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APOPTOSIS AND PROLIFERATION DURING DICHLOROACETIC ACID (DCA) INDUCED HEPTACELLULAR CARCINOGENESIS IN THE F344 MALE RAT
Citation:
Carter, J. H., R. E. Richmond, E. R. Hugo, T. Chen, T. Bhatt, L. E. Douglass, A B. DeAngelo, AND S Nesnow. APOPTOSIS AND PROLIFERATION DURING DICHLOROACETIC ACID (DCA) INDUCED HEPTACELLULAR CARCINOGENESIS IN THE F344 MALE RAT. Presented at American Association of Cancer Research, San Francisco, CA, April 6-10, 2002.
Description:
Apoptosis and Proliferation During DicWoroacetic Acid (DCA) Induced Hepatocellular
Carcinogenesis in the F344 Male Rat
Chlorine, introduced into public drinking \\'ater supplies for disinfection, can react with organic compounds in surface waters to form toxic by-products such as dicWoroacetic acid (DCA). The question of the health effects of chronic DCA exposure led to carcinogenicity testing in rodent models. DCA is a complete hepatocarcinogen in the male and female B6C3F1 mouse and in the male F344 rat. Suppression of spontaneous apoptosis by DCA has been documented in mouse liver, suggesting that DCA acts by suppressing the natural process for eliminating initiated cells. To test this hypothesis in the rat, this study examined apoptosis and proliferation in normal, hyperplastic and neoplastic hepatocytes in male F344 rats given DCA in the drinking water at mean daily doses (MDD) of3.6, 40.2, and 139 mg/kg body weightlday compared to distilled water controls. Groups of animals were euthanized at 14-25 week intervals for up to 103 weeks exposure. Apoptosis was quantified following nJNEL labeling in histologic sections of routinely processed livers and hepatic lesions. Antibodies to proliferating cell nuclear antigen (PCNA) and glutatlllone S-transferase (GST-P) were used to identify and quantify proliferating cells and enzyme altered foci (AF) in adjacent immunohistochemically
stained histologic sections. Apoptosis was suppressed in hepatocytes of rats receiving
DCA relative to controls at all MDD up to 60 weeks. At 60 or 78 weeks, GST -P+ AF
were found in all groups. GST-P-+ AF had significantly more apoptosis than normal liver . Cell proliferation was absent in most GST-P+ AF at 60 or 78 weeks, but rare foci had up to a 75-100~,/o PCNA labeling index. Hyperplastic nodules (HN), adenomas (AD) and
carcinomas (CA) found in animals receiving MMD of40.2 and 139 mg/kg/day DCA for
103 weeks had both increased apoptosis and proliferation relative to adjacent liver. These data are consistent with the conclusion that DCA, by suppressing apoptosis in hepatocytes. permits survival of initiated cells in F344 male rat liver.
(This abstract does not reflect EP A policy).