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

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

Author information

1
Veterinary Sciences Department, University of Trás-os-Montes and Alto Douro (UTAD), Quinta de Prados, 5000-911 Vila Real, Portugal; Center for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), University of Trás-os-Montes and Alto Douro, Vila Real, Portugal. Electronic address: nunopsantos@msn.com.
2
Veterinary Sciences Department, University of Trás-os-Montes and Alto Douro (UTAD), Quinta de Prados, 5000-911 Vila Real, Portugal; Veterinary and Animal Science Research Centre (CECAV), Veterinary Science Department, University of Trás-os-Montes and Alto Douro (UTAD), Quinta de Prados, 5000-911 Vila Real, Portugal.
3
Laboratory for Process Engineering, Environment, Biotechnology and Energy (LEPABE), Chemical Engineering Department, Faculty of Engineering, University of Porto (FEUP), Rua Dr. Roberto Frias, 4200-465 Porto, Portugal; Experimental Pathology and Therapeutics Group, CI-IPOP, Portuguese Institute of Oncology, Rua Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal.
4
CQVR, Chemistry Department, University of Trás-os-Montes and Alto Douro, Vila Real, Portugal.
5
Center for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), University of Trás-os-Montes and Alto Douro, Vila Real, Portugal. Electronic address: fpeixoto@utad.pt.
6
Veterinary Sciences Department, University of Trás-os-Montes and Alto Douro (UTAD), Quinta de Prados, 5000-911 Vila Real, Portugal; Center for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), University of Trás-os-Montes and Alto Douro, Vila Real, Portugal; Center for the Study of Animal Sciences (CECA), Food and Agrarian Sciences and Technologies Institute (ICETA), University of Porto, Rua Padre Armando Quintas, 4485-661 Vairão, Portugal. Electronic address: pamo@utad.pt.

Abstract

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)

PMID:
25097018
DOI:
10.1016/j.etp.2014.07.002
[Indexed for MEDLINE]

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