MECHANISMS OF HEPATIC TUMOR PROMOTION BY PCB'S

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Polychlorinated biphenyls (PCBs) are ubiquitous environmental contaminants which are carcinogenic in experiment animal models. Individual PCB congeners as well as commercial PCB mixtures have been shown to be efficacious hepatic tumor promoters in two-stage hepatocarcinogenesis in rats. The biochemical mechanisms by which PCBs promote hepatic foci and tumors, however, have never been determined. Additionally, it is not known if PCB congeners act synergistically in two-stage hepatocarcinogenesis, which is important since humans are exposed to PCB mixtures. Finally, it is not known how to accurately estimate the promoting potential of PCBs which are not ligands of the Ah receptor. We therefore propose to test the hypotheses that 1)PCBs promote two-stage hepatocarcinogenesis by inducing oxidative DNA damage, increasing long-term cell proliferation, and/or altering eicosanoid metabolism; 2) the promotion index of non-Ah binding PCBs can be estimated by their ability to induce cytochrome P-450 2B1/2; and 3) PCBs act synergistically in the promotion of hepatocarcinogenesis. In the first studies, PCBs will be administered for varying periods of time, and their ability to induce 8-hydroxyguanosine, increase cell proliferation in normal hepatocytes, and alter the concentrations of prostaglandins E2 and F2alpha and other eicosanoids will be determined. In the tumor promotion studies, PCBs will be administered after diethylnitrosamine administration, and we will determine their ability to 1) induce altered hepatic foci as predicted by their 2B1/2 inducing activity and 2) act synergistically in the induction of altered hepatic foci. These studies will show how PCBs promote hepatic carcinogenesis, whether they act synergistically, and if their promoting ability can be easily predicted. This information will help in understanding and quantifying the risks for humans exposed to Superfund chemicals.