Date on Master's Thesis/Doctoral Dissertation

5-2012

Document Type

Master's Thesis

Degree Name

M.S.

Department

Pharmacology and Toxicology

Committee Chair

Cave, Matthew C.

Author's Keywords

Polychlorinated biphenyls; Non-alcoholic fatty liver disease; High fat diet; Adipokines; Obesity; PCB 153

Subject

Polychlorinated biphenyls--Physiological effect; Liver--Diseases

Abstract

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 suspected nonalcoholic fatty liver disease (NAFLD), obesity and metabolic syndrome in epidemiological studies. The purpose of this study is to determine if PCB 153 induces NAFLD in mice fed a control diet (CD), and exacerbates NAFLD in mice fed a high fat diet (HFD). C57BL6/J mice were fed either control or 42% milk fat diet for 12 weeks with or without PCB 153 coexposure (50 mg/kg i.p. x 4). Glucose tolerance tests were performed, and plasma/tissues were obtained at necropsy for measurements of adipocytokine levels, histology, and gene expression microarrays. In mice fed CD, the addition of PCB 153 had little to no effect on any of the measured parameters. In contrast, PCB 153 co-exposure in high fat-fed mice was associated with dramatically increased visceral adiposity, hepatic steatosis and increased plasma adipokines including adiponectin, leptin, resistin and plasminogen activator inhibitor-1 levels. Likewise, co-exposure reduced expression of hepatic genes implicated in ~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. However, HFD+PCB 153 appeared to induce an endoplasmic reticulum (ER) stress response. Therefore, PCB 153 is an obesogen which exacerbates hepatic steatosis; alters adipocytokines; and disrupts normal hepatic lipid metabolism when administered with HFD. Because all U.S. adults have been exposed to PCB 153, this particular nutrient-toxicant interaction potentially impacts on the progression of human NAFLD.

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