Molecular mechanisms of complex mixture toxicity

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DESCRIPTION (Taken from application) The objectives of this research project are, (1) to evaluate the effects of mixtures of benzo[a]pyrene (B[a]P), a prototypical polycyclic aromatic hydrocarbon (PAH), and the carcinogenic metals chromium or arsenic on the expression of Phase I and Phase II detoxification genes, and (2) to elucidate the molecular mechanisms responsible for these effects. 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, may be observed. Since most individuals 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, is responsible for the transcriptional activation of phase I detoxification genes, such as those coding for the cytochromes P450 monooxygenases CYP1A1, CYP1B1 and CYP1A2, and of phase II detoxification genes, such as those coding for quinone oxido-reductase (NQO1), glutathione-S-transferase (GST1) and UDP-glucuronosyl transferase (UDPGT). 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 Ah receptor ligands. Chromate inhibits induction of phase II genes to a greater extent than induction of phase I genes, whereas arsenite has little effect on phase I gene induction but superinduces phase II genes. These observations have lead us to the hypothesis that combined exposure to a mixture of B[a]P and chromate or arsenite, (1) disrupts the regulatory mechanisms that control transcription from B[a]P-inducible gene promoters; (2) causes an uncoupling of phase I and phase II gene expression and a concomitant imbalance in B[a]P metabolism; and (3) produces a characteristic "gene expression signature" that can be used as a molecular biomarker of exposure and of the health effects of the mixture. Results from this work will help develop a means to predict the health risks arising from exposure to chemical mixtures.