Date on Master's Thesis/Doctoral Dissertation

12-2014

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Pharmacology and Toxicology

Committee Chair

Cave, Matthew C.

Committee Co-Chair (if applicable)

Clark, Barbara J.

Committee Member

States, J. Christopher

Committee Member

Arteel, Gavin E.

Committee Member

Prough, Russell A.

Subject

Fatty liver; Liver--Diseases; Polychlorinated biphenyls--Physiological effect

Abstract

Polychlorinated biphenyls (PCBs) are persistent environmental toxicants, present in 100% of US adults and dose-dependently associated with nonalcoholic fatty liver disease (NAFLD) in epidemiologic studies. PCBs are predicted to interact with receptors previously implicated in xenobiotic/energy metabolism and NAFLD. These receptors include the aryl hydrocarbon receptor (AhR), pregnane xenobiotic receptor (PXR), constitutive androstane receptor (CAR), peroxisome proliferator-activated receptors (PPARs), liver-X-receptor and farnesoid-X-receptor. This study evaluated the hepatic effects of the PCB mixture, Aroclor 1260, whose composition mimics human bioaccumulation patterns, in a mouse model of diet-induced obesity. Male C57Bl/6J mice were fed a control or 42% high fat diet (HFD) and exposed to Aroclor 1260 (20 or 200 mg/kg in corn oil) for 12 weeks. Aroclor 1260 exposure was associated with decreased body fat in HFD-fed mice. Aroclor 1260+HFD co-exposed mice demonstrated increased inflammatory foci at both doses while serum cytokines and hepatic expression of IL-6 and TNFα were increased only at 20 mg/kg. Aroclor 1260 induced hepatic Cyp3a11 (PXR target) and Cyp2b10 (CAR target) expression but Cyp2b10 inducibility was diminished with HFD-feeding. Cyp1a2 (AhR target) was induced only at 200 mg/kg. In PXR-/- and CAR-/- mice, Aroclor 1260 exposure resulted in steatohepatitis with increased basal hepatic TNFα and IL-6 expression. PXR-/- mice had increased % body fat and liver to body weight ratio regardless of exposure. HOMA-IR decreased in all groups following Aroclor 1260 exposure. PXR-/- mice exposed to Aroclor 1260 showed impaired glucose uptake, increased hepatic gluconeogenic and lipogenic gene expression. The knockout groups demonstrated increased basal mTOR1 activity while Aroclor 1260 exposure increased AMPKα activity. Thus, PXR and CAR participate in hepatic energy metabolism and are protective in Aroclor 1260-induced liver injury. The study further evaluated Aroclor 1260 and selected congeners as potential ligands for human receptors utilizing HepG2 and COS-1 cell lines; and primary human hepatocytes. The results suggested that Aroclor 1260 is a human AhR, PXR and CAR3 agonist, a mixed agonist/antagonist for CAR2 and an antagonist for human PPARα. In summary, Aroclor 1260 worsened hepatic inflammation in diet-induced obesity. HFD decreased the protective CAR/PXR activation illustrating the importance of dietary co-exposures in PCB-mediated steatohepatitis.

Download

Share

COinS