Date on Senior Honors Thesis

5-2016

Document Type

Senior Honors Thesis

Department

Biology

Degree Program

College of Arts and Sciences

Author's Keywords

PVC; vinyl chloride metabolite; toxicant associated steatohepatitis; TASH; hepatotoxicity

Abstract

Background. Vinyl chloride (VC) is an environmental pollutant found in many industrial sites and it ranks 4th on the 2013 Hazardous Substances Priority List published by Agency for Toxic Substances and Disease Registry’s (ATSDR). We have previously reported increased hepatocellular necrosis with high occupational VC exposure in human and in in vitro models; however, the effect of subtoxic VC exposure on liver with underlying conditions is unknown. The purpose of the current study is to investigate the hepatic injury caused by chloroethanol (CE; VC metabolite) and inflammatory response in two experimental models of high-fat diet (HFD) induced obesity. Methods. Mice were administered a bolus dose of CE or vehicle after 10 weeks of high saturated fatty acid diet (HSFA; 42% milk fat), high polyunsaturated fatty acid diet (HPUFA; 42% corn oil) or low fat control diet (LFD; 13% milk fat LSFA or 13% corn oil LPUFA). Samples were harvested 24 hours after CE exposure for determination of liver damage, inflammation and inflammasome activation. Results. In LFD-fed control mice, CE did not cause any significant changes to the liver. Chloroethanol induced significant liver damage and inflammation in HSFA fed mice, as well as HPUFA fed mice but to a lesser degree. Moreover, steatosis, hepatocyte ballooning, infiltrating 3 inflammatory cells and hepatic expression of proinflammatory cytokines that were observed with CE after HSFA-feeding was blunted by HPUFA-feeding. Conclusions. Chloroethanol (as a surrogate VC exposure) exacerbated liver injury in a ‘2-hit’ paradigm through inflammasome activation and endoplasmic reticulum (ER) stress. This serves as proof-of-concept that VC hepatotoxicity may be modified by diet-induced obesity and nonalcoholic fatty liver disease (NAFLD). These data implicate exposure to VC interact uniquely with saturated and polyunsaturated fatty acids to exacerbate NAFLD.

Lay Summary

The goal of Beier lab is to investigate the effect of gaseous toxin vinyl chloride often found in surrounding residential areas of industrial complexes. While occupational exposure to this compound has been regulated, there are indications that low-level exposure to this compound can cause increased liver injury in residents that have underlying liver conditions due to their life style. For this project, we examine the interactions between vinyl chloride and fatty diet that involves either saturated or unsaturated fat

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