Cypermethrin Induces Macrophages Death through Cell Cycle Arrest and Oxidative Stress-Mediated JNK/ERK Signaling Regulated Apoptosis.
Cypermethrin is one of the most highly effective synthetic pyrethroid insecticides. The toxicity of cypermethrin to the reproductive and nervous systems has been well studied. However, little is known about the toxic effect of cypermethrin on immune cells such as macrophages. Here, we investigated the cytotoxicity of cypermethrin on macrophages and the underlying molecular mechanisms. We found that cypermethrin reduced cell viability and induced apoptosis in RAW 264.7 cells. Cypermethrin also increased reactive oxygen species (ROS) production and DNA damage in a dose-dependent manner. Moreover, cypermethrin-induced G1 cell cycle arrest was associated with an enhanced expression of p21, wild-type p53, and down-regulation of cyclin D1, cyclin E and CDK4. In addition, cypermethrin treatment activated MAPK signal pathways by inducing c-Jun N-terminal kinase (JNK) and extracellular regulated protein kinases 1/2 ERK1/2 phosphorylation, and increased the cleaved poly ADP-ribose polymerase (PARP). Further, pretreatment with antioxidant N-acetylcysteine (NAC) effectively abrogated cypermethrin-induced cell cytotoxicity, G1 cell cycle arrest, DNA damage, PARP activity, and JNK and ERK1/2 activation. The specific JNK inhibitor (SP600125) and ERK1/2 inhibitor (PD98059) effectively reversed the phosphorylation level of JNK and ERK1/2, and attenuated the apoptosis. Taken together, these data suggested that cypermethrin caused immune cell death via inducing cell cycle arrest and apoptosis regulated by ROS-mediated JNK/ERK pathway.
Department of Toxicology, Zhejiang University School of Public Health, 866 Yu-Hang-Tang Road, Hangzhou 310058, China. huangfang0794@163.com.
Fang
F
Huang
Department of Toxicology, Zhejiang University School of Public Health, 866 Yu-Hang-Tang Road, Hangzhou 310058, China. 21418122@zju.edu.cn.
Qiaoyun
Q
Liu
Department of Toxicology, Zhejiang University School of Public Health, 866 Yu-Hang-Tang Road, Hangzhou 310058, China. xieshujun@zju.edu.cn.
Shujun
S
Xie
Department of Toxicology, Zhejiang University School of Public Health, 866 Yu-Hang-Tang Road, Hangzhou 310058, China. hyyxxj@163.com.
Jian
J
Xu
Department of Toxicology, Zhejiang University School of Public Health, 866 Yu-Hang-Tang Road, Hangzhou 310058, China. huangbo1991@zju.edu.cn.
Bo
B
Huang
Department of Toxicology, Zhejiang University School of Public Health, 866 Yu-Hang-Tang Road, Hangzhou 310058, China. georgewuer@126.com.
Yihua
Y
Wu
Department of Toxicology, Zhejiang University School of Public Health, 866 Yu-Hang-Tang Road, Hangzhou 310058, China. dxia@zju.edu.cn.
Dajing
D
Xia
D000818:Animals; D017209:Apoptosis; D059447:Cell Cycle Checkpoints; D002460:Cell Line; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics / Q000378:metabolism; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D007306:Insecticides / Q000633:toxicity*; D020935:MAP Kinase Signaling System; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011722:Pyrethrins / Q000633:toxicity*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
D016213:Cyclins; D007306:Insecticides; D047428:Protein Kinase Inhibitors; D011722:Pyrethrins; D016159:Tumor Suppressor Protein p53; C017160:cypermethrin; D011065:Poly(ADP-ribose) Polymerases; C495902:Cdk4 protein, mouse; D051358:Cyclin-Dependent Kinase 4; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
JNK/ERK; apoptosis; cell cycle arrest; cypermethrin; oxidative stress