Date on Master's Thesis/Doctoral Dissertation

12-2020

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Pharmacology and Toxicology

Degree Program

Pharmacology and Toxicology, PhD

Committee Chair

Cave, Matthew

Committee Co-Chair (if applicable)

Conklin, Daniel

Committee Member

Conklin, Daniel

Committee Member

Hood, Joshua

Committee Member

Mokshagundam, Sriprakash

Committee Member

Freedman, Jonathan

Author's Keywords

PCB126; dioxin-like PCB; NAFLD

Abstract

Polychlorinated biphenyls (PCBs) are persistent organic pollutants associated with non-alcoholic fatty liver disease (NAFLD) and diabetes. Based on their ability to activate the aryl hydrocarbon receptor (AhR), PCBs are subdivided into two classes: dioxin-like (DL) and non- dioxin-like (NDL) PCBs. This study not only evaluated the chronic effect of DL PCBs (PCB126), NDL PCBs (Aroclor1260 mainly contains NDL), and the DL/NDL PCB mixture (PCB126/Aroclor1260 mixture) on liver, but also explored the acute hepatic effects of DL PCB and potential mechanisms in NAFLD and the role of AhR in regulating hepatic proteome and lipid metabolism, and whether the process independent of PCB exposure. Additionally, the acute effects of different doses of Aroclor1260/PCB126 on pancreatic proteome in female mice model were evaluated. HFD fed male C57BL/6J mice were treated with same exposures above for 12 weeks; and chow diet fed male C57BL/6J and AhR-/- mice were exposed to PCB 126 (20 µg/kg) for 2 weeks. Besides, chow diet fed female C57BL/6J mice were treatd with low dose and high dose Aroclor 1260/PCB 126 mixture for 2 weeks. Chronic exposure experiments revealed Aroclor1260 increased hepatic inflammation and promoted phosphoprotein signaling disruption; PCB126 altered cytoskeletal remodeling, metal homeostasis, and disruption of intermediary/xenobiotic metabolism. Aroclor1260+PCB126 exposure enriched multiple epigenetic processes. AhR-/- mice fed control diet had histological steatosis with higher levels of hepatic free fatty acids and triglycerides. AhR ablation upregulated lipogenic genes (Cd36, Perilipin-2) and downregulated lipolytic genes (Pnpla3). Pancreatic proteome in acute female mice showed transcription factors related to pancreas function were overconnected with low dose and high dose Aroclor 1260/PCB 126, including NEUROD5, HNF1-beta, HNF4-alpha, E2F1, FOXP3, HNF1-alpha. Processes associated with the insulin signal pathway were enriched by low dose or high dose Aroclor 1260/PCB126, including ‘insulin-like growth factor receptor signaling pathway’, ‘receptor tyrosine kinase signaling pathway’, ‘signal transduction_insulin signaling. In summary, PCB exposures differentially regulated the hepatic proteome and the histologic severity of diet induced NAFLD. AhR plays a pivotal role in maintenance of lipid metabolism and energy homeostasis and suggested AhR regulated the hepatic proteome and lipid metabolism independent of PCB exposure. Aroclor1260+PCB126 exposure was overconnected transcription factors related to pancreas function and enriched receptor tyrosine kinase signaling pathways, including insulin signaling pathways.

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