Vinyl chloride enhances diet-induced liver injury via metabolic dyshomeostasis : critical role of mitochondria.

hepatoxicity;organochlorine;liver disease;vinyl chloride;rubbertown

Anna L. Lang

University:University of Louisville

Department:Pharmacology and Toxicology

关键词: hepatoxicity;    organochlorine;    liver disease;    vinyl chloride;    rubbertown;   

Others  :  https://ir.library.louisville.edu/cgi/viewcontent.cgi?article=4067&context=etd

美国|英语

来源: The Universite of Louisville's Institutional Repository

【 摘 要 】

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.