title: Effects of the polycyclic aromatic hydrocarbon heterocycles, carbazole and dibenzothiophene, on in vivo and in vitro CYP1A activity and polycyclic aromatic hydrocarbon-derived embryonic deformities.
abstract: Heterocyclic derivatives of polycyclic aromatic hydrocarbons (PAHs) are often significant components of environmental contaminant mixtures; however, their contribution to the toxicity of these mixtures is not well characterized. These heterocycles commonly co-occur in PAH mixtures, which contain agonists for the aryl hydrocarbon receptor (AHR). Our goal for these studies was to explore the effects of two PAH heterocycles, carbazole (CB) and dibenzothiophene (DBT), alone and in combination with a PAH-type agonist for the AHR (beta-naphthoflavone [BNF]) on AHR-mediated cytochrome P4501A (CYP1A) activity and on fish embryotoxicity. Embryos of Fundulus heteroclitus were exposed to CB or DBT, with and without coexposure to BNE Carbazole alone slightly induced, whereas DBT alone slightly reduced, in ovo CYP1A-mediated ethoxyresorufin-O-deethylase (EROD) activity compared to control values. However, exposure to CB or DBT reduced in ovo EROD activity in embryos coexposed to BNE Carbazole and DBT were characterized in vitro as noncompetitive CYP1A inhibitors. Carbazole and DBT enhanced the embryotoxicity of BNF, although neither compound was embryotoxic by itself. The co-occurrence of CB and DBT with PAH-type AHR inducers in contaminated ecosystems may increase the toxicity of PAH-type AHR agonists in these settings and may need to be considered when estimating the embryotoxicity of PAH mixtures.
authors.affiliation: Nicholas School of the Environment and Earth Sciences and Integrated Toxicology Program, Box 90328, Duke University, Durham, North Carolina 27708, USA. deena@duke.edu
authors.forename: Deena M
authors.initials: DM
authors.lastname: Wassenberg
authors.forename: Abby L
authors.initials: AL
authors.lastname: Nerlinger
authors.forename: Lauren P
authors.initials: LP
authors.lastname: Battle
authors.forename: Richard T
authors.initials: RT
authors.lastname: Di Giulio
mesh_terms: D000818:Animals; D002227:Carbazoles / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity*; D000013:Congenital Abnormalities / Q000209:etiology / Q000662:veterinary; D019363:Cytochrome P-450 CYP1A1 / Q000187:drug effects / Q000378:metabolism; D004347:Drug Interactions; D004625:Embryo, Nonmammalian; D004790:Enzyme Induction; D023781:Fundulidae / Q000196:embryology; D018336:Receptors, Aryl Hydrocarbon / Q000187:drug effects* / Q000502:physiology; D013876:Thiophenes / Q000633:toxicity*
chemical_list: D002227:Carbazoles; D002273:Carcinogens; D018336:Receptors, Aryl Hydrocarbon; D013876:Thiophenes; C041514:carbazole; D019363:Cytochrome P-450 CYP1A1; C016366:dibenzothiophene