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Title of Abstract: Mechanisms underlying synergistic developmental toxicity of polycyclic aromatic hydrocarbons in zebrafish (Danio rerio)

EPA Grant Number: F5D40841
Title: Title of Abstract: Mechanisms underlying synergistic developmental toxicity of polycyclic aromatic hydrocarbons in zebrafish (Danio rerio)
Investigators: Timme-Laragy, Alicia R.
Institution: Duke University
EPA Project Officer: McClure, Karen
Project Period: August 29, 2005 through May 1, 2007
Project Amount: $103,346
RFA: STAR Graduate Fellowships (2005)
Research Category: Academic Fellowships

Description:

Objective:

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

Approach:

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.

Expected Results:

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.

Supplemental Keywords:

polycyclic aromatic hydrocarbons, aryl hydrocarbon receptor, cytochrome P450 1A, zebrafish, development, teratogenesis, morpholino, oxidative stress, , Scientific Discipline, Health, Risk Assessments, Ecological Risk Assessment, Environmental Chemistry, Environmental Monitoring, analysis of chemical exposure, molecular mechanisms, zebrafish, human health risk, morpholino approach, chemical exposure, PAH, human exposure

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The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.

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