NTP researchers identify mechanism in vinylidene chloride renal tumor formation
A two-year study, by National Toxicology Program researchers, found that male B6C3F1/N mice exposed to vinylidene chloride (VDC) exhibited dose-dependent increases in renal cell hyperplasia, renal cell adenoma, and renal cell carcinoma (RCC). VDC is widely used in production of food packaging plastics, commercial resins, and flame retardant coatings. Occupational exposure to VDC may occur by inhalation or dermal contact. The general population is exposed by contaminated drinking water.
The objective of this NTP study was to understand the mechanisms of carcinogenesis in kidney, or renal, cells, by examining global gene expression profiles and mutations in mouse RCC resulting from chronic VDC exposure.
Researchers found that in 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. The susceptibility of male but not female mice may be related to the activity of CYP2E1, which differs in male and female mice, and its subsequent metabolism.
Consistent with previous observations that VDC acts as a nongenotoxic carcinogen, the authors found VDC-induced RCC may be secondary to renal cytotoxicity, regenerative hyperplasia, and subsequent neoplasia. (GK)
Citation: Hayes SA, Pandiri AR, Ton TT, Hong HL, Clayton NP, Shockley KR, Peddada SD, Gerrish K, Wyde M, Sills RC, Hoenerhoff MJ. 2015. Renal cell carcinomas in vinylidene chloride-exposed male B6C3F1 mice are characterized by oxidative stress and TP53 pathway dysregulation. Toxicol Pathol 44(1):71-87.