. It is proposed that the observed increase in nuclear ploidy in the mouse may reflect an adaptive response to dieldrin exposure.
Insights
Dieldrin exposure increases liver cell DNA synthesis and ploidy in mice but not rats, suggesting a nongenotoxic adaptive response. This mechanism is specific to mice, the only species susceptible to dieldrin-induced liver cancer.
Area of Science:
- Toxicology
- Hepatocarcinogenesis
- Cell Biology
Background:
- Dieldrin-induced liver cancer in mice occurs via a nongenotoxic pathway.
- Nongenotoxic carcinogens can increase hepatocyte nuclear ploidy without increasing cell division.
Purpose of the Study:
- To investigate the effects of dieldrin on DNA synthesis, mitosis, apoptosis, and ploidy in mouse and rat liver.
- To elucidate the mechanism of dieldrin-induced hepatocarcinogenesis in mice.
Main Methods:
- Male F344 rats and B6C3F1 mice were fed diets containing 0, 1, 3, or 10 mg dieldrin/kg for up to 90 days.
- Liver tissues were analyzed for DNA synthesis, mitotic index, apoptosis, and ploidy levels.
Main Results:
- Mice exposed to 10 mg/kg dieldrin showed significantly increased DNA synthesis and mitosis.
- Dieldrin exposure led to increased octaploid hepatocytes and decreased diploid hepatocytes in mice.
- No significant changes in DNA synthesis, mitosis, or ploidy were observed in rats.
Conclusions:
- Dieldrin exposure induces increased nuclear ploidy and mitosis in mouse liver, but not rat liver.
- The observed changes in mouse liver suggest an adaptive response to dieldrin exposure.
- This study highlights species-specific responses to dieldrin and its nongenotoxic carcinogenic mechanism.
