title: Oxidative stress-related DNA damage and homologous recombination repairing induced by N,N-dimethylformamide.
abstract: The intensified anthropogenic release of N,N-dimethylformamide (DMF) has been proven to have hepatotoxic effects. However, the potential mechanism for DMF-induced toxicity has rarely been investigated. Our research implicated that DMF induced a significantly dose-dependent increase in reactive oxygen species (ROS) in HL-7702 human liver cells. Moreover, oxidative stress-related DNA damage, marked as 8-hydroxy-2'-deoxyguanosine, was increased 1.5-fold at 100 mmol l(-1) . The most severe DNA lesion (double-strand break, DSB), measured as the formation of γH2AX foci, was increased at/above 6.4 mmol l(-1) , and approximately 50% of cells underwent DSB at the peak induction. Subsequently, the DNA repair system triggered by molecules of RAD50 and MRE11A induced the homologous recombination (HR) pathway by upregulation of both gene and protein levels of RAD50, RAD51, XRCC2 and XRCC3 at 16 mmol l(-1) and was attenuated at 40 mmol l(-1) . Consequently, cellular death observed at 40 mmol l(-1) was exaggerated compared with exposure at 16 mmol l(-1) . Although the exact mechanism relying on the DMF-induced hepatotoxicity needs further clarification, oxidative stress and DNA damage involved in DSBs partially explain the reason for DMF-induced liver injury. Oxidative stress-induced DNA damage should be first considered during risk assessment on liver-targeted chemicals. Copyright © 2015 John Wiley & Sons, Ltd.
authors.affiliation: College of Life Science, Zhejiang Chinese Medical University, Hangzhou, 310053, China.
authors.forename: Cui
authors.initials: C
authors.lastname: Wang
authors.affiliation: College of Life Science, Zhejiang Chinese Medical University, Hangzhou, 310053, China.
authors.forename: Jinhuan
authors.initials: J
authors.lastname: Yang
authors.affiliation: College of Life Science, Zhejiang Chinese Medical University, Hangzhou, 310053, China.
authors.forename: Dezhao
authors.initials: D
authors.lastname: Lu
authors.affiliation: College of Life Science, Zhejiang Chinese Medical University, Hangzhou, 310053, China.
authors.forename: Yongsheng
authors.initials: Y
authors.lastname: Fan
authors.affiliation: Research Center of Environmental Science, College of Biological and Environmental Engineering, Zhejiang University of Technology, Hangzhou, 310032, China.
authors.forename: Meirong
authors.initials: M
authors.lastname: Zhao
authors.affiliation: College of Life Science, Zhejiang Chinese Medical University, Hangzhou, 310053, China.
authors.forename: Zhuoyu
authors.initials: Z
authors.lastname: Li
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D017766:Acid Anhydride Hydrolases; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects*; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D004126:Dimethylformamide / Q000633:toxicity*; D005786:Gene Expression Regulation; D059765:Homologous Recombination; D006801:Humans; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D051135:Rad51 Recombinase / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D017382:Reactive Oxygen Species; C110901:X-ray repair cross complementing protein 3; C113187:XRCC2 protein, human; D004126:Dimethylformamide; D000080242:8-Hydroxy-2'-Deoxyguanosine; C495153:RAD51 protein, human; D051135:Rad51 Recombinase; D017766:Acid Anhydride Hydrolases; C112158:RAD50 protein, human; D045643:DNA Repair Enzymes; D003849:Deoxyguanosine
keywords: DNA double-strand break; DNA oxidative damage; N,N-dimethylformamide; homologous recombination pathway; γH2AX