title: Trichloroethylene Exposure Reduces Liver Injury in a Mouse Model of Primary Biliary Cholangitis.
abstract: Trichloroethylene (TCE) is a persistent environmental contaminant proposed to contribute to autoimmune disease. Experimental studies in lupus-prone MRL+/+ mice have suggested that TCE exposure can trigger autoimmune hepatitis. The vast majority of studies examining the connection between TCE and autoimmunity utilize this model, and the impact of TCE exposure in other established models of autoimmune liver disease is not known. We tested the hypothesis that TCE exposure exacerbates experimental hepatic autoimmunity in dominant negative transforming growth factor beta receptor type II (dnTGFBRII) mice, which develop serological and histological features resembling human primary biliary cholangitis. Female 8-week-old wild-type and dnTGFBRII mice were exposed to TCE (0.5 mg/ml) or vehicle (1% ethoxylated castor oil) in the drinking water for 12 or 22 weeks. Liver histopathology in 20- and 30-week-old wild-type mice was unremarkable irrespective of treatment. Mild portal inflammation was observed in vehicle-exposed 20-week-old dnTGFBRII mice and was not exacerbated by TCE exposure. Vehicle-exposed 30-week-old dnTGFBRII mice developed anti-mitochondrial antibodies, marked hepatic inflammation with necrosis, and hepatic accumulation of both B and T lymphocytes. To our surprise, TCE exposure dramatically reduced hepatic parenchymal inflammation and injury in 30-week-old dnTGFBRII mice, reflected by changes in hepatic proinflammatory gene expression, serum chemistry, and histopathology. Interestingly, TCE did not affect hepatic B cell accumulation or induction of the anti-inflammatory cytokine IL10. These data indicate that TCE exposure reduces autoimmune liver injury in female dnTGFBRII mice and suggests that the precise effect of environmental chemicals in autoimmunity depends on the experimental model.
authors.affiliation: Department of Pathobiology and Diagnostic Investigation.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Ray
authors.affiliation: Department of Pathobiology and Diagnostic Investigation.|Institute for Integrative Toxicology.
authors.forename: Anna K
authors.initials: AK
authors.lastname: Kopec
authors.affiliation: Department of Pathobiology and Diagnostic Investigation.|Institute for Integrative Toxicology.|Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan.
authors.forename: Nikita
authors.initials: N
authors.lastname: Joshi
authors.affiliation: Department of Pathobiology and Diagnostic Investigation.
authors.forename: Holly
authors.initials: H
authors.lastname: Cline-Fedewa
authors.affiliation: Department of Pharmacology, Wayne State University School of Medicine, Detroit, Michigan.
authors.forename: Lawrence H
authors.initials: LH
authors.lastname: Lash
authors.affiliation: Department of Pathobiology and Diagnostic Investigation.
authors.forename: Kurt J
authors.initials: KJ
authors.lastname: Williams
authors.affiliation: Department of Internal Medicine Division of Rheumatology, Allergy and Clinical Immunology, University of California Davis School of Medicine, Davis, California.
authors.forename: Patrick S
authors.initials: PS
authors.lastname: Leung
authors.affiliation: Department of Internal Medicine Division of Rheumatology, Allergy and Clinical Immunology, University of California Davis School of Medicine, Davis, California.
authors.forename: M Eric
authors.initials: ME
authors.lastname: Gershwin
authors.affiliation: Department of Pathobiology and Diagnostic Investigation.|Institute for Integrative Toxicology.|Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan.
authors.forename: James P
authors.initials: JP
authors.lastname: Luyendyk
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D002761:Cholangitis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D059647:Gene-Environment Interaction; D019693:Hepatitis, Autoimmune / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008297:Male; D008822:Mice, Transgenic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics; D014241:Trichloroethylene / Q000633:toxicity*
chemical_list: D001323:Autoantibodies; D018125:Receptors, Transforming Growth Factor beta; D014241:Trichloroethylene; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II
keywords: autoimmune; cholangitis; immunotoxicology; liver; primary biliary; systems toxicology.; trichloroethylene