title: Developmental toxicity of 4-ring polycyclic aromatic hydrocarbons in zebrafish is differentially dependent on AH receptor isoforms and hepatic cytochrome P4501A metabolism.
abstract: Polycyclic aromatic hydrocarbons (PAHs) derived from fossil fuels are ubiquitous contaminants and occur in aquatic habitats as highly variable and complex mixtures of compounds containing 2 to 6 rings. For aquatic species, PAHs are generally accepted as acting through either of two modes of action: (1) "dioxin-like" toxicity mediated by activation of the aryl hydrocarbon receptor (AHR), which controls a battery of genes involved in PAH metabolism, such as cytochrome P4501A (CYP1A) and (2) "nonpolar narcosis", in which tissue uptake is dependent solely on hydrophobicity and toxicity is mediated through non-specific partitioning into lipid bilayers. As part of a systematic analysis of mechanisms of PAH developmental toxicity in zebrafish, we show here that three tetracyclic PAHs (pyrene, chrysene, and benz[a]anthracene) activate the AHR pathway tissue-specifically to induce distinct patterns of CYP1A expression. Using morpholino knockdown of ahr1a, ahr2, and cyp1a, we show that distinct embryolarval syndromes induced by exposure to two of these compounds are differentially dependent on tissue-specific activation of AHR isoforms or metabolism by CYP1A. Exposure of embryos with and without circulation (silent heart morphants) resulted in dramatically different patterns of CYP1A induction, with circulation required to deliver some compounds to internal tissues. Therefore, biological effects of PAHs cannot be predicted simply by quantitative measures of AHR activity or a compound's hydrophobicity. These results indicate that current models of PAH toxicity in fish are greatly oversimplified and that individual PAHs are pharmacologically active compounds with distinct and specific cellular targets.
authors.affiliation: Ecotoxicology and Environmental Fish Health Program, Environmental Conservation Division, Northwest Fisheries Science Center, 2725 Montlake Blvd E, Seattle, WA 98112, USA. john.incardona@noaa.gov
authors.forename: John P
authors.initials: JP
authors.lastname: Incardona
authors.forename: Heather L
authors.initials: HL
authors.lastname: Day
authors.forename: Tracy K
authors.initials: TK
authors.lastname: Collier
authors.forename: Nathaniel L
authors.initials: NL
authors.lastname: Scholz
mesh_terms: D000014:Abnormalities, Drug-Induced; D000818:Animals; D001551:Benz(a)Anthracenes / Q000633:toxicity; D002911:Chrysenes / Q000633:toxicity; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis*; D004625:Embryo, Nonmammalian / Q000187:drug effects* / Q000196:embryology / Q000378:metabolism; D004790:Enzyme Induction; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics; D006330:Heart Defects, Congenital / Q000139:chemically induced / Q000473:pathology; D007814:Larva / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D009025:Morpholines / Q000494:pharmacology; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D011084:Polycyclic Aromatic Hydrocarbons / Q000633:toxicity*; D020033:Protein Isoforms; D011721:Pyrenes / Q000633:toxicity; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism*; D014874:Water Pollutants, Chemical / Q000633:toxicity*; D015027:Zebrafish
chemical_list: D001551:Benz(a)Anthracenes; D002911:Chrysenes; D009025:Morpholines; D016376:Oligonucleotides, Antisense; D011084:Polycyclic Aromatic Hydrocarbons; D020033:Protein Isoforms; D011721:Pyrenes; D018336:Receptors, Aryl Hydrocarbon; D014874:Water Pollutants, Chemical; C031180:chrysene; C030984:pyrene; C030935:benz(a)anthracene; D019363:Cytochrome P-450 CYP1A1