title: Synergistic embryotoxicity of polycyclic aromatic hydrocarbon aryl hydrocarbon receptor agonists with cytochrome P4501A inhibitors in Fundulus heteroclitus.
abstract: Widespread contamination of aquatic systems with polycyclic aromatic hydrocarbons (PAHs) has led to concern about effects of PAHs on aquatic life. Some PAHs have been shown to cause deformities in early life stages of fish that resemble those elicited by planar halogenated aromatic hydrocarbons (pHAHs) that are agonists for the aryl hydrocarbon receptor (AHR). Previous studies have suggested that activity of cytochrome P4501A, a member of the AHR gene battery, is important to the toxicity of pHAHs, and inhibition of CYP1A can reduce the early-life-stage toxicity of pHAHs. In light of the effects of CYP1A inhibition on pHAH-derived toxicity, we explored the impact of both model and environmentally relevant CYP1A inhibitors on PAH-derived embryotoxicity. We exposed Fundulus heteroclitus embryos to two PAH-type AHR agonists, ss-naphthoflavone and benzo(a)pyrene, and one pHAH-type AHR agonist, 3,3 ,4,4 ,5-pentachlorobiphenyl (PCB-126), alone and in combination with several CYP1A inhibitors. In agreement with previous studies, coexposure of embryos to PCB-126 with the AHR antagonist and CYP1A inhibitor alpha-naphthoflavone decreased frequency and severity of deformities compared with embryos exposed to PCB-126 alone. In contrast, embryos coexposed to the PAHs with each of the CYP1A inhibitors tested were deformed with increased severity and frequency compared with embryos dosed with PAH alone. The mechanism by which inhibition of CYP1A increased embryotoxicity of the PAHs tested is not understood, but these results may be helpful in elucidating mechanisms by which PAHs are embryotoxic. Additionally, these results call into question additive models of PAH embryotoxicity for environmental PAH mixtures that contain both AHR agonists and CYP1A inhibitors.
authors.affiliation: Nicholas School of the Environment and Earth Sciences, Integrated Toxicology Program, Duke University, Durham, North Carolina, USA. deena@duke.edu
authors.forename: Deena M
authors.initials: DM
authors.lastname: Wassenberg
authors.forename: Richard T
authors.initials: RT
authors.lastname: Di Giulio
mesh_terms: D000818:Animals; D000013:Congenital Abnormalities / Q000209:etiology / Q000662:veterinary; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D004347:Drug Interactions; D004625:Embryo, Nonmammalian / Q000187:drug effects; D004785:Environmental Pollutants / Q000633:toxicity*; D023781:Fundulidae / Q000502:physiology; D011084:Polycyclic Aromatic Hydrocarbons / Q000633:toxicity*; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists / Q000502:physiology*; D018675:Toxicity Tests
chemical_list: D004785:Environmental Pollutants; D011084:Polycyclic Aromatic Hydrocarbons; D018336:Receptors, Aryl Hydrocarbon; D019363:Cytochrome P-450 CYP1A1