Trichloroethylene (TCE), perchloroethylene (PCE) and related chlorinated hydrocarbons constitute an important class of environmental pollutants that are of specific interest to Superfund cleanup efforts. Occupational and environmental exposure to these chemicals is associated with a number of adverse health effects including liver, kidney and central nervous system toxicity. Rodent model systems have established that the hepatotoxic and hepatocarcinogenic effects of TCE and PCE are directly related to the extent of their metabolism by liver cytochrome p450 enzymes, and these effects are mediated, at least in part, by an orphan receptor protein termed PPAR, peroxisome proliferator-activated receptor. Studies are proposed to investigate the metabolism of TCE and PCE by human liver P450 enzymes and to characterize the mechanisms by which these chlorinated hydrocarbons and their metabolites activate human PPARs in intact cellular systems. The specific goals of these studies are four-fold: (a) to identify the specific cytochrome P450 catalysts of TCE and PCE activation in human liver, the major site of metabolism; (b) to delineate the responsiveness of human PPAR receptor proteins to TCE, PCE and their metabolites using a cellular assay for PPAR trans-activation; (c) to investigate the adrenal steroid and peroxisome proliferator dehydroepiandrosterone=3beta-sulfate (DHEA-S) as a naturally-occurring PPAR activator, and to characterize the effects of TCE, PCE and their active metabolites on DHEA-S-stimulated receptor activation; and (d) to elucidate the cellular mechanisms whereby chlorinated hydrocarbons and endogenous steroids activate PPAR to initiate a peroxisome proliferative response. Together, these studies will facilitate the assessment of toxicity risks associated with environmental and occupational exposure to chlorinated hydrocarbons as a function of liver enzyme profiles and receptor levels in human populations. In addition, the studies proposed will greatly enhance our understanding of the biochemical, cellular and molecular basis for the action and tissue-specific effects of chlorinated hydrocarbon pollutants, which together comprise an important class of non-genotoxic environmental carcinogens.
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