The role of CYP1A inhibition in the embryotoxic in

Authors: Carrie R Fleming Richard T Di Giulio

Publish Date: 2011/06/26

Volume: 20, Issue: 6, Pages: 1300-1314

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Abstract

Polycyclic aromatic hydrocarbons PAHs are ubiquitous environmental pollutants with elevated concentrations in waters that may also experience hypoxia Previous research has shown interactions between hypoxia and some PAHs fluoranthene αnaphthoflavone but no interaction with others benzoapyrene BaP βnaphthoflavone Here we examine how hypoxia 74 oxygen ~35 of normoxia affects the embryotoxicity of PAHs that act through different mechanisms and the role that CYP1A inhibition may play in these interactions About 500 μg/l BaP and 1–200 μg/l benzokfluoranthene BkF interacted synergistically with hypoxia to induce pericardial edema in developing zebrafish Danio rerio Hypoxia protected from the embryotoxicity of pyrene PY and had no effect on the toxicity of polychlorinated biphenyl126 Despite previous reports of other CYP1A inhibitors interacting with hypoxia up to 2000 μg/l dibenzothiophene 2aminoanthracene AA and carbazole CB all failed to induce embryotoxicity under normoxic or hypoxic conditions The toxicity of PAH mixtures—including binary mixtures of BaP/AA and BaP/CB and two environmentally relevant complex mixtures—were exacerbated severely by hypoxia to induce or worsen pericardial edema and cause mortality The interactions between hypoxia and BkF and PY were closely mimicked by morpholino knockdown of CYP1A indicating a potential role for metabolism of these compounds in their toxicity Our results indicate that various PAHs may exhibit synergistic antagonistic or additive toxicity with hypoxia The enhanced toxicity of environmental mixtures of PAHs under hypoxia suggests that risk assessments that do not take into account potential interactions with hypoxia may underestimate the threat of PAHs to fish in contaminated sitesWe would like to thank Kyle Erwin in the laboratory of Margaret Kirby for the generous gift of the PCB126 and βactin primers used in these experiments We would also like to thank Bryan Clark and Lindsey Van Tiem for technical assistance in the collection and preparation of the Elizabeth River Sediment Extract and Cole Matson for statistical advice Funding was provided by the National Institute of Environmental Health Sciencessupported Duke University Superfund Research Center P42ES10356 the Integrated Toxicology and Environmental Health Program T32ES007031 and an Environmental Protection Agency STAR grant to C Fleming

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