期刊
ARCHIVES OF TOXICOLOGY
卷 87, 期 10, 页码 1829-1840出版社
SPRINGER HEIDELBERG
DOI: 10.1007/s00204-013-1043-3
关键词
Ochratoxin A; G(2) arrest; DNA damage; Ataxia telangiectasia mutated; Oxidative stress
类别
资金
- Special funds of National Natural Science Foundation of China [81041072]
- General Program of National Natural Science Foundation of China [81171889]
- Hebei Province Natural Science Foundation for the Youth [H2012206053]
Ochratoxin A (OTA), one of the most abundant mycotoxin food contaminants, is classified as possibly carcinogenic to humans. Our previous study showed that OTA could induce a G(2) arrest in immortalized human gastric epithelium cells (GES-1). To explore the putative roles of oxidative DNA damage and the ataxia telangiectasia-mutated (ATM) pathways on the OTA-induced G(2) arrest, the current study systematically evaluated the roles of reactive oxygen species (ROS) production, DNA damage, and ATM-dependent pathway activation on the OTA-induced G(2) phase arrest in GES-1 cells. The results showed that OTA exposure elevated intracellular ROS production, which directly induced DNA damage and increased the levels of 8-OHdG and DNA double-strand breaks (DSBs). In addition, it was found that OTA treatment induced the phosphorylation of the ATM protein, as well as its downstream molecules Chk2 and p53, in response to DNA DSBs. Inhibition of ATM by the pharmacological inhibitor caffeine or siRNA effectively prevented the activation of ATM-dependent pathways and rescued the G(2) arrest elicited by OTA. Finally, pretreatment with the antioxidant N-acetyl-l-cysteine (NAC) reduced the OTA-induced DNA DSBs, ATM phosphorylation, and G(2) arrest. In conclusion, the results of this study suggested that OTA-induced oxidative DNA damage triggered the ATM-dependent pathways, which ultimately elicited a G(2) arrest in GES-1 cells.
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