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Possible involvement of oxidative stress in dicyclanil-induced hepatocarcinogenesis in mice
Mitsuyoshi Moto1, Takashi Umemura, Miwa Okamura
1Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, Fuchu-shi 183-8509, Tokyo, Japan. m-moto@cc.tuat.ac.jp
Abstract:
Our previous study suggested the possibilities that dicyclanil (DC), a nongenotoxic carcinogen, produces oxidative stress in the liver of the two-stage hepatocarcinogenesis model of mice and the stress induced probably causes secondary oxidative DNA damage. However, clear evidences demonstrating the relationship between DC-induced hepatocarcinogenesis, oxidative stress, and oxidative DNA damage have not been obtained. To clarify the relationship, further investigations were performed in the liver of the partially hepatectomized (PH) mice maintained on diet containing 1,500 ppm of DC for 13 and 26 weeks after intraperitoneal injection of dimethylnitrosamine (DMN). Significant increases in mRNA expressions of some metabolism- and oxidative stress-related genes with a formation of gamma-glutamyltranspeptidase (GGT) positive foci were observed in the DMN + DC + PH group by the treatment of DC for 13 and 26 weeks. The levels of 8-hydroxy-deoxyguanosine (8-OHdG) in the liver DNA also significantly increased in mice of the DMN + DC + PH group at weeks 13 and 26 and mice given DC alone for 26 weeks. The in vitro measurement of reactive oxygen species (ROS) generation from the mouse liver microsomes showed a significant increase of ROS production in the presence of DC. These results suggest that DC induces oxidative stress which is probably derived from its metabolic pathway, partly, and support our previous speculation that oxidative stress plays one of the important roles in the DC-induced hepatocarcinogenesis in mice.
Insights
Dicyclanil (DC) exposure causes liver oxidative stress and DNA damage in mice, contributing to cancer development. This study confirms DC
Area of Science:
- Hepatocarcinogenesis research
- Toxicology and molecular mechanisms
- Oxidative stress studies
Background:
- Previous research suggested dicyclanil (DC), a non-genotoxic carcinogen, induces liver oxidative stress and DNA damage in mice.
- A clear link between DC-induced hepatocarcinogenesis, oxidative stress, and DNA damage remained unestablished.
- Understanding these mechanisms is crucial for assessing DC's carcinogenic potential.
Purpose of the Study:
- To investigate the relationship between dicyclanil (DC) exposure, oxidative stress, and DNA damage in a mouse model of hepatocarcinogenesis.
- To clarify the role of oxidative stress in DC-induced liver cancer development.
Main Methods:
- Partially hepatectomized (PH) mice were administered dimethylnitrosamine (DMN) followed by a diet containing 1,500 ppm of DC for 13 and 26 weeks.
- Gene expression (mRNA) of metabolism and oxidative stress markers, gamma-glutamyltranspeptidase (GGT) positive foci, and 8-hydroxy-deoxyguanosine (8-OHdG) levels in liver DNA were analyzed.
- In vitro reactive oxygen species (ROS) generation from mouse liver microsomes was measured in the presence of DC.
Main Results:
- DC treatment significantly increased mRNA expression of metabolism and oxidative stress genes and induced GGT-positive foci in DMN + DC + PH mice.
- Significant increases in liver DNA 8-OHdG levels were observed in DMN + DC + PH mice and mice treated with DC alone.
- In vitro studies showed DC significantly increased ROS production in mouse liver microsomes.
Conclusions:
- Dicyclanil (DC) induces oxidative stress, likely through its metabolic pathway.
- The findings support the hypothesis that oxidative stress plays a key role in DC-induced hepatocarcinogenesis.
- DC exposure leads to oxidative DNA damage, contributing to liver cancer development in mice.
