title: The role of CYP1A inhibition in the embryotoxic interactions between hypoxia and polycyclic aromatic hydrocarbons (PAHs) and PAH mixtures in zebrafish (Danio rerio).
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, α-naphthoflavone) but no interaction with others (benzo[a]pyrene (BaP), β-naphthoflavone). Here we examine how hypoxia (7.4% 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 benzo[k]fluoranthene (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 biphenyl-126. Despite previous reports of other CYP1A inhibitors interacting with hypoxia, up to 2,000 μg/l dibenzothiophene, 2-aminoanthracene (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 sites.
authors.affiliation: Integrated Toxicology and Environmental Health Program, Nicholas School for the Environment and Earth Sciences, Duke University, Durham, NC, USA.
authors.forename: Carrie R
authors.initials: CR
authors.lastname: Fleming
authors.forename: Richard T
authors.initials: RT
authors.lastname: Di Giulio
mesh_terms: D000818:Animals; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004147:Dioxins / Q000633:toxicity; D004625:Embryo, Nonmammalian / Q000002:abnormalities / Q000187:drug effects* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000633:toxicity; D005068:Eutrophication; D005260:Female; D008297:Male; D011078:Polychlorinated Biphenyls / Q000633:toxicity; D011084:Polycyclic Aromatic Hydrocarbons / Q000633:toxicity*; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists / Q000378:metabolism; D014874:Water Pollutants, Chemical / Q000633:toxicity*; D015027:Zebrafish / Q000196:embryology
chemical_list: D004147:Dioxins; D004791:Enzyme Inhibitors; D011084:Polycyclic Aromatic Hydrocarbons; D018336:Receptors, Aryl Hydrocarbon; D014874:Water Pollutants, Chemical; D011078:Polychlorinated Biphenyls; D019363:Cytochrome P-450 CYP1A1; C023035:3,4,5,3',4'-pentachlorobiphenyl