Western diet unmasks tumorigenic potential of transient vinyl chloride exposure at sub-OSHA level concentrations; potential role of the (epi-)transcriptome.

ABSTRACT: Vinyl chloride (VC) monomer is a volatile organic compound commonly used in industry to produce polyvinyl chloride (PVC). At high exposure levels, VC causes hepatic angiosarcoma and toxicant-associated steatohepatitis. However, our group has recently shown that lower exposure levels (i.e., < OSHA exposure limits), which do not directly damage the liver, enhance injury caused by a Western diet (WD). Although these lower exposure levels are currently considered 'safe,' it is unknown if the long-term impact of transient low-concentration VC enhances the risk of liver cancer development. Low-concentration VC is especially a concern given that fatty liver disease is in and of itself a risk factor for the development of liver cancer. To evaluate the long-term effects of VC exposure C57Bl/6J, mice were fed WD or control diet (CD) for 1 year. During the first 12 weeks of feeding, mice were also exposed to VC via inhalation at concentrations below the current OSHA limit (<1 ppm) or air for 6 hours/day, 5 days/week. During the remaining 9 months of feeding, mice were not exposed to VC. Feeding WD for 1 year caused significant hepatic injury, including steatohepatitis and moderate fibrosis, which was exacerbated by VC. Additionally, VC increased the number of tumors ranging from moderately to poorly differentiated HCC. Transcriptomic analysis demonstrated VC-induced changes in metabolic but also ribosomal processes. Epitranscriptomic analysis showed a VC-induced shift of the modification pattern that has been associated with metabolic disease, mitochondrial dysfunction and cancer. These data indicate that VC sensitizes the liver to other stressors (e.g., WD), resulting in enhanced tumorigenesis. These data raise concerns about a potential interaction between VC exposure and WD. Furthermore, it also emphasizes that current OSHA safety restrictions may be insufficient to account for other factors that can influence hepatotoxicity.

ORGANISM(S): Mus musculus

PROVIDER: GSE197038 | GEO | 2023/05/10

REPOSITORIES: GEO