Occupational exposures at a polyvinyl chloride production facility are associated with significant changes to the plasma metabolome

• Published in: Toxicology and applied pharmacology 2016-12, Vol.313, p.47-56
• Main Authors: Guardiola, John J., Beier, Juliane I., Falkner, K. Cameron, Wheeler, Benjamin, McClain, Craig James, Cave, Matt
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; Adult; AMP; ARACHIDONIC ACID; Blood Proteins - metabolism; CARNITINE; Case-Control Studies; CHLORIDES; CYSTEINE; GAS CHROMATOGRAPHY; Hemangiosarcoma; HOMOCYSTEINE; Humans; INJURIES; LINOLEIC ACID; LIPIDS; LIQUID COLUMN CHROMATOGRAPHY; LIVER; MASS SPECTROSCOPY; METABOLITES; Metabolomics; METHIONINE; Middle Aged; NEOPLASMS; OCCUPATIONAL EXPOSURE; Occupational Health; PHOSPHOTRANSFERASES; Polyvinyl Chloride - chemical synthesis; Polyvinyl Chloride - toxicity; PVC; RECEPTORS; TASH; Toxicant Associated Steatohepatitis; VINYL CHLORIDE
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2016.10.001

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. 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/MS2 analysis. Following ion identification/quantification, Ingenuity pathway analysis was performed. 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. 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. •Occupational vinyl chloride exposure is linked to toxicant-associated steatohepatitis, liver cancer, and other diseases.•Vinyl chloride exposure led to a distinct plasma metabolome with markedly altered lipid and amino acid metabolites.•A metabolomics approach can provide useful information regarding exposure in chemical workers.