title: Modulation of the DNA repair system and ATR-p53 mediated apoptosis is relevant for tributyltin-induced genotoxic effects in human hepatoma G2 cells.
abstract: 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.
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361102, China. Electronic address: bowen_li@126.com.
authors.forename: Bowen
authors.initials: B
authors.lastname: Li
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361102, China; Department of Gynaecology, The Affiliated Chenggong Hospital of Xiamen University, Xiamen 361002, China.
authors.forename: Lingbin
authors.initials: L
authors.lastname: Sun
authors.affiliation: Department of Gynaecology, The Affiliated Chenggong Hospital of Xiamen University, Xiamen 361002, China.
authors.forename: Jiali
authors.initials: J
authors.lastname: Cai
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361102, China.
authors.forename: Chonggang
authors.initials: C
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361102, China.
authors.forename: Mengmeng
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Gynaecology, The Affiliated Chenggong Hospital of Xiamen University, Xiamen 361002, China. Electronic address: chongmznl@163.com.
authors.forename: Huiling
authors.initials: H
authors.lastname: Qiu
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361102, China. Electronic address: zuozhenghong@xmu.edu.cn.
authors.forename: Zhenghong
authors.initials: Z
authors.lastname: Zuo
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D004249:DNA Damage; D004260:DNA Repair; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000633:toxicity*; D056945:Hep G2 Cells; D006801:Humans; D009152:Mutagenicity Tests; D060888:Real-Time Polymerase Chain Reaction; D014220:Trialkyltin Compounds / Q000633:toxicity*
chemical_list: D004785:Environmental Pollutants; D014220:Trialkyltin Compounds; C011559:tributyltin
keywords: Apoptosis; DNA damage; DNA repair; Rad-3 related (ATR) protein kinase; Tributyltin