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: Banrida Wahlang, Ming Song, Juliane I Beier, K Cameron Falkner, Laila Al-Eryani, Heather B Clair, Russell A Prough, Tanasa S Osborne, David E Malarkey, J Christopher States, Matthew C Cave
• Journal: Toxicology and applied pharmacology (Toxicol Appl Pharmacol) Vol. 279 Issue 3 Pg. 380-390 (Sep 15 2014) ISSN: 1096-0333 [Electronic] United States
• PMID: 24998970 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014. Published by Elsevier Inc.

Chemical References

• 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

Topics

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