Evaluation of Aroclor 1260 Exposure in a Mouse Model of Diet-Induced Obesity and Non-Alcoholic Fatty Liver Disease

Toxicol Appl Pharmacol. 2014 Sep 15;279(3):380-390. doi: 10.1016/j.taap.2014.06.019. Epub 2014 Jul 3.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipokines / metabolism
  • Adipose Tissue / pathology
  • Animals
  • Aroclors / toxicity*
  • Aryl Hydrocarbon Hydroxylases / biosynthesis
  • Aryl Hydrocarbon Hydroxylases / genetics
  • Blood Glucose / metabolism
  • Cholesterol / metabolism
  • Cytochrome P-450 CYP3A / biosynthesis
  • Cytochrome P-450 CYP3A / genetics
  • Cytochrome P450 Family 2
  • Diet
  • Environmental Pollutants / toxicity*
  • Fatty Liver / chemically induced*
  • Fatty Liver / pathology
  • Gene Expression / drug effects
  • Glucose Tolerance Test
  • Inflammation / chemically induced
  • Inflammation / pathology
  • Liver / pathology
  • Membrane Proteins / biosynthesis
  • Membrane Proteins / genetics
  • Mice
  • Mice, Inbred C57BL
  • Non-alcoholic Fatty Liver Disease
  • Obesity / chemically induced*
  • Obesity / pathology
  • Real-Time Polymerase Chain Reaction
  • Receptors, Aryl Hydrocarbon / biosynthesis
  • Receptors, Aryl Hydrocarbon / genetics
  • Steroid Hydroxylases / biosynthesis
  • Steroid Hydroxylases / genetics
  • Toll-Like Receptor 4 / biosynthesis
  • Toll-Like Receptor 4 / genetics
  • Triglycerides / metabolism

Substances

  • Adipokines
  • Aroclors
  • Blood Glucose
  • Environmental Pollutants
  • Membrane Proteins
  • Receptors, Aryl Hydrocarbon
  • Toll-Like Receptor 4
  • Triglycerides
  • aroclor 1260
  • Cholesterol
  • Steroid Hydroxylases
  • Aryl Hydrocarbon Hydroxylases
  • Cyp2b10 protein, mouse
  • Cyp3a11 protein, mouse
  • Cytochrome P-450 CYP3A
  • Cytochrome P450 Family 2