Polychlorinated biphenyl 153 is a diet-dependent obesogen that worsens nonalcoholic fatty liver disease in male C57BL6/J mice

Abstract

Background Polychlorinated biphenyls (PCBs) are persistent environmental pollutants which are detectable in the serum of all American adults. Amongst PCB congeners, PCB 153 has the highest serum level. PCBs have been dose-dependently associated with obesity, metabolic syndrome, and nonalcoholic fatty liver disease (NAFLD) in epidemiological studies. Objective The purpose of this study is to determine mechanisms by which PCB 153 worsens diet-induced obesity and NAFLD in male mice fed a high fat diet (HFD). Methods Male C57BL6/J mice were fed either control or 42% milk fat diet for 12 weeks with or without PCB 153 co-exposure (50 mg/kg i.p. × 4). Glucose tolerance test was performed, and plasma and tissues were obtained at necropsy for measurements of adipocytokine levels, histology and gene expression. Results In control diet-fed mice, addition of PCB 153 had minimal effects on any of the measured parameters. However, PCB 153 treatment in high fat-fed mice was associated with increased visceral adiposity, hepatic steatosis and plasma adipokines including adiponectin, leptin, resistin and plasminogen activator inhibitor-1 levels. Likewise, co-exposure reduced expression of hepatic genes implicated in β-oxidation while increasing the expression of genes associated with lipid biosynthesis. Regardless of diet, PCB 153 had no effect on insulin resistance or tumor necrosis factor alpha levels. Conclusion PCB 153 is an obesogen which exacerbates hepatic steatosis; alters adipocytokines; and disrupts normal hepatic lipid metabolism when administered with HFD, but not control diet. Because all U.S. adults have been exposed to PCB 153, this particular nutrient-toxicant interaction potentially impacts human obesity/NAFLD.

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.…”

“…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 .…”

Evaluation of Relationship Between Obesity and Endocrine Disrupting Chemicals-II: Polychlorinated Biphenyls: Review

“…Araştırmacılar, yüksek yağ içerikli diyetle birlikte maruz kalındığında, PCB153'ün karaciğer yağlan-masına neden olan, adipositokinleri değiştiren ve normal lipit metabolizmasını bozan bir obeziteye neden olucu ajan (obezojen) olarak etki gösterdiği sonucuna varmışlardır. 49 Yukarıda belirtilen hayvan çalışmalarının özeti Tablo 2'de görülmektedir.…”

Evaluating the effects of aroclor 1260 in non-alcoholic fatty liver disease : the role of xenobiotic receptors.

“…The "Yucheng" incident was one of the two known major human PCB intoxication episodes, where the victims ingested cooking oil that was highly contaminated with PCBs. Additionally; rodent studies have correlated PCB exposures with NAFLD, obesity and the metabolic syndrome (48,49).…”