title: Evaluation of Aroclor 1260 exposure in a mouse model of diet-induced obesity and non-alcoholic fatty liver disease.
abstract: Polychlorinated biphenyls (PCBs) are persistent organic pollutants associated with non-alcoholic fatty liver disease (NAFLD) in epidemiologic studies. The purpose of this study was to evaluate the hepatic effects of a PCB mixture, Aroclor 1260, whose composition mimics human bioaccumulation patterns, in a mouse model of diet-induced obesity (DIO). Male C57Bl/6J mice were fed control diet or 42% high fat diet (HFD) and exposed to Aroclor 1260 (20mg/kg or 200mg/kg in corn oil) for 12weeks. A glucose tolerance test was performed; plasma/tissues were obtained at necropsy for measurements of adipocytokine levels, histology, and gene expression. Aroclor 1260 exposure was associated with decreased body fat in HFD-fed mice but had no effect on blood glucose/lipid levels. Paradoxically, Aroclor 1260+HFD co-exposed mice demonstrated increased hepatic inflammatory foci at both doses while the degree of steatosis did not change. Serum cytokines, ALT levels and hepatic expression of IL-6 and TNFα were increased only at 20mg/kg, suggesting an inhibition of pro-inflammatory cytokine production at the 200mg/kg exposure. Aroclor 1260 induced hepatic expression of cytochrome P450s including Cyp3a11 (Pregnane-Xenobiotic Receptor target) and Cyp2b10 (constitutive androstane receptor target) but Cyp2b10 inducibility was diminished with HFD-feeding. Cyp1a2 (aryl hydrocarbon Receptor target) was induced only at 200mg/kg. In summary, Aroclor 1260 worsened hepatic and systemic inflammation in DIO. The results indicated a bimodal response of PCB-diet interactions in the context of inflammation which could potentially be explained by xenobiotic receptor activation. Thus, PCB exposure may be a relevant "second hit" in the transformation of steatosis to steatohepatitis.
authors.affiliation: Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40202, USA.
authors.forename: Banrida
authors.initials: B
authors.lastname: Wahlang
authors.affiliation: Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Louisville School of Medicine, Louisville, KY 40202, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Song
authors.affiliation: Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40202, USA.
authors.forename: Juliane I
authors.initials: JI
authors.lastname: Beier
authors.affiliation: Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Louisville School of Medicine, Louisville, KY 40202, USA.
authors.forename: K
authors.initials: K
authors.lastname: Cameron Falkner
authors.affiliation: Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40202, USA.
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, KY 40202, USA.
authors.forename: Heather B
authors.initials: HB
authors.lastname: Clair
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Louisville School of Medicine, Louisville, KY 40202, USA.
authors.forename: Russell A
authors.initials: RA
authors.lastname: Prough
authors.affiliation: Cellular and Molecular Pathology Branch, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
authors.forename: Tanasa S
authors.initials: TS
authors.lastname: Osborne
authors.affiliation: Cellular and Molecular Pathology Branch, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Malarkey
authors.affiliation: Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40202, USA.
authors.forename: J Christopher
authors.initials: JC
authors.lastname: States
authors.affiliation: Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40202, USA; Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Louisville School of Medicine, Louisville, KY 40202, USA; The Robley Rex Veterans Affairs Medical Center, Louisville, KY 40206, USA. Electronic address: matt.cave@louisville.edu.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Cave
mesh_terms: D054392:Adipokines / Q000378:metabolism; D000273:Adipose Tissue / Q000473:pathology; D000818:Animals; D001140:Aroclors / Q000633:toxicity*; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis / Q000235:genetics; D001786:Blood Glucose / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis / Q000235:genetics; D000072467:Cytochrome P450 Family 2; D004032:Diet; D004785:Environmental Pollutants / Q000633:toxicity*; D005234:Fatty Liver / Q000139:chemically induced* / Q000473:pathology; D015870:Gene Expression / Q000187:drug effects; D005951:Glucose Tolerance Test; D007249:Inflammation / Q000139:chemically induced / Q000473:pathology; D008099:Liver / Q000473:pathology; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease; D009765:Obesity / Q000139:chemically induced* / Q000473:pathology; D060888:Real-Time Polymerase Chain Reaction; D018336:Receptors, Aryl Hydrocarbon / Q000096:biosynthesis / Q000235:genetics; D013250:Steroid Hydroxylases / Q000096:biosynthesis / Q000235:genetics; D051197:Toll-Like Receptor 4 / Q000096:biosynthesis / Q000235:genetics; D014280:Triglycerides / Q000378:metabolism
chemical_list: D054392:Adipokines; D001140:Aroclors; D001786:Blood Glucose; D004785:Environmental Pollutants; D008565:Membrane Proteins; D018336:Receptors, Aryl Hydrocarbon; D051197:Toll-Like Receptor 4; D014280:Triglycerides; C026987:aroclor 1260; D002784:Cholesterol; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C101679:Cyp2b10 protein, mouse; C496508:Cyp3a11 protein, mouse; D051544:Cytochrome P-450 CYP3A; D000072467:Cytochrome P450 Family 2
keywords: AhR; Aroclor 1260; CAR; NAFLD; PCBs; PXR