MOLECULAR MECHANISMS OF COMPLEX MIXTURE TOXICITY

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The long-range goal of this research is to develop an understanding of the mechanisms underlying the adverse health effects and toxicity resulting from exposure to complex mixtures of polycyclic aromatic hydrocarbons (PAH) and the carcinogenic metals arsenic and chromium, often found as co-contaminants in the environment. The objectives of this research project are, (1) to elucidate the mechanisms by which arsenic and chromium affect inducible gene expression, and (2), to evaluate the effect of mixtures of benzo[alpha]pyrene (B[alpha]P), a prototypical PAK and chromium and arsenic on the expression of phase I and phase II detoxification genies. Development of environmental policy relies on risk information about the chemicals to which individuals are exposed. Although mechanisms are in place to test the health effects of individual chemicals, there is little data on the toxicity of complex environmental mixtures. In the absence of specific data, default assumptions must be used when conducting risk assessment for mixtures. For example, in the absence of evidence. to the contrary, two chemicals having similar toxic effects are assumed to act in an additive manner. This approach is not satisfactory for many complex mixtures in which a wide spectrum of interactions, from repression of effects to synergy, exist. Since most humane are exposed to complex mixtures of environmental contaminants, methods for assessing the risk of these exposures need to be developed. Most if not all the toxic effects of PAH exposure are mediated by the aromatic hydrocarbon (Ah) receptor, a ligand-activated transcription factor that, in combination with the Ah receptor nuclear translocator (ARNT) causes the transcriptional activation of phase I detoxification genes, such as those coding for the cytochromes P450 monooxygenases CYP1Al, CYP1B1 and CYPIA2, and of phase II detoxification genes, such as those coding for quinone oxidoreductase (NQO1), glutathione-S-transferase (GSTP) and UDP-glucuronosyl transferase (UGTIA6). Phase II genes can also be induced by antioxidants and electrophiles through Ah receptor-independent mechanisms. Preliminary work from our laboratory has shown that exposure of cultured mammalian cells to chromate or arsenite disrupts the coordinate induction of phase I and phase II genes by dioxin, the protype halogenated aromatic hydrocarbon Ah receptor ligand. Chromate inhibits induction of phase II genes to a greater extent than induction of phase I genes, whereas arsenite inhibits phase I gene induction and elicits a dose-dependent oxidative stress response that superinduces electrophile response element (EpRE)- mediated transcription of phase II genes. These observations lead us to me hypothesis that combined exposure to a mixture B[alpha]P and chromate or arsenite, (1) Will disrupt the regulatory mechanisms that control transcription from B[alpha]P- inducible gene promoters, and (2) will cause an uncoupling of phase I and phase II gene expression and concomitant imbalance in B[alpha]P metabolism. Results from this work will help develop a means to predict the health risks arising from exposure to chemical mixtures.