Western diet unmasks transient low-level vinyl chloride-induced tumorigenesis; potential role of the (epi-)transcriptome

• Published in: Toxicology and applied pharmacology Vol. 468; p. 116514
• Main Authors: Liu, Silvia, He, Liqing, Bannister, Olivia B., Li, Jiang, Schnegelberger, Regina D., Vanderpuye, Charis-Marie, Althouse, Andrew D., Schopfer, Francisco J., Wahlang, Banrida, Cave, Matthew C., Monga, Satdarshan P., Zhang, Xiang, Arteel, Gavin E., Beier, Juliane I.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.06.2023
• Subjects: Animals; Carcinogenesis - metabolism; Carcinoma, Hepatocellular - pathology; Cell Transformation, Neoplastic - metabolism; Chloroethylene; Diet, Western; Exposure; Hepatocellular cancer; Liver - metabolism; Liver Disease; Liver Neoplasms - chemically induced; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Mice; Non-alcoholic Fatty Liver Disease - metabolism; Transcriptome; Vinyl Chloride - metabolism; Vinyl Chloride - toxicity; Volatile Organic Compound; Volatile Organic Compound; Chloroethylene; Exposure; Liver Disease; Hepatocellular cancer
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2023.116514

Vinyl chloride (VC) monomer is a volatile organic compound commonly used in industry. At high exposure levels, VC causes liver cancer and toxicant-associated steatohepatitis. However, lower exposure levels (i.e., sub-regulatory exposure limits) that do not directly damage the liver, enhance injury caused by Western diet (WD). It is still unknown if the long-term impact of transient low-concentration VC enhances the risk of liver cancer development. This is especially a concern given that fatty liver disease is in and of itself a risk factor for the development of liver cancer. C57Bl/6 J mice were fed WD or control diet (CD) for 1 year. During the first 12 weeks of feeding only, mice were also exposed to VC via inhalation at sub-regulatory limit concentrations (<1 ppm) or air for 6 h/day, 5 days/week. Feeding WD for 1 year caused significant hepatic injury, which was exacerbated by VC. Additionally, VC increased the number of tumors which ranged from moderately to poorly differentiated hepatocellular carcinoma (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 potential interactions between VC exposure and WD. It also emphasizes that current safety restrictions may be insufficient to account for other factors that can influence hepatotoxicity. •Transient VC exposure enhances tumorigenesis caused by Western diet•Transient VC alters metabolic and ribosomal processes•Transient VC changes epitranscriptomic regulation•A unique gene signature of VC-induced tumors correlates with a subset of human HCC