Modulation of the DNA repair system and ATR-p53 mediated apoptosis is relevant for tributyltin-induced genotoxic effects in human hepatoma G2 cells  

作　　者：Bowen Li Lingbin Sun Jiali Cai Chonggang Wang Mengmeng Wang Huiling Qiu Zhenghong Zuo 

机构地区：[1]State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University [2]Department of Gynaecology, The Affiliated Chenggong Hospital of Xiamen University

出　　处：《Journal of Environmental Sciences》2015年第1期108-114,共7页环境科学学报（英文版）

基　　金：supported by the National Natural Science Foundation of China (No. 40606027);the Project of the Xiamen Science and Technology Program (No. 2013Z20134027)

摘　　要：The toxic effects of tributyltin（TBT） have been extensively documented in several types of cells, but the molecular mechanisms related to the genotoxic effects of TBT have still not been fully elucidated. Our study showed that exposure of human hepatoma G2 cells to 1–4 μmol/L TBT for 3 hr caused severe DNA damage in a concentration-dependent manner. Moreover, the expression levels of key DNA damage sensor genes such as the replication factor C, proliferating cell nuclear antigen and poly（ADP-ribose）polymerase-1 were inhabited in a concentration-dependent manner. We further demonstrated that TBT induced cell apoptosis via the p53-mediated pathway, which was most likely activated by the ataxia telangiectasia mutated and rad-3 related（ATR）protein kinase. The results also showed that cytochrome c, caspase-3, caspase-8,caspase-9, and the B-cell lymphoma 2 were involved in this process. Taken together, we demonstrated for the first time that the inhibition of the DNA repair system might be more responsible for TBT-induced genotoxic effects in cells. Then the generated DNA damage induced by TBT initiated ATR-p53-mediated apoptosis.The toxic effects of tributyltin（TBT） have been extensively documented in several types of cells, but the molecular mechanisms related to the genotoxic effects of TBT have still not been fully elucidated. Our study showed that exposure of human hepatoma G2 cells to 1–4 μmol/L TBT for 3 hr caused severe DNA damage in a concentration-dependent manner. Moreover, the expression levels of key DNA damage sensor genes such as the replication factor C, proliferating cell nuclear antigen and poly（ADP-ribose）polymerase-1 were inhabited in a concentration-dependent manner. We further demonstrated that TBT induced cell apoptosis via the p53-mediated pathway, which was most likely activated by the ataxia telangiectasia mutated and rad-3 related（ATR）protein kinase. The results also showed that cytochrome c, caspase-3, caspase-8,caspase-9, and the B-cell lymphoma 2 were involved in this process. Taken together, we demonstrated for the first time that the inhibition of the DNA repair system might be more responsible for TBT-induced genotoxic effects in cells. Then the generated DNA damage induced by TBT initiated ATR-p53-mediated apoptosis.

关 键 词：Tributyltin DNA damage DNA repair Rad-3 related（ATR） protein kinase Apoptosis 

分 类 号：R735.7[医药卫生—肿瘤]