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Toxicol Appl Pharmacol. 2014 Sep 15;279(3):380-90. doi: 10.1016/j.taap.2014.06.019. Epub 2014 Jul 3.

Evaluation of Aroclor 1260 exposure in a mouse model of diet-induced obesity and non-alcoholic fatty liver disease.

Author information

1
Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40202, USA.
2
Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Louisville School of Medicine, Louisville, KY 40202, USA.
3
Department of Biochemistry and Molecular Biology, University of Louisville School of Medicine, Louisville, KY 40202, USA.
4
Cellular and Molecular Pathology Branch, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
5
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.

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.

KEYWORDS:

AhR; Aroclor 1260; CAR; NAFLD; PCBs; PXR

PMID:
24998970
PMCID:
PMC4225625
DOI:
10.1016/j.taap.2014.06.019
[Indexed for MEDLINE]
Free PMC Article

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