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Oxidative stress‐related DNA damage and homologous recombination repairing induced by N , N ‐dimethylformamide
Author(s) -
Wang Cui,
Yang Jinhuan,
Lu Dezhao,
Fan Yongsheng,
Zhao Meirong,
Li Zhuoyu
Publication year - 2016
Publication title -
journal of applied toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.784
H-Index - 87
eISSN - 1099-1263
pISSN - 0260-437X
DOI - 10.1002/jat.3226
Subject(s) - rad51 , oxidative stress , dna damage , homologous recombination , reactive oxygen species , dna repair , dna , chemistry , deoxyguanosine , xrcc3 , microbiology and biotechnology , rad50 , gene , biochemistry , biology , dna binding protein , transcription factor , genotype , single nucleotide polymorphism
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.