| Synergistic Embryotoxicity of Polycyclic Aromatic Hydrocarbon Aryl Hydrocarbon Receptor Agonists with Cytochrome P4501A Inhibitors in Fundulus heteroclitus Deena M. Wassenberg and Richard T. Di Giulio Nicholas School of the Environment and Earth Sciences, Integrated Toxicology Program, Duke University, Durham, North Carolina, USA 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  -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. Keywords:-naphthoflavone, aryl hydrocarbon receptor, benzo(a) pyrene, ß-naphthoflavone, cytochrome P4501A, deformity, fluoranthene, Fundulus heteroclitus, polychlorinated biphenyls, polycyclic aromatic hydrocarbons. Environ Health Perspect 112: 1658-1664 (2004) . doi:10.1289/ehp.7168 available via http://dx.doi.org/ [Online 18 August 2004]
Address correspondence to D.M. Wassenberg, Room 449 Jones Building, Research Dr., Duke University Medical Center, Durham, NC 27710 USA. Telephone: (919) 684-6744. Fax: (919) 668-1799. E-mail: deena@duke.edu We thank L. Barber for help with fish care, M. Rocca for help with statistics, and J. Meyer for thoughtful review of the manuscript. This research was supported by the Superfund Basic Research Programs grant P42 ES10356 and a U.S. Environmental Protection Agency STAR fellowship awarded to D.M.W. The authors declare they have no competing financial interests. Received 12 April 2004 ; accepted 18 August 2004.
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