Chloroacetic acid induced neuronal cells death through oxidative stress-mediated p38-MAPK activation pathway regulated mitochondria-dependent apoptotic signals
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 d...
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Veröffentlicht in: | Toxicology (Amsterdam) 2013-01, Vol.303 (7), p.72-82 |
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creator | Chen, Chun-Hung Chen, Sz-Jie Su, Chin-Chuan Yen, Cheng-Chieh Tseng, To-Jung Jinn, Tzyy-Rong Tang, Feng-Cheng Chen, Kuo-Liang Su, Yi-Chang Lee, kuan-I Hung, Dong-Zong Huang, Chun-Fa |
description | 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 3mM), 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 Bax 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 Bax 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. |
doi_str_mv | 10.1016/j.tox.2012.10.008 |
format | Article |
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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 3mM), 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 Bax 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 Bax 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.</description><identifier>ISSN: 0300-483X</identifier><identifier>EISSN: 1879-3185</identifier><identifier>DOI: 10.1016/j.tox.2012.10.008</identifier><identifier>PMID: 23103613</identifier><language>eng</language><publisher>Ireland: Elsevier Ireland Ltd</publisher><subject>Acetates - administration & dosage ; Acetates - toxicity ; acetic acid ; acetylcysteine ; Activated ; Activation ; Animals ; Anthracenes - pharmacology ; antioxidants ; Apoptosis ; Apoptosis - drug effects ; Byproducts ; caspases ; Cell Line, Tumor ; chlorination ; Chloroacetic acid (CA) ; cytochrome c ; cytotoxicity ; disinfectants ; disinfection ; Dose-Response Relationship, Drug ; drinking water ; Emergency ; glutathione ; Glutathione - metabolism ; herbicides ; Imidazoles - pharmacology ; industry ; Inhibitors ; mammals ; messenger RNA ; Mice ; Mitochondria - drug effects ; Mitochondria - pathology ; Mitochondrial dysfunction ; mitogen-activated protein kinase ; Neuroblastoma - metabolism ; neurons ; Neurons - drug effects ; Neurons - pathology ; Neurotoxicity ; Neurotoxicity Syndromes - etiology ; Neurotoxicity Syndromes - pathology ; Oxidative stress ; Oxidative Stress - drug effects ; p38 Mitogen-Activated Protein Kinases - drug effects ; p38 Mitogen-Activated Protein Kinases - metabolism ; p38-MAPK ; Pathways ; phosphorylation ; Pyridines - pharmacology ; Toxic ; Toxicology</subject><ispartof>Toxicology (Amsterdam), 2013-01, Vol.303 (7), p.72-82</ispartof><rights>Elsevier Ireland Ltd</rights><rights>2012 Elsevier Ireland Ltd</rights><rights>Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c564t-648a81857f14d7c40895c8303e4390ae90ebc43974b5a8571c981b17c8fbe3fc3</citedby><cites>FETCH-LOGICAL-c564t-648a81857f14d7c40895c8303e4390ae90ebc43974b5a8571c981b17c8fbe3fc3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.tox.2012.10.008$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23103613$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chen, Chun-Hung</creatorcontrib><creatorcontrib>Chen, Sz-Jie</creatorcontrib><creatorcontrib>Su, Chin-Chuan</creatorcontrib><creatorcontrib>Yen, Cheng-Chieh</creatorcontrib><creatorcontrib>Tseng, To-Jung</creatorcontrib><creatorcontrib>Jinn, Tzyy-Rong</creatorcontrib><creatorcontrib>Tang, Feng-Cheng</creatorcontrib><creatorcontrib>Chen, Kuo-Liang</creatorcontrib><creatorcontrib>Su, Yi-Chang</creatorcontrib><creatorcontrib>Lee, kuan-I</creatorcontrib><creatorcontrib>Hung, Dong-Zong</creatorcontrib><creatorcontrib>Huang, Chun-Fa</creatorcontrib><title>Chloroacetic acid induced neuronal cells death through oxidative stress-mediated p38-MAPK activation pathway regulated mitochondria-dependent apoptotic signals</title><title>Toxicology (Amsterdam)</title><addtitle>Toxicology</addtitle><description>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 3mM), 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 Bax 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 Bax 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.