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    Antioxidant responses and NRF2 in synergistic developmental toxicity of PAHs in zebrafish

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    Author Posting. Ā© The Authors, 2009. This is the author's version of the work. It is posted here by permission of Oxford University Press for personal use, not for redistribution. The definitive version was published in Toxicological Sciences 109 (2009): 217-227, doi:10.1093/toxsci/kfp038.Early piscine life-stages are sensitive to polycyclic aromatic hydrocarbon (PAH) exposure, which can cause pericardial effusion and craniofacial malformations. We previously reported that certain combinations of PAHs cause synergistic developmental toxicity, as observed with co-exposure to the aryl hydrocarbon receptor (AHR) agonist Ī²-naphthoflavone (BNF) and cytochrome P4501A inhibitor Ī±-naphthoflavone (ANF). Herein, we hypothesized that oxidative stress is a component of this toxicity. We examined induction of antioxidant genes in zebrafish embryos (Danio rerio) exposed to BNF or ANF individually, a BNF+ANF combination, and a pro-oxidant positive control, tert-butylhydroperoxide (tBOOH). We measured total glutathione, and attempted to modulate deformities using the glutathione synthesis inhibitor buthionine sulfoxamine (BSO) and increase glutathione pools with N-acetyl cysteine (NAC). In addition, we used a morpholino to knockdown expression of the antioxidant response element transcription factor NRF2 to determine if this would alter gene expression or increase deformity severity. BNF+ANF co-exposure significantly increased expressions of superoxide dismutase1 and2, glutathione peroxidase 1, pi class glutathione-s-transferase, and glutamate cysteine-ligase to a greater extent than tBOOH, BNF, or ANF alone. BSO pretreatment decreased some glutathione levels, but did not worsen deformities, nor did NAC diminish toxicity. Knockdown of NRF2 increased mortality following tBOOH challenge, prevented significant upregulation of antioxidant genes following both tBOOH and BNF+ANF exposures, and exacerbated BNF+ANFā€related deformities. Collectively, these findings demonstrate that antioxidant responses are a component of PAH synergistic developmental toxicity, and that NRF2 is protective against prooxidant and PAH challenges during development.This work was supported by the National Institute for Environmental Health Sciencessupported Duke University Superfund Basic Research Program (P42 ES10356), National Institute for Environmental Health Sciencesā€supported Duke University Integrated Toxicology & Environmental Health Program (TS ES07031), United States Environmental Protection Agency STAR fellowship (to A.T.ā€L.), Duke University RJRā€Leon Golberg Memorial Postdoctoral Training Program in Toxicology (to A.T.ā€L.), and the Postdoctoral Scholar Program at the Woods Hole Oceanographic Institution, with funding provided by the J. Seward Johnson Fund and The Walter A. and Hope Noyes Smith Chair (to A.Tā€L)
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