Date on Master's Thesis/Doctoral Dissertation

5-2018

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Pharmacology and Toxicology

Degree Program

Pharmacology and Toxicology, PhD

Committee Chair

Beier, Juliane

Committee Co-Chair (if applicable)

Arteel, Gavin

Committee Member

Arteel, Gavin

Committee Member

Cave, Matt

Committee Member

Wise, John

Committee Member

Freedman, Jonathan

Committee Member

Prough, Russel

Author's Keywords

hepatoxicity; organochlorine; liver disease; vinyl chloride; rubbertown

Abstract

Background. Vinyl chloride (VC) is an environmental toxicant and has been shown to be directly hepatotoxic at high exposures. However, recent studies suggest low-level toxicant exposure can cause subtle changes to the liver. Given the high prevalence of non-alcoholic fatty liver disease (NAFLD) in the United States, it is important to determine the impact of low-level toxicant exposure on the progression of underlying liver injury when combined with other factors. Therefore, the overarching goal of this dissertation was to develop a model of VC co-exposure with high-fat diet (HFD) and to determine the mechanisms by which VC contributes to the development of liver injury. Methods. Mice were fed a low fat diet (LFD) or high fat diet (HFD) and exposed to sub-OSHA levels of VC (0.85 ± 0.1 ppm) or room air 6 hours per day, 5 days per week, for either 6, 8, or 12 weeks. Metabolic phenotyping, biochemical and histological assessment of liver injury, indices for oxidative and endoplasmic reticulum (ER) stress, and mitochondrial function were examined for each time point. Results. Chapter III of this dissertation describes a VC inhalation model in which co-exposure to a HFD significantly enhances liver injury associated with NAFLD. Specifically, mice exposed to both VC and HFD had significantly enhanced indices of liver injury, inflammation, and cell death. In Chapter IV, metabolic dyshomeostasis is evaluated as a mechanism by which VC exposure sensitizes the liver to secondary insults. Indeed, mice exposed to VC alone had significant alterations in glucose homeostasis in addition to enhanced oxidative and ER stress. Finally, Chapter V examines the effect of VC exposure on mitochondrial integrity and function. Importantly, VC’s detrimental effect on mitochondria is specific to enzymes involved in oxidative phosphorylation, rather than general mito-toxic action. Discussion. In conclusion, the work presented in this dissertation has shown that sub-OHSA levels of VC exposure are sufficient to enhance underlying liver injury. Moreover, VC exposure can cause metabolic disruption even in combination with a LFD. VC directly targets complexes of oxidative respiration which sensitize hepatocytes to subsequent injury and cell death.

Download

Included in

Toxicology Commons

Share

COinS