Renal Cell Carcinomas in Vinylidene Chloride-exposed Male B6C3F1 Mice Are Characterized by Oxidative Stress and TP53 Pathway Dysregulation

Toxicol Pathol. 2016 Jan;44(1):71-87. doi: 10.1177/0192623315610820. Epub 2015 Dec 17.


Vinylidene chloride (VDC) has been widely used in the production of plastics and flame retardants. Exposure of B6C3F1 mice to VDC in the 2-year National Toxicology Program carcinogenicity bioassay resulted in a dose-dependent increases in renal cell hyperplasia, renal cell adenoma, and renal cell carcinomas (RCCs). Among those differentially expressed genes from controls and RCC of VDC-exposed mice, there was an overrepresentation of genes from pathways associated with chronic xenobiotic and oxidative stress as well as c-Myc overexpression and dysregulation of TP53 cell cycle checkpoint and DNA damage repair pathways in RCC. Trend analysis comparing RCC, VDC-exposed kidney, and chamber control kidney showed a conservation of pathway dysregulation in terms of overrepresentation of xenobiotic and oxidative stress, and DNA damage and cell cycle checkpoint pathways in both VDC-exposed kidney and RCC, suggesting that these mechanisms play a role in the pathogenesis of RCC in VDC-exposed mice.

Keywords: National Toxicology Program; carcinogenicity bioassay; global gene expression; immunohistochemistry; microarray; mutation analysis; quantitative PCR; renal cell carcinoma; renal tubular hyperplasia; vinylidene chloride.

MeSH terms

  • Animals
  • Carcinoma, Renal Cell* / chemically induced
  • Carcinoma, Renal Cell* / metabolism
  • Carcinoma, Renal Cell* / pathology
  • Carcinoma, Renal Cell* / physiopathology
  • Dichloroethylenes / toxicity*
  • Dose-Response Relationship, Drug
  • Female
  • Gene Expression Profiling
  • Kidney / drug effects
  • Kidney / pathology
  • Kidney Neoplasms* / chemically induced
  • Kidney Neoplasms* / metabolism
  • Kidney Neoplasms* / pathology
  • Kidney Neoplasms* / physiopathology
  • Male
  • Mice
  • Mutation
  • Oxidative Stress / drug effects*
  • Signal Transduction / drug effects*
  • Toxicity Tests, Chronic
  • Tumor Suppressor Protein p53 / genetics*
  • Tumor Suppressor Protein p53 / metabolism


  • Dichloroethylenes
  • Tumor Suppressor Protein p53
  • vinylidene chloride