title: Occupational exposures at a polyvinyl chloride production facility are associated with significant changes to the plasma metabolome.
abstract: BACKGROUND
  Occupational vinyl chloride (VC) exposures have been associated with toxicant-associated steatohepatitis and liver cancer. Metabolomics has been used to clarify mode of action in drug-induced liver injury but has not been performed following VC exposures.
  
  
  METHODS
  Plasma samples from 17 highly exposed VC workers without liver cancer and 27 unexposed healthy volunteers were obtained for metabolite extraction and GC/MS and LC/MS2analysis. Following ion identification/quantification, Ingenuity pathway analysis was performed.
  
  
  RESULTS
  613 unique named metabolites were identified. Of these, 189 metabolites were increased in the VC exposure group while 94 metabolites were decreased. Random Forest analysis indicated that the metabolite signature could separate the groups with 94% accuracy. VC exposures were associated with increased long chain (including arachidonic acid) and essential (including linoleic acid) fatty acids. Occupational exposure increased lipid peroxidation products including monohydroxy fatty acids (including 13-HODE); fatty acid dicarboxylates; and oxidized arachidonic acid products (including 5,9, and 15-HETE). Carnitine and carnitine esters were decreased, suggesting peroxisomal/mitochondrial dysfunction and alternate modes of lipid oxidation. Differentially regulated metabolites were shown to interact with extracellular-signal-regulated kinase 1/2 (ERK1/2), Akt, AMP-activated protein kinase (AMPK), and the N-Methyl-d-aspartate (NMDA) receptor. The top canonical pathways affected by occupational exposure included tRNA charging, nucleotide degradation, amino acid synthesis/degradation and urea cycle. Methionine and homocysteine was increased with decreased cysteine, suggesting altered 1-carbon metabolism.
  
  
  CONCLUSIONS
  Occupational exposure generated a distinct plasma metabolome with markedly altered lipid and amino acid metabolites. ERK1/2, Akt, AMPK, and NMDA were identified as protein targets for vinyl chloride toxicity.
authors.affiliation: University of Louisville Department of Medicine, Louisville, KY 40206, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Guardiola
authors.affiliation: Department of Pharmacology and Toxicology, Louisville, KY 40206, USA.
authors.forename: Juliane I
authors.initials: JI
authors.lastname: Beier
authors.affiliation: Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, Louisville, KY 40206, USA.
authors.forename: K Cameron
authors.initials: KC
authors.lastname: Falkner
authors.affiliation: Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, Louisville, KY 40206, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Wheeler
authors.affiliation: Department of Pharmacology and Toxicology, Louisville, KY 40206, USA; Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, Louisville, KY 40206, USA; The Robley Rex Veterans Affairs Medical Center, Louisville, KY, 40206, USA; The Kentucky One Health Jewish Hospital Liver Transplant Program, Louisville, KY 40202, USA.
authors.forename: Craig James
authors.initials: CJ
authors.lastname: McClain
authors.affiliation: Department of Pharmacology and Toxicology, Louisville, KY 40206, USA; Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, Louisville, KY 40206, USA; The Robley Rex Veterans Affairs Medical Center, Louisville, KY, 40206, USA; The Kentucky One Health Jewish Hospital Liver Transplant Program, Louisville, KY 40202, USA; Department of Biochemistry and Molecular Biology, Louisville, KY, 40202, USA. Electronic address: matt.cave@louisville.edu.
authors.forename: Matt
authors.initials: M
authors.lastname: Cave
mesh_terms: D000328:Adult; D001798:Blood Proteins / Q000378:metabolism*; D016022:Case-Control Studies; D006801:Humans; D055432:Metabolomics; D008875:Middle Aged; D016273:Occupational Exposure; D011143:Polyvinyl Chloride / Q000138:chemical synthesis / Q000633:toxicity*
chemical_list: D001798:Blood Proteins; D011143:Polyvinyl Chloride
keywords: Hemangiosarcoma; Metabolomics; Occupational Health; TASH; Toxicant Associated Steatohepatitis; Vinyl Chloride