Environmental chemicals can exert their effects on humans via their mutagenic, cytotoxic and/or epigenetic consequences on cells. Since many halogenated aromatic hydrocarbons (HAH) and volatile organic chemicals (VOCs) are suspect carcinogens and tumor promoters, and since they are widespread pollutants in ground water, the assessment of potential risks to human health, alone or in combination, depends upon an understanding of their mechanisms of action at the cellular and molecular level. Many of these chemicals have been shown not to be genotoxic. Therefore, this proposal aims to focus on the central theme that these toxicants exert their epigenetic (non-genotoxic) effects by modulation of protein expression. A major emphasis of this proposal is also to develop in vitro predictive """"""""biomarkers"""""""" (cellular/biochemical) of toxic cellular interactions of non-genotoxic environmental chemicals. The hypotheses to be tested are: 1) that epigenetic effects are exerted through modulation of gene expression of key cellular regulatory proteins and/or enzymes; and 2) that the attenuation of adverse effects may be achieved by inhibitory chemicals. A select number of human and rodent derived cell culture models will be used to study 1) the modulation of gap junctional intercellular communication (GJIC); and 2) changes in the expression of plasminogen activators (PA) and their inhibitor, PAI-1, via transforming growth factor beta, by individual environmental chemicals (VOCs, PCBs, HAHs) or as mixtures. The biochemical and molecular mechanisms, mainly perturbations in the cellular signal transduction system involving protein kinase C (PKC), and intracellular calcium, by which these chemicals might exert their toxic effects will be examined. Finally, using known inhibitor chemicals of protein kinase C and PA, the abolition of the toxic effects of the environmental chemicals will be determined. Identification of the mechanisms involved in tumor promotion and in other non-genotoxic effects of environmental toxicants and the exploration of the mechanism for attenuation of their toxic effects have important implications in assessing and ameliorating health risks to humans.
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