Involvement of ROS-mediated mitochondrial dysfunction and SIRT3 down-regulation in tris(2-chloroethyl)phosphate-induced cell cycle arrest

Wenjuan Zhang; Youjian Zhang; Tian Xu; Zhiyuan Wang; Jing Wang; Wei Xiong; Wenhong Lu; Hongyan Zheng; Jing Yuan

doi:10.1039/c5tx00229j

Involvement of ROS-mediated mitochondrial dysfunction and SIRT3 down-regulation in tris(2-chloroethyl)phosphate-induced cell cycle arrest

Toxicol Res (Camb). 2015 Dec 14;5(2):461-470. doi: 10.1039/c5tx00229j. eCollection 2016 Mar 1.

Authors

Wenjuan Zhang^{1

2}, Youjian Zhang^{1

2}, Tian Xu^{1

2}, Zhiyuan Wang^{1

2}, Jing Wang^{1

2}, Wei Xiong^{1

2}, Wenhong Lu^{1

2}, Hongyan Zheng^{1

2}, Jing Yuan^{1

2}

Affiliations

¹ Department of Occupational and Environmental Health , Ministry of Education & Ministry of Environmental Protection , and State Key Laboratory of Environmental Health (Incubating) , School of Public Health , Tongji Medical College , Huazhong University of Science and Technology , Wuhan 430030 , Hubei , P. R. China . Email: jyuan@tjh.tjmu.edu.cn ; ; Tel: +86 27 83693209.
² Key Laboratory of Environment and Health , Ministry of Education & Ministry of Environmental Protection , and State Key Laboratory of Environmental Health (Incubating) , School of Public Health , Tongji Medical College , Huazhong University of Science and Technology , Wuhan 430030 , Hubei , P. R. China.

Abstract

Tris(2-chloroethyl)phosphate (TCEP) is a flame retardant in plastics. It is bio-accumulative and persistent in the environment and has been detected in ambient and indoor air, surface and groundwater, food, house dust, and consumer products. Studies showed that TCEP can cause damage to the liver and kidneys of rats. However, the mechanisms underlying TCEP remain unclear. To investigate the effect of TCEP on mitochondrial function and cell fate, Chang liver cells were treated with TCEP (3.12, 12.50, 50.00, and 200.00 mg L^-1) for 24 and 48 h. The results showed that TCEP increased mitochondrial reactive oxygen species production, disrupted mitochondrial integrity and caused mitochondrial dysfunction, representing increased intercellular free Ca²⁺ levels, decreased mitochondrial membrane potential and mitochondrial DNA copies as well as reduced ATP synthesis, and G2/M cell cycle arrest with down-regulation of SIRT3, forkhead box O3a and manganese superoxide dismutase proteins. The findings suggest that TCEP caused cell cycle arrest through down-regulation of SIRT3 is involved in mitochondrial oxidative stress.