Mechanisms of fibrosis exacerbation by trichloroethylene in hepatic autoimmunity

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DESCRIPTION (provided by applicant): Human exposure to trichloroethylene (TCE) remains a pressing concern in the United States and abroad. The categorization of TCE in recent years as a human carcinogen has further emphasized the need to completely define the potential of TCE exposure to both cause and exacerbate human disease. Strong experimental evidence from rodent studies links TCE exposure to the development of autoimmune liver disease. This connection is substantiated by epidemiological studies indicating an increased prevalence of primary biliary cirrhosis, an autoimmune liver disease, near hazardous waste sites contaminated with TCE. However, there is an insufficient understanding of the risks of TCE exposure in patients with concurrent hepatic autoimmunity, and no existing delineation of the mechanisms whereby TCE influences the progression of autoimmune liver disease. The long-term goal is to define the mechanisms whereby TCE exacerbates liver fibrosis induced by persistent autoimmune-mediated liver damage. The investigators found that exposure of mice to an occupationally-relevant TCE exposure level significantly increased liver fibrosis in mice with coexisting hepatic autoimmunity. The overall objective of these studies is to determine the effect of TCE exposure on the progression of liver fibrosis in non-obese diabetic (NOD).c3c4 mice, a mouse model of autoimmune cholangitis, and concurrently to define the impact of autoimmunity in NOD.c3c4 mice on TCE metabolism. Their central hypothesis is that TCE exposure exacerbates liver fibrosis in hepatic autoimmunity by promoting hepatic synthesis of RANTES and that TCE toxicity is further exacerbated by altered TCE metabolism in autoimmune liver disease. The investigators' grant application includes a comprehensive analysis of the dose- and time-dependent impact of TCE exposure on the pathogenesis of autoimmune liver disease in NOD.c3c4 mice. Reciprocally, these studies draw on the expertise of the investigative team to determine the effect of hepatic autoimmunity on TCE metabolism. To enable identification of mechanistic biomarkers of TCE exposure in hepatic autoimmunity, the proposed studies utilize RNA sequencing to identify genes differentially dysregulated by TCE exposure in liver and blood leukocytes. Moreover, the investigators will determine the effect of the RANTES receptor (CCR1/CCR5) antagonist Met- RANTES on the exacerbation of liver fibrosis elicited by TCE exposure in NOD.c3c4 mice. The expected outcome of these studies would be an improved understanding and detection of individual susceptibility to deleterious effects of TCE. Moreover, these studies would provide currently unavailable therapeutic strategies to counteract the exacerbation of fibrotic responses by TCE in individuals with autoimmunity.