Date on Master's Thesis/Doctoral Dissertation


Document Type

Doctoral Dissertation

Degree Name

Ph. D.


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

Feng, Wenke

Committee Member

Freedman, Jonathan

Committee Member

Hoyle, Gary

Author's Keywords

livery injury; vinyl chloride; high-fat diet; aldehyde; dehyrogenase


Background. Vinyl chloride (VC) is an abundant environmental contaminant that causes steatohepatitis at high exposure levels. We have shown previously that low concentrations of VC exacerbate high fat diet (HFD)-induced liver injury in mice. The mechanisms involved in the progression of liver injury caused by VC and HFD include oxidative stress, inflammation, metabolic and mitochondrial dysfunction. Mitochondrial aldehyde dehydrogenase 2 (ALDH2) serves as a key line of defense against most reactive aldehydes, including lipid aldehydes (e.g., 4-HNE) and chloroacetaldehyde (VC metabolite). We hypothesize that this defense may play a key role in the interaction between HFD and VC in fatty liver disease. Methods. Mice were exposed to VC via inhalation at concentrations below the current OSHA limit (<1 >ppm), or room air for 6 hours per day, 5 days per week for 12 weeks. Mice were fed HFD or a low-fat control diet. Some mice were administered ALDH2 agonist Alda-1 (i.p. 20 mg/kg, 3 times/week) for 3 weeks prior to sacrifice. Metabolic phenotyping, biochemical and histological assessment of liver injury, indices for oxidative stress, inflammation and mitochondrial function were examined. Results. ALDH2 is a direct target of VC metabolite toxicity. Moreover, we demonstrated that ALDH2 activation by Alda-1 pre-treatment decreased lipid accumulation, oxidative stress, and prevented liver injury induced by acute exposure to VC metabolites. Chapter IV describes a chronic model of low-dose VC exposure with HFD. The interaction of VC and HFD decreased ALDH2 expression and activity in mitochondria. Liver injury was characterized by enhanced steatosis, inflammation and oxidative stress. This interaction correlated with mitochondrial dysfunction and metabolic stress. Administration of ALDH2 agonist Alda-1 prevented the decrease in ALDH2 activity and conferred profound protection against these changes caused by HFD+VC. Conclusion: Taken together, these results support the hypothesis that ALDH2 appears to be a direct target of VC exposure, which likely contributes to the enhancement of liver injury under these conditions. Importantly, ALDH2 plays a critical role in liver injury caused low-level VC exposure and HFD and may therefore be a potential target for future therapies.