Impact/Purpose:

To understand the mechanisms underlying synergistic developmental toxicity of combinations of polycyclic aromatic hydrocarbons (PAHs).

Description:

Understanding the molecular pathways of synergistic developmental toxicity of PAHs will lead to benefits for human as well as wildlife health. As additive models of toxicity are currently used to estimate the hazard of complex mixtures, implementation of synergistic models when appropriate will allow risk assessors and regulatory agencies to accurately estimate levels of toxicity in a more realistic exposure scenario.

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Roles of the specific AHR and pathway related enzymes and receptors involved in this PAH synergistic effect will be examined. A morpholino approach will be used to knock down gene targets in developing zebrafish embryos during exposure to PAH combinations of an aryl hydrocarbon receptor agonist (β-naphthoflavone) and a cytochrome P4501A inhibitor (α-naphthoflavone). Furthermore, a biochemical and molecular understanding of the role of oxidative stress in this PAH synergistic toxicity will be pursued. Treatment with antioxidants will precede co-exposure to PAHs that result in synergistic teratogenesis. Morpholinos will also be used to determine the influence of antioxidant genes in defending against PAH synergistic toxicity. Endpoints will include in vivo ethoxyresorufin-O-deethylase activity, pericardial edema, truncation of the lower jaw, markers of oxidative stress, and whole-mount immunolocalization.

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