Gene expression of mesothelioma in vinylidene chloride-exposed F344/N rats reveal immune dysfunction, tissue damage, and inflammation pathways

Toxicol Pathol. 2015 Feb;43(2):171-85. doi: 10.1177/0192623314537885. Epub 2014 Jun 23.


A majority (∼80%) of human malignant mesotheliomas are asbestos-related. However, non-asbestos risk factors (radiation, chemicals, and genetic factors) account for up to 30% of cases. A recent 2-year National Toxicology Program carcinogenicity bioassay showed that male F344/N rats exposed to the industrial toxicant vinylidene chloride (VDC) resulted in a marked increase in malignant mesothelioma. Global gene expression profiles of these tumors were compared to spontaneous mesotheliomas and the F344/N rat mesothelial cell line (Fred-PE) in order to characterize the molecular features and chemical-specific profiles of mesothelioma in VDC-exposed rats. As expected, mesotheliomas from control and VDC-exposed rats shared pathways associated with tumorigenesis, including cellular and tissue development, organismal injury, embryonic development, inflammatory response, cell cycle regulation, and cellular growth and proliferation, while mesotheliomas from VDC-exposed rats alone showed overrepresentation of pathways associated with pro-inflammatory pathways and immune dysfunction such as the nuclear factor kappa-light-chain-enhancer of activated B cells signaling pathway, interleukin (IL)-8 and IL-12 signaling, interleukin responses, Fc receptor signaling, and natural killer and dendritic cells signaling, as well as overrepresentation of DNA damage and repair. These data suggest that a chronic, pro-inflammatory environment associated with VDC exposure may exacerbate disturbances in oncogene, growth factor, and cell cycle regulation, resulting in an increased incidence of mesothelioma.

Keywords: F344/N rat; Fred-PE cells; National Toxicology Program; gene expression; mesothelial cell; mesothelioma; microarray; vinylidene chloride.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • DNA Damage
  • Dichloroethylenes / toxicity*
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Genes, cdc / drug effects
  • Immune System Diseases / chemically induced*
  • Immune System Diseases / immunology
  • Inflammation / chemically induced*
  • Inflammation / physiopathology
  • Lung Neoplasms / chemically induced*
  • Lung Neoplasms / genetics*
  • Male
  • Mesothelioma / chemically induced*
  • Mesothelioma / genetics*
  • Mesothelioma, Malignant
  • Microarray Analysis
  • Peritoneal Neoplasms / chemically induced
  • Peritoneal Neoplasms / pathology
  • RNA, Neoplasm / biosynthesis
  • Rats
  • Rats, Inbred F344
  • Signal Transduction / drug effects
  • Testicular Neoplasms / chemically induced
  • Testicular Neoplasms / pathology


  • Dichloroethylenes
  • RNA, Neoplasm
  • vinylidene chloride