Carcinogenicity and proteomic analysis of N-nitrosodiethylamine in rats

Abstract

N-nitrosodiethylamine (NDEA), a probable human carcinogen, is commonly used in rodent experimental hepatocarcinogenesis research. We evaluated both clastogenicity and carcinogenicity in rats using various concentrations of NDEA via a liver micronucleus assay and a medium-term carcinogenicity test. The administration of repeated NDEA injections ranging from 10 to 50 mg/kg bw together with partial hepatectomy resulted in significantly more liver micronuclei compared to control rats, while the mitotic index was indifferent. However, the highest dose (50 mg/kg bw) was lethal to the rats. Similarly, medium-term exposure at 100 mg/kg bw of NDEA increased the formation of glutathione S-transferase placental form (GST-P) positive foci, a preneoplastic lesion of liver cancer in rats. A proteomic analysis revealed overexpression of hepatic proteins involved in the PI3K/Akt/mTOR pathway after treatment with NDEA. This pathway may play a key role in the mechanisms that influence NDEA-initiated hepatocarcinogenesis in this model. In conclusion, the amount of NDEA used in the present study can be considered as clastogenic and carcinogenic to rat hepatocytes. This finding can further our knowledge concerning the establishment of experimental cancer chemoprevention models in rats.