</description><subject>Acetates - administration & dosage</subject><subject>Acetates - toxicity</subject><subject>acetic acid</subject><subject>acetylcysteine</subject><subject>Activated</subject><subject>Activation</subject><subject>Animals</subject><subject>Anthracenes - pharmacology</subject><subject>antioxidants</subject><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>Byproducts</subject><subject>caspases</subject><subject>Cell Line, Tumor</subject><subject>chlorination</subject><subject>Chloroacetic acid (CA)</subject><subject>cytochrome c</subject><subject>cytotoxicity</subject><subject>disinfectants</subject><subject>disinfection</subject><subject>Dose-Response Relationship, Drug</subject><subject>drinking water</subject><subject>Emergency</subject><subject>glutathione</subject><subject>Glutathione - metabolism</subject><subject>herbicides</subject><subject>Imidazoles - pharmacology</subject><subject>industry</subject><subject>Inhibitors</subject><subject>mammals</subject><subject>messenger RNA</subject><subject>Mice</subject><subject>Mitochondria - drug effects</subject><subject>Mitochondria - pathology</subject><subject>Mitochondrial dysfunction</subject><subject>mitogen-activated protein kinase</subject><subject>Neuroblastoma - metabolism</subject><subject>neurons</subject><subject>Neurons - drug effects</subject><subject>Neurons - pathology</subject><subject>Neurotoxicity</subject><subject>Neurotoxicity Syndromes - etiology</subject><subject>Neurotoxicity Syndromes - pathology</subject><subject>Oxidative stress</subject><subject>Oxidative Stress - drug effects</subject><subject>p38 Mitogen-Activated Protein Kinases - drug effects</subject><subject>p38 Mitogen-Activated Protein Kinases - metabolism</subject><subject>p38-MAPK</subject><subject>Pathways</subject><subject>phosphorylation</subject><subject>Pyridines - pharmacology</subject><subject>Toxic</subject><subject>Toxicology</subject><issn>0300-483X</issn><issn>1879-3185</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkstu1DAUhiMEokPhAdhAlmwyHMdO7AgJqRpxE0UglUrsLI9zMuMhEwfbKZ2n4VU5YQoLFtDV8eX7z0Xnz7LHDJYMWP18t0z-elkCK-m-BFB3sgVTsik4U9XdbAEcoBCKfznJHsS4A4CSi_p-dlJyBrxmfJH9WG17H7yxmJzNjXVt7oZ2stjmA07BD6bPLfZ9zFs0aZunbfDTZpv7a9ea5K4wjylgjMUeW2cSyUauig9nn95TMvonxg_5SNLv5pAH3Ez9L2rvkrdbP7TBmaLFEYcWh5Sb0Y_Jz61Et6Ha8WF2r6OAj27iaXb5-tXn1dvi_OObd6uz88JWtUhFLZRRNLTsmGilFaCayioOHAVvwGADuLZ0lGJdGcKYbRRbM2lVt0beWX6aPTvmHYP_NmFMeu_iPLgZ0E9Rs1oyUSopxS3QGqASvOK3QIWktQHU_0dLWVLxijWEsiNqg48xYKfH4PYmHDQDPRtD7zQZQ8_GmJ-oAmme3KSf1rSqP4rfTiDg6RHojNdmE1zUlxeUoQJgAmRdEfHiSCDt4cph0NE6HMgqLqBNuvXunw28_Ettezc4a_qveMC481OY962ZjqUGfTF7d7YuKwF4pST_CYux6L8</recordid><startdate>20130107</startdate><enddate>20130107</enddate><creator>Chen, Chun-Hung</creator><creator>Chen, Sz-Jie</creator><creator>Su, Chin-Chuan</creator><creator>Yen, Cheng-Chieh</creator><creator>Tseng, To-Jung</creator><creator>Jinn, Tzyy-Rong</creator><creator>Tang, Feng-Cheng</creator><creator>Chen, Kuo-Liang</creator><creator>Su, Yi-Chang</creator><creator>Lee, kuan-I</creator><creator>Hung, Dong-Zong</creator><creator>Huang, Chun-Fa</creator><general>Elsevier Ireland Ltd</general><scope>FBQ</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7ST</scope><scope>7TK</scope><scope>7U7</scope><scope>C1K</scope><scope>SOI</scope><scope>8FD</scope><scope>FR3</scope><scope>KR7</scope></search><sort><creationdate>20130107</creationdate><title>Chloroacetic acid induced neuronal cells death through oxidative stress-mediated p38-MAPK activation pathway regulated mitochondria-dependent apoptotic signals</title><author>Chen, Chun-Hung ; Chen, Sz-Jie ; Su, Chin-Chuan ; Yen, Cheng-Chieh ; Tseng, To-Jung ; Jinn, Tzyy-Rong ; Tang, Feng-Cheng ; Chen, Kuo-Liang ; Su, Yi-Chang ; Lee, kuan-I ; Hung, Dong-Zong ; Huang, Chun-Fa</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c564t-648a81857f14d7c40895c8303e4390ae90ebc43974b5a8571c981b17c8fbe3fc3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Acetates - administration & dosage</topic><topic>Acetates - toxicity</topic><topic>acetic acid</topic><topic>acetylcysteine</topic><topic>Activated</topic><topic>Activation</topic><topic>Animals</topic><topic>Anthracenes - pharmacology</topic><topic>antioxidants</topic><topic>Apoptosis</topic><topic>Apoptosis - drug effects</topic><topic>Byproducts</topic><topic>caspases</topic><topic>Cell Line, Tumor</topic><topic>chlorination</topic><topic>Chloroacetic acid (CA)</topic><topic>cytochrome c</topic><topic>cytotoxicity</topic><topic>disinfectants</topic><topic>disinfection</topic><topic>Dose-Response Relationship, Drug</topic><topic>drinking