Project 3: Systems Approach to Define Toxicity of Complex PAH Mixtures (Tanguay,

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PROJECT SUMMARY (See instructions): Polycyclic aromatic hydrocarbons (PAHs), are routinely found at Superfund sites, are widespread environmental contaminants and have been shown to cross the placenta. Consequently, developmental exposure to PAHs has the potential to cause adverse health outcomes. This supposition is supported by recent epidemiological data indicating strong associations between early life stage PAH exposures and the increased occurrence of birth defects and increases in significant neurobehavioral deficits and heart disease. Human exposure to Superfund PAHs is complex; exposures always occur as complex mixtures rather than as individual parent PAHs. The potency for individual parent PAHs to produce adverse developmental outcomes is not well-defined, and more importantly the additive, antagonistic or synergistic effects of PAHs in mixtures is unknown. An added level of uncertainty is that PAHs are environmentally transformed, and the toxicity of these transformed PAHs is largely unstudied. Risk assessors are desperately in need of relevant in vivo data to develop comprehensive models for predictive toxicity. An immediate goal is to identify the environmentally relevant mixtures that pose hazard, and to identify the gene responses that drive the toxic endpoints. This project will use systems approaches in zebrafish to begin to define the mechanism of PAH toxicity. Our underlying hypothesis is that exposure to complex mixtures containing PAHs produce toxicity by aryl hydrocarbon receptor (AHR)-dependent and AHR-independent mechanisms, dependent on the structure and composition of the mixtures. We will test this hypothesis in three Specific Aims: 1) Determine the phenotypic impact of embryonic exposure to individual environmentally relevant PAHs, complex mixtures, and environmentally transformed PAHs and define the role of AHRs in the response; 2) To continue to use next generation sequencing to identify the early developmental biomarkers of PAH exposure to individual environmentally relevant PAHs, complex mixtures, and environmentally transformed PAHs; 3) To define the long lasting impacts of these embryonic exposure on the adult cardiovascular and central nervous systems.