title: Human receptor activation by aroclor 1260, a polychlorinated biphenyl mixture.
abstract: Polychlorinated biphenyls (PCBs) are persistent environmental toxicants, present in 100% of U.S. adults and dose-dependently associated with obesity and non-alcoholic fatty liver disease (NAFLD). PCBs are predicted to interact with receptors previously implicated in xenobiotic/energy metabolism and NAFLD. These receptors include the aryl hydrocarbon receptor (AhR), pregnane xenobiotic receptor (PXR), constitutive androstane receptor (CAR), peroxisome proliferator-activated receptors (PPARs), liver-X-receptor (LXRα), and farnesoid-X-receptor (FXR). This study evaluates Aroclor 1260, a PCB mixture with congener composition mimicking that of human adipose tissue, and selected congeners, as potential ligands for these receptors utilizing human hepatoma-derived (HepG2) and primate-derived (COS-1) cell lines, and primary human hepatocytes. Aroclor 1260 (20 μg/ml) activated AhR, and PCB 126, a minor component, was a potent inducer. Aroclor 1260 activated PXR in a simple concentration-dependent manner at concentrations ≥10 μg/ml. Among the congeners tested, PCBs 138, 149, 151, 174, 183, 187, and 196 activated PXR. Aroclor 1260 activated CAR2 and CAR3 variants at lower concentrations and antagonize CAR2 activation by the CAR agonist, CITCO, at higher concentrations (≥20 μg/ml). Additionally, Aroclor 1260 induced CYP2B6 in primary hepatocytes. At subtoxic doses, Aroclor 1260 did not activate LXR or FXR and had no effect on LXR- or FXR-dependent induction by the agonists T0901317 or GW4064, respectively. Aroclor 1260 (20 μg/ml) suppressed PPARα activation by the agonist nafenopin, although none of the congeners tested demonstrated significant inhibition. The results suggest that Aroclor 1260 is a human AhR, PXR and CAR3 agonist, a mixed agonist/antagonist for CAR2, and an antagonist for human PPARα.
authors.affiliation: Department of Pharmacology and Toxicology.
authors.forename: Banrida
authors.initials: B
authors.lastname: Wahlang
authors.affiliation: Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition.
authors.forename: K Cameron
authors.initials: KC
authors.lastname: Falkner
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Louisville School of Medicine, Louisville, Kentucky 40202.
authors.forename: Heather B
authors.initials: HB
authors.lastname: Clair
authors.affiliation: Department of Pharmacology and Toxicology.
authors.forename: Laila
authors.initials: L
authors.lastname: Al-Eryani
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Louisville School of Medicine, Louisville, Kentucky 40202.
authors.forename: Russell A
authors.initials: RA
authors.lastname: Prough
authors.affiliation: Department of Pharmacology and Toxicology.
authors.forename: J Christopher
authors.initials: JC
authors.lastname: States
authors.affiliation: Center for Molecular Toxicology, Penn State University, University Park, Pennsylvania 16802.
authors.forename: Denise M
authors.initials: DM
authors.lastname: Coslo
authors.affiliation: Center for Molecular Toxicology, Penn State University, University Park, Pennsylvania 16802.
authors.forename: Curtis J
authors.initials: CJ
authors.lastname: Omiecinski
authors.affiliation: Department of Pharmacology and Toxicology Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition The Robley Rex Veterans Affairs Medical Center, Louisville, Kentucky 40206 matt.cave@louisville.edu.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Cave
mesh_terms: D001140:Aroclors / Q000633:toxicity*; D001483:Base Sequence; D045424:Complex Mixtures; D017931:DNA Primers; D056945:Hep G2 Cells; D006801:Humans
chemical_list: D001140:Aroclors; D045424:Complex Mixtures; D017931:DNA Primers; C026987:aroclor 1260
keywords: Aroclor 1260; PCBs; aryl hydrocarbon receptor; nuclear receptors