Chloroacetic acid induced neuronal cells death through oxidative stress-mediated p38-MAPK activation pathway regulated mitochondria-dependent apoptotic signals

被引：45

作者：

Chen, Chun-Hung ^{[1
,2
]}

Chen, Sz-Jie ^{[1
]}

Su, Chin-Chuan ^{[3
]}

Yen, Cheng-Chieh ^{[4
,5
]}

Tseng, To-Jung ^{[6
]}

Jinn, Tzyy-Rong ^{[7
]}

Tang, Feng-Cheng ^{[8
]}

Chen, Kuo-Liang ^{[9
,10
]}

Su, Yi-Chang ^{[7
]}

Lee, Kuan-I ^{[11
]}

Hung, Dong-Zong ^{[12
]}

Huang, Chun-Fa ^{[7
]}

机构：

[1] China Med Univ, Coll Pharm, Sch Pharm, Taichung 404, Taiwan

[2] China Med Univ Hosp, Dept Emergency, Taichung 404, Taiwan

[3] Changhua Christian Hosp, Dept Otorhinolaryngol Head & Neck Surg, Changhua 500, Taiwan

[4] Chung Shan Med Univ, Coll Hlth Care & Management, Dept Occupat Safety & Hlth, Taichung 402, Taiwan

[5] Chung Shan Med Univ Hosp, Dept Occupat Med, Taichung 402, Taiwan

[6] China Med Univ, Dept Anat, Coll Med, Taichung 404, Taiwan

[7] China Med Univ, Coll Chinese Med, Sch Chinese Med, Taichung 404, Taiwan

[8] Changhua Christian Hosp, Dept Occupat Med, Changhua 500, Taiwan

[9] China Med Univ Hosp, Dept Urol, Taichung 404, Taiwan

[10] China Med Univ, Sch Med, Taichung 404, Taiwan

[11] Buddhist Tzu Chi Gen Hosp, Taichung Branch, Dept Emergency, Taichung 427, Taiwan

[12] China Med Univ Hosp, Trauma & Emergency Ctr, Div Toxicol, Taichung 404, Taiwan

来源：

TOXICOLOGY | 2013年 / 303卷 / 01期

关键词：

Chloroacetic acid (CA); Neurotoxicity; Apoptosis; Oxidative stress; Mitochondrial dysfunction; p38-MAPK; ENDOPLASMIC-RETICULUM STRESS; DISINFECTION BY-PRODUCTS; MONOCHLOROACETIC ACID; SODIUM MONOCHLOROACETATE; SKIN EXPOSURE; PC12; CELLS; TOXICITY; DYSFUNCTION; DISEASES; ROLES;

D O I：

10.1016/j.tox.2012.10.008

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

Chloroacetic acid (CA), a toxic chlorinated analog of acetic acid, is widely used in chemical industries as an herbicide, detergent, and disinfectant, and chemical intermediates that are formed during the synthesis of various products. In addition, CA has been found as a by-product of chlorination disinfection of drinking water. However, there is little known about neurotoxic injuries of CA on the mammalian, the toxic effects and molecular mechanisms of CA-induced neuronal cell injury are mostly unknown. In this study, we examined the cytotoxicity of CA on cultured Neuro-2a cells and investigated the possible mechanisms of CA-induced neurotoxicity. Treatment of Neuro-2a cells with CA significantly reduced the number of viable cells (in a dose-dependent manner with a range from 0.1 to 3 mM), increased the generation of ROS, and reduced the intracellular levels of glutathione depletion. CA also increased the number of sub-G1 hypodiploid cells; increased mitochondrial dysfunction (loss of MMP, cytochrome c release, and accompanied by Bcl-2 and Mcl-1 down-regulation and Box up-regulation), and activated the caspase cascades activations, which displayed features of mitochondria-dependent apoptosis pathway. These CA-induced apoptosis-related signals were markedly prevented by the antioxidant N-acetylcysteine (NAC). Moreover, CA activated the JNK and p38-MAPK pathways, but did not that ERK1/2 pathway, in treated Neuro-2a cells. Pretreatment with NAC and specific p38-MAPK inhibitor (SB203580), but not JNK inhibitor (SP600125) effectively abrogated the phosphorylation of p38-MAPK and attenuated the apoptotic signals (including: decrease in cytotoxicity, caspase-3/-7 activation, the cytosolic cytochrome c release, and the reversed alteration of Bcl-2 and Box mRNA) in CA-treated Neuro-2a cells. Taken together, these data suggest that oxidative stress-induced p38-MAPK activated pathway-regulated mitochondria-dependent apoptosis plays an important role in CA-caused neuronal cell death. (C) 2012 Elsevier Ireland Ltd. All rights reserved.

引用

页码：72 / 82

页数：11

共 80 条

[1] Carmustine induces ERK- and JNK-dependent cell death of neuronally-differentiated PC12 cells via generation of reactive oxygen species [J].