University of Louisville

Poster Title

Mechanistic Insight Into Vinyl Chloride-Induced Liver Injury

Institution

University of Louisville

Abstract

Vinyl chloride (VC), a ubiquitous environmental contaminant, ranks 4th on the ATSDR Hazardous Substances Priority List. It has been shown to cause liver cancer and other hepatic dysfunctions. This study aims to investigate hepatic injury in vivo and its mechanisms including the role of endoplasmic reticulum (ER) stress in vitro. Chow-fed C57Bl/6J mice received chloroethanol (ClEtOH), a VC metabolite, and lipopolysaccharide (LPS) after ClEtOH. High fat diet (HFD)-fed mice received a bolus dose of ClEtOH after 10 weeks, 24 hours prior to sacrifice. Liver damage, inflammation, ER stress and changes in carbohydrate and lipid metabolism were determined. HepG2 cells were treated with chloroacetaldehyde (CLA), VC metabolite. RNA was extracted for analysis of ER stress markers. In chow-fed mice, ClEtOH caused no liver damage but caused changes in carbohydrate and lipid regulating genes. LPS exposure caused oxidative stress, lipid accumulation and inflammation, which was exacerbated by ClEtOH preexposure. ClEtOH increased monocyte and neutrophil activation, transaminase levels, necroinflammatory foci and fatty acids. The combination of ClEtOH and LPS decreased TUNEL-positive cells, suggesting a switch to necrosis. In HFD-fed mice, ClEtOH increased HFD-induced injury, steatosis, infiltrating inflammatory cells, hepatic expression of proinflammatory cytokines and ER stress. CLA decreased oxygen consumption, ATP levels, and mitochondrial function. VC metabolites sensitize the liver to a “second hit.” This serves as proofof- concept that VC hepatotoxicity may be modified by underlying liver diseases, which commonly occurs in liver disease. These data implicate VC exposure as a risk factor in the development of liver disease in susceptible populations.

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Mechanistic Insight Into Vinyl Chloride-Induced Liver Injury

Vinyl chloride (VC), a ubiquitous environmental contaminant, ranks 4th on the ATSDR Hazardous Substances Priority List. It has been shown to cause liver cancer and other hepatic dysfunctions. This study aims to investigate hepatic injury in vivo and its mechanisms including the role of endoplasmic reticulum (ER) stress in vitro. Chow-fed C57Bl/6J mice received chloroethanol (ClEtOH), a VC metabolite, and lipopolysaccharide (LPS) after ClEtOH. High fat diet (HFD)-fed mice received a bolus dose of ClEtOH after 10 weeks, 24 hours prior to sacrifice. Liver damage, inflammation, ER stress and changes in carbohydrate and lipid metabolism were determined. HepG2 cells were treated with chloroacetaldehyde (CLA), VC metabolite. RNA was extracted for analysis of ER stress markers. In chow-fed mice, ClEtOH caused no liver damage but caused changes in carbohydrate and lipid regulating genes. LPS exposure caused oxidative stress, lipid accumulation and inflammation, which was exacerbated by ClEtOH preexposure. ClEtOH increased monocyte and neutrophil activation, transaminase levels, necroinflammatory foci and fatty acids. The combination of ClEtOH and LPS decreased TUNEL-positive cells, suggesting a switch to necrosis. In HFD-fed mice, ClEtOH increased HFD-induced injury, steatosis, infiltrating inflammatory cells, hepatic expression of proinflammatory cytokines and ER stress. CLA decreased oxygen consumption, ATP levels, and mitochondrial function. VC metabolites sensitize the liver to a “second hit.” This serves as proofof- concept that VC hepatotoxicity may be modified by underlying liver diseases, which commonly occurs in liver disease. These data implicate VC exposure as a risk factor in the development of liver disease in susceptible populations.