water</topic><topic>Emergency</topic><topic>glutathione</topic><topic>Glutathione - metabolism</topic><topic>herbicides</topic><topic>Imidazoles - pharmacology</topic><topic>industry</topic><topic>Inhibitors</topic><topic>mammals</topic><topic>messenger RNA</topic><topic>Mice</topic><topic>Mitochondria - drug effects</topic><topic>Mitochondria - pathology</topic><topic>Mitochondrial dysfunction</topic><topic>mitogen-activated protein kinase</topic><topic>Neuroblastoma - metabolism</topic><topic>neurons</topic><topic>Neurons - drug effects</topic><topic>Neurons - pathology</topic><topic>Neurotoxicity</topic><topic>Neurotoxicity Syndromes - etiology</topic><topic>Neurotoxicity Syndromes - pathology</topic><topic>Oxidative stress</topic><topic>Oxidative Stress - drug effects</topic><topic>p38 Mitogen-Activated Protein Kinases - drug effects</topic><topic>p38 Mitogen-Activated Protein Kinases - metabolism</topic><topic>p38-MAPK</topic><topic>Pathways</topic><topic>phosphorylation</topic><topic>Pyridines - pharmacology</topic><topic>Toxic</topic><topic>Toxicology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chen, Chun-Hung</creatorcontrib><creatorcontrib>Chen, Sz-Jie</creatorcontrib><creatorcontrib>Su, Chin-Chuan</creatorcontrib><creatorcontrib>Yen, Cheng-Chieh</creatorcontrib><creatorcontrib>Tseng, To-Jung</creatorcontrib><creatorcontrib>Jinn, Tzyy-Rong</creatorcontrib><creatorcontrib>Tang, Feng-Cheng</creatorcontrib><creatorcontrib>Chen, Kuo-Liang</creatorcontrib><creatorcontrib>Su, Yi-Chang</creatorcontrib><creatorcontrib>Lee, kuan-I</creatorcontrib><creatorcontrib>Hung, Dong-Zong</creatorcontrib><creatorcontrib>Huang, Chun-Fa</creatorcontrib><collection>AGRIS</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Environment Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Environment Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Civil Engineering Abstracts</collection><jtitle>Toxicology (Amsterdam)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chen, Chun-Hung</au><au>Chen, Sz-Jie</au><au>Su, Chin-Chuan</au><au>Yen, Cheng-Chieh</au><au>Tseng, To-Jung</au><au>Jinn, Tzyy-Rong</au><au>Tang, Feng-Cheng</au><au>Chen, Kuo-Liang</au><au>Su, Yi-Chang</au><au>Lee, kuan-I</au><au>Hung, Dong-Zong</au><au>Huang, Chun-Fa</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Chloroacetic acid induced neuronal cells death through oxidative stress-mediated p38-MAPK activation pathway regulated mitochondria-dependent apoptotic signals</atitle><jtitle>Toxicology (Amsterdam)</jtitle><addtitle>Toxicology</addtitle><date>2013-01-07</date><risdate>2013</risdate><volume>303</volume><issue>7</issue><spage>72</spage><epage>82</epage><pages>72-82</pages><issn>0300-483X</issn><eissn>1879-3185</eissn><abstract>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 3mM), 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 Bax 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 Bax 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.</abstract><cop>Ireland</cop><pub>Elsevier Ireland Ltd</pub><pmid>23103613</pmid><doi>10.1016/j.tox.2012.10.008</doi><tpages>11</tpages></addata></record> |
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subjects | Acetates - administration & dosage Acetates - toxicity acetic acid acetylcysteine Activated Activation Animals Anthracenes - pharmacology antioxidants Apoptosis Apoptosis - drug effects Byproducts caspases Cell Line, Tumor chlorination Chloroacetic acid (CA) cytochrome c cytotoxicity disinfectants disinfection Dose-Response Relationship, Drug drinking water Emergency glutathione Glutathione - metabolism herbicides Imidazoles - pharmacology industry Inhibitors mammals messenger RNA Mice Mitochondria - drug effects Mitochondria - pathology Mitochondrial dysfunction mitogen-activated protein kinase Neuroblastoma - metabolism neurons Neurons - drug effects Neurons - pathology Neurotoxicity Neurotoxicity Syndromes - etiology Neurotoxicity Syndromes - pathology Oxidative stress Oxidative Stress - drug effects p38 Mitogen-Activated Protein Kinases - drug effects p38 Mitogen-Activated Protein Kinases - metabolism p38-MAPK Pathways phosphorylation Pyridines - pharmacology Toxic Toxicology |
title | Chloroacetic acid induced neuronal cells death through oxidative stress-mediated p38-MAPK activation pathway regulated mitochondria-dependent apoptotic signals |
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