N-diethylnitrosamine mouse hepatotoxicity: time-related effects on histology and oxidative stress

Exp Toxicol Pathol. 2014 Dec;66(9-10):429-36. doi: 10.1016/j.etp.2014.07.002. Epub 2014 Aug 2.


Animal models, namely mice, have been used to study chemically induced carcinogenesis due to their similarity to the histological and genetic features of human patients. Hepatocellular carcinoma (HCC) is a common malignancy with poor clinical outcome. The high incidence of HCC might be related to exposure to known risk factors, including carcinogenic compounds, such as N-nitrosamines, which cause DNA damage. N-nitrosamines affect cell mitochondrial metabolism, disturbing the balance between reactive oxygen species (ROS) and antioxidants, causing oxidative stress and DNA damage, potentially leading to carcinogenesis. This work addresses the progressive histological changes in the liver of N-diethylnitrosamine (DEN)-exposed mice and its correlation with oxidative stress. Male ICR mice were randomly divided into five DEN-exposed and five matched control groups. DEN was IP administered, once a week, for eight consecutive weeks. Samples were taken 18 h after the last DEN injection (8 weeks post-exposure). The following sampling occurred at weeks 15th, 22nd, 29th and 36th after the first DEN injection. DEN resulted in early toxic lesions and, from week 29 onwards, in progressive proliferative lesions. Between 15 and 29 weeks, DEN-exposed animals showed significant changes in hepatic antioxidant (glutathione, glutathione reductase, and catalase) status (p<0.05) compared with controls. These results point to an association between increased DEN-induced oxidative stress and the early histopathological alterations, suggesting that DEN disrupted the antioxidant defense mechanism, thereby triggering liver carcinogenesis.

Keywords: Antioxidants; Hepatocellular carcinoma; Liver; Mice; N-diethylnitrosamine (DEN); Reactive oxygen species (ROS).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkylating Agents / toxicity*
  • Animals
  • Diethylnitrosamine / toxicity*
  • Liver / drug effects*
  • Liver / pathology
  • Male
  • Mice
  • Mice, Inbred ICR
  • Oxidative Stress / drug effects*
  • Time


  • Alkylating Agents
  • Diethylnitrosamine