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Giovan Cholico

December 2, 2019 @ 9:00 am - 11:00 am MST

Dissertation Information

Title: Acute Exposure To TCDD Increases Liver Disease Progression in Mice with Carbon Tetrachloride-induced Liver Injury

Program: Doctor of Philosophy in Biomolecular Sciences

Advisor: Dr. Kristen Mitchell, Biological Sciences

Committee Members: Dr. Allan Albig, Biological Sciences, Dr. Denise Wingett, Biological Sciences, Dr. Daniel Fologea, Physics, and Dr. Kenneth Cornell, Chemistry and Biochemistry

Abstract:

Liver disease is a worldwide problem and the 9th leading cause of death in the United States. Common causes of liver disease include alcohol abuse, virus infection, and nonalcoholic fatty liver. Regardless of etiology, liver damage elicits inflammation and drives the activation of hepatic stellate cells (HSCs), which deposit collagen throughout the liver. During chronic injury, excessive collagen deposition, referred to as fibrosis or “scarring”, can progress to cirrhosis, cancer, and organ failure. Emerging evidence indicates a strong association between liver disease and exposure to environmental chemicals. This research investigated mechanisms by which exposure to the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) impacts liver disease. TCDD is representative of a family of chemicals that elicit toxicity through the aryl hydrocarbon receptor (AhR). A mouse model system was used in which liver damage was first induced with carbon tetrachloride, and TCDD was administered as a “second hit.” We used mice with the AhR selectively removed from either HSCs or hepatocytes. Results indicate that TCDD treatment exacerbated injury, inflammation and HSC activation through a mechanism that required AhR signaling in hepatocytes. Furthermore, TCDD treatment produced changes in gene expression consistent with a condition called non-alcoholic fatty liver disease. The results raise the intriguing possibility that exposure to environmental contaminants may facilitate liver disease progression in an already-injured liver.