Oxidative DNA damage is involved in ochratoxin A-induced G2 arrest through ataxia telangiectasia-mutated (ATM) pathways in human gastric epithelium GES-1 cells in vitro.

Abstract

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 G2 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 G2 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 G2 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 G2 arrest elicited by OTA. Finally, pretreatment with the antioxidant N-acetyl-L-cysteine (NAC) reduced the OTA-induced DNA DSBs, ATM phosphorylation, and G2 arrest. In conclusion, the results of this study suggested that OTA-induced oxidative DNA damage triggered the ATM-dependent pathways, which ultimately elicited a G2 arrest in GES-1 cells.

• Authors: Jinfeng Cui, Jing Liu, Sha Wu, Yuan Wang, Haitao Shen, Lingxiao Xing, Junling Wang, Xia Yan, Xianghong Zhang
• Journal: Archives of toxicology (Arch Toxicol) Vol. 87 Issue 10 Pg. 1829-40 (Oct 2013) ISSN: 1432-0738 [Electronic] Germany
• PMID: 23515941 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antioxidants
• Ochratoxins
• RNA, Small Interfering
• Reactive Oxygen Species
• ochratoxin A
• Caffeine
• Ataxia Telangiectasia Mutated Proteins
• Acetylcysteine

Topics

• Acetylcysteine (pharmacology)
• Antioxidants (pharmacology)
• Ataxia Telangiectasia Mutated Proteins (metabolism)
• Caffeine (pharmacology)
• Cell Line
• DNA Breaks, Double-Stranded (drug effects)
• DNA Damage (drug effects)
• G2 Phase Cell Cycle Checkpoints (drug effects)
• Gastric Mucosa (drug effects, metabolism, pathology)
• Humans
• Ochratoxins (toxicity)
• Oxidative Stress (drug effects)
• Phosphorylation (drug effects)
• RNA, Small Interfering (administration & dosage)
• Reactive Oxygen Species (metabolism)