Date on Master's Thesis/Doctoral Dissertation

12-2017

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Biochemistry and Molecular Biology

Degree Program

Biochemistry and Molecular Biology, PhD

Committee Chair

Cave, Matthew C.

Committee Co-Chair (if applicable)

Prough, Russell A.

Committee Member

Prough, Russell A.

Committee Member

Clark, Barbara J.

Committee Member

Bhatnagar, Aruni

Committee Member

Arteel, Juliane I.

Author's Keywords

steatohepatitis; polychlorinated biphenyls; metabolism-disrupting chemicals; Anniston, Alabama; non-alcoholic fatty liver disease

Abstract

Metabolic diseases, including fatty liver disease, hyperglycemia, and obesity, result when body systems responsible for managing allostasis (dynamic homeostasis across systems) are pressured beyond their collective compensatory reserve. Nutritional excess contributes to this state, the capacity of which is limited by genetic variation, and failure of one system will gradually lead to pathological overload in the others. Agents which act directly on the communication machinery linking these connected systems can also change the point at which allostatic load becomes allostatic overload. Environmental exposure to polychlorinated biphenyls (PCBs), a class of persistent organic pollutant, is associated with a specific form of toxicant-associated steatohepatitis, fatty liver disease with inflammatory infiltration. PCBs are known to be ligands for the xenobiotic receptors, which, when activated, modulate the transcription of both xenobiotic and intermediary metabolic targets. We investigated the prevalence and characteristics of liver disease in a human population with high environmental PCB exposure, transcriptional changes in the liver in a mouse model of PCB/high-fat diet coexposure, and transcriptional changes attributable to xenobiotic receptors in a primary hepatocyte model.

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