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 (20 mg/kg or 200 mg/kg in corn oil) for 12 weeks. 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 20 mg/kg, suggesting an inhibition of pro-inflammatory cytokine production at the 200 mg/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 200 mg/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.

CYP3A Activity and Expression in Nonalcoholic Fatty Liver Disease

“…For comparison, we examined the expression of the predominant mouse hepatic Cyp3a11 enzyme in the SS model and found a trend toward lower (20% 6 6%, P = 0.10) mRNA expression levels in mice on a high-fat diet (n = 6) than in those on a normal diet (n = 6). In the context of previous reports, results in mouse models of NAFLD have been heterogeneous with some demonstrating decreased (Yoshinari et al, 2006;Ghose et al, 2011;Wahlang et al, 2014) or induced (Fisher et al, 2008;Spruiell et al, 2014) expression of Cyp3a11. Similarly, rat models of hepatic steatosis are conflicting, with some reporting decreased Cyp3a expression (Leclercq et al, 1998) and others showing higher levels (Ghoneim et al, 2015).…”

PCB-associated steatohepatitis and the role of nuclear receptors.

“…Future experimental studies are required to evaluate the possible mechanistic role of PCBs in liver cell death. While animal studies have reported interactions between PCB exposures and diet-induced obesity in steatohepatitis 22,23 , no significant interaction was found between ƩPCBs and BMI on liver disease status in this study. However, this analysis may have been limited by the high prevalence of overweight/obesity and the elevated PCB levels in this population.…”

“…Although not directly tested in this study, it is conceivable that PCBs could mediate a transition from NASH to TASH by decreasing apoptosis and promoting more proinflammatory necrotic hepatocyte death. While PCBs were a 'second hit' in the transition from dietinduced steatosis to more advanced liver disease in animal studies 23,[107][108][109] , a significant interaction between PCBs and BMI on liver disease status was not observed in the present study. Perhaps the high rates of overweight/obesity and elevated PCB levels in the cohort limited the ability to detect interactions occurring at lower exposures and body weights.…”

“…Previous epidemiologic studies have demonstrated dose responses for PCBs in liver disease [95][96][97][98][99] , and animal studies have demonstrated interactions between PCBs and diet-induced obesity in steatohepatitis 22,23 . Univariate analysis was performed in the ACHS-1 cohort to determine associations between ƩPCBs and the liver injury biomarkers used to derive the liver injury categories (Table 13).…”

“…These functions may ultimately explain both the link between PCB exposure and metabolic disruption and some complexities of diet/PCB coexposures in metabolic disease. Our laboratory reported that, in mice, exposure to Aroclor 1260 alone was insufficient to induce a phenotype of steatohepatitis, and that a coexposure to high fat diet was required to observe the phenotypes of fatty liver and diabetes 22,23 .…”