title: The DNA de-methylating agent 5-azacytidine does not restore CYP1A induction in PCB resistant Newark Bay killifish (Fundulus heteroclitus).
abstract: Newark Bay (NB) killifish (Fundulus heteroclitus) have been chronically exposed to environmental contaminants that activate the aryl hydrocarbon receptor (AHR) and are tolerant to toxic effects and CYP1A induction provoked by AHR ligands. Resistance to CYP1A induction could be due to an epigenetic mechanism such as DNA methylation. We measured in-ovo CYP1A catalytic activity (ethoxyresorufin-O-deethylase, EROD) in NB and reference site killifish embryos aqueously exposed to various concentrations of the de-methylating agent 5-azacytidine, 5-AC (5, 50 and 500 micro(micro)M) with or without 0.2 micro(micro)g/l of the CYP1A inducer 3,3',4,4',5 pentachlorobiphenyl (IUPAC PCB126). Neither PCB126 alone, nor PCB126 plus 5-AC, induced EROD above levels in vehicle treated Newark Bay fish. In reference site fish, the same PCB126 dose provoked a 7.4-fold EROD induction relative to controls. We conclude that Newark Bay killifish are resistant to CYP1A induction by co-planar PCBs during early embryological development and our data suggests that DNA methylation does not play a critical role in resistance to CYP1A induction in this model.
authors.affiliation: Graduate Center for Toxicology and Department of Biology, University of Kentucky, Lexington, KY 40506-0225, USA. xarzu2@uky.edu
authors.forename: Xabier
authors.initials: X
authors.lastname: Arzuaga
authors.forename: Wanda
authors.initials: W
authors.lastname: Calcaño
authors.forename: Adria
authors.initials: A
authors.lastname: Elskus
mesh_terms: D000818:Animals; D001374:Azacitidine / Q000378:metabolism / Q000633:toxicity*; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis* / Q000235:genetics; D019175:DNA Methylation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D023781:Fundulidae / Q000378:metabolism*; D009515:New Jersey; D010063:Ovum / Q000378:metabolism; D011078:Polychlorinated Biphenyls / Q000378:metabolism / Q000633:toxicity; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D012623:Seawater; D017422:Sequence Analysis, DNA
chemical_list: D011078:Polychlorinated Biphenyls; D019363:Cytochrome P-450 CYP1A1; D001374:Azacitidine; C023035:3,4,5,3',4'-pentachlorobiphenyl