title: Hypoxia inhibits induction of aryl hydrocarbon receptor activity in topminnow hepatocarcinoma cells in an ARNT-dependent manner.
abstract: Hypoxic events often occur in waters contaminated with toxic chemicals, including agonists of the aryl hydrocarbon receptor (AhR). HIF-1alpha, the mediator of cellular responses to hypoxia, shares a dimerization partner (ARNT) with AhR and reciprocal crosstalk may occur. Studies addressing AhR/hypoxia crosstalk in mammalian cells have produced contradictory results regarding whether reciprocal crosstalk actually occurs between these pathways and the role ARNT plays in this interaction. We assessed hypoxia-AhR crosstalk in fish cells (PLHC-1) treated with hypoxia (1% O(2)) or normoxia (21% O(2)) and AhR agonists (benzo[a]pyrene (BaP), 3,3',4,4',5-pentachlorobiphenyl (PCB-126), and benzo[k]fluoranthene (BkF)) with and without overexpression of ARNT. Hypoxia limited the induction of a transiently transfected AhR reporter by all three of the AhR agonists; overexpression of ARNT eliminated this effect. PCB-126 had no effect on induction of a transiently transfected hypoxia reporter. BkF caused a minor increase in basal and induced hypoxia reporter activity. BaP decreased basal and induced hypoxia reporter activity; overexpression of ARNT did not alter this effect indicating that this interference with hypoxia pathway activity occurs through an alternate mechanism. Reduced hypoxia pathway activity with BaP treatment may be the result of a metabolite. This study supports the hypothesis that HIF-1alpha is able to sequester ARNT from AhR and limit the activity of the AhR pathway, but suggests that the converse is not true.
authors.affiliation: Nicholas School of the Environment, Duke University, Durham, NC 27708, USA. Crf10@duke.edu
authors.forename: Carrie R
authors.initials: CR
authors.lastname: Fleming
authors.forename: Sonya M
authors.initials: SM
authors.lastname: Billiard
authors.forename: Richard T
authors.initials: RT
authors.lastname: Di Giulio
mesh_terms: D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000502:physiology*; D001564:Benzo(a)pyrene / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000378:metabolism; D045744:Cell Line, Tumor; D023781:Fundulidae / Q000378:metabolism; D000860:Hypoxia / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D011078:Polychlorinated Biphenyls / Q000494:pharmacology; D055503:Protein Multimerization; D018336:Receptors, Aryl Hydrocarbon / Q000096:biosynthesis* / Q000235:genetics; D014874:Water Pollutants, Chemical / Q000494:pharmacology
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018336:Receptors, Aryl Hydrocarbon; D014874:Water Pollutants, Chemical; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D001564:Benzo(a)pyrene; D011078:Polychlorinated Biphenyls; C023035:3,4,5,3',4'-pentachlorobiphenyl