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/MS2 analysis. 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.

Vinyl chloride dysregulates metabolic homeostasis and enhances diet‐induced liver injury in mice

“…The impact of VC exposure on the mitochondria seems relatively specific for components of the electron transport chain. For example, similar to published data of a cohort of VC‐exposed humans, mitochondria fatty acid β‐oxidation, another key mitochondrial source of cellular energy, was unaffected by VC exposure (Fig. C).…”

“…During the 1970s, a rare form of liver cancer, hepatic angiosarcoma, was found to be directly associated with extremely high occupational exposure to VC (>1,000 ppm) . More recently, Guardiola et al and Cave et al described a pathology unique to VC exposure, toxicant‐associated steatohepatitis (TASH), in chemical plant workers exposed to VC. This new pathology is distinct from malignancies previously associated with VC exposure.…”

Vinyl Chloride and High-Fat Diet as a Model of Environment and Obesity Interaction

“…The VC-inhalation plus high fat diet (HFD) model described here (see Figure 1 for timeline), is the first model of chronic, low-dose VC exposure (i.e., sub-OSHA concentration), in which mice are exposed to the toxicant under conditions that mimic human exposure much more closely. Indeed, data from this model recapitulated results observed in humans exposed to VC, such as the impact on metabolic pathways 20 , oxidative stress and mitochondrial dysfunction 4 . Other mouse models of inhalation, such as head-only and nose-only models 21 , require that the animal be restrained, causing stress to the animal.…”

Improving the Healthiness of Sustainable Construction: Example of Polyvinyl Chloride (PVC)

“…These compounds are both able to bind to proteins, DNA and RNA and may also form DNA adducts [52]. Exposure to VCM has been shown to lead to chromosomal damage [61][62][63], specific point mutations and altered mRNA expression of genes involved in cell processes [60,64], and markedly altered lipid and amino acid metabolites which may increase the risk of disease [65]. Studies of workers exposed to VCM and patients with existing angiosarcoma of the liver or pre-malignant angiosarcoma lesions identified the presence of specific point mutations in serum.…”