title: Vinyl Chloride Metabolites Potentiate Inflammatory Liver Injury Caused by LPS in Mice.
abstract: Vinyl chloride (VC) is a ubiquitous environmental contaminant for which human risk is incompletely understood. We have previously reported that high occupational exposure to VC directly caused liver damage in humans. However, whether VC may also potentiate liver injury from other causes is not known. C57Bl/6J mice were administered chloroethanol (CE), a major metabolite of VC, and lipopolysaccharide (LPS) 24 h after CE. Samples were harvested for determination of liver damage, inflammation, and changes in carbohydrate and lipid metabolism. In mice, CE exposure alone caused no detectable liver damage. LPS exposure caused inflammatory liver damage, oxidative stress, lipid accumulation, and glycogen depletion; the effect of all of these variables was potentiated by CE pre-exposure. In vitro experiments suggest that VC metabolite chloroacetaldehyde (CAA) directly damages mitochondria, which may explain the sensitization effect observed in vivo Moreover, co-exposure of cells to CAA and TNFα caused increased cell death, supporting the hypothesis of sensitization by VC metabolites. Taken together, these data demonstrate that exposure to VC/metabolites at levels that are not overtly hepatotoxic can potentiate liver injury caused by another hepatotoxicant. This serves as proof-of-concept that VC hepatotoxicity may be modified by an additional metabolic stress such as endotoxemia, which commonly occurs in acute (eg, sepsis) and chronic (eg, NAFLD) diseases.
authors.affiliation: *Department of Pharmacology and Toxicology Department of Medicine.
authors.forename: Lisanne C
authors.initials: LC
authors.lastname: Anders
authors.affiliation: *Department of Pharmacology and Toxicology.
authors.forename: Anna L
authors.initials: AL
authors.lastname: Lang
authors.affiliation: *Department of Pharmacology and Toxicology.
authors.forename: Anwar
authors.initials: A
authors.lastname: Anwar-Mohamed
authors.affiliation: *Department of Pharmacology and Toxicology.
authors.forename: Amanda N
authors.initials: AN
authors.lastname: Douglas
authors.affiliation: *Department of Pharmacology and Toxicology.
authors.forename: Adrienne M
authors.initials: AM
authors.lastname: Bushau
authors.affiliation: Department of Medicine.
authors.forename: Keith Cameron
authors.initials: KC
authors.lastname: Falkner
authors.affiliation: Department of Medicine Diabetes and Obesity Center.
authors.forename: Bradford G
authors.initials: BG
authors.lastname: Hill
authors.affiliation: Department of Microbiology and Immunology, University of Louisville Health Sciences Center, Louisville, Kentucky 40292; and.
authors.forename: Nikole L
authors.initials: NL
authors.lastname: Warner
authors.affiliation: *Department of Pharmacology and Toxicology.
authors.forename: Gavin E
authors.initials: GE
authors.lastname: Arteel
authors.affiliation: *Department of Pharmacology and Toxicology Department of Medicine Robley Rex Louisville VAMC, Louisville, Kentucky 40206.
authors.forename: Matt
authors.initials: M
authors.lastname: Cave
authors.affiliation: *Department of Pharmacology and Toxicology Department of Medicine Robley Rex Louisville VAMC, Louisville, Kentucky 40206.
authors.forename: Craig J
authors.initials: CJ
authors.lastname: McClain
authors.affiliation: *Department of Pharmacology and Toxicology juliane.beier@louisville.edu.
authors.forename: Juliane I
authors.initials: JI
authors.lastname: Beier
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000079:Acetaldehyde / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity; D000818:Animals; D050260:Carbohydrate Metabolism / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects; D008070:Lipopolysaccharides / Q000633:toxicity*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D013997:Time Factors; D014752:Vinyl Chloride / Q000378:metabolism / Q000633:toxicity*
chemical_list: D008070:Lipopolysaccharides; C482199:lipopolysaccharide, E coli O55-B5; C004656:chloroacetaldehyde; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D000079:Acetaldehyde; D014752:Vinyl Chloride
keywords: PVC; TASH; hepatotoxicity.; toxicant-associated steatohepatitis; vinyl chloride metabolite