title: Arsenic induces reactive oxygen species-caused neuronal cell apoptosis through JNK/ERK-mediated mitochondria-dependent and GRP 78/CHOP-regulated pathways.
abstract: Arsenic (As), a well-known high toxic metal, is an important environmental and industrial contaminant, and it induces oxidative stress, which causes many adverse health effects and diseases in humans, particularly in inorganic As (iAs) more harmful than organic As. Recently, epidemiological studies have suggested a possible relationship between iAs exposure and neurodegenerative disease development. However, the toxicological effects and underlying mechanisms of iAs-induced neuronal cell injuries are mostly unknown. The present study demonstrated that iAs significantly decreased cell viability and induced apoptosis in Neuro-2a cells. iAs also increased oxidative stress damage (production of malondialdehyde (MDA) and ROS, and reduction of Nrf2 and thioredoxin protein expression) and induced several features of mitochondria-dependent apoptotic signals, including: mitochondrial dysfunction, the activations of PARP and caspase cascades, and the increase in caspase-3 activity. Pretreatment with the antioxidant N-acetylcysteine (NAC) effectively reversed these iAs-induced responses. iAs also increased the phosphorylation of JNK and ERK1/2, but did not that p38-MAPK, in treated Neuro-2a cells. NAC and the specific JNK inhibitor (SP600125) and ERK1/2 inhibitor (PD98059) abrogated iAs-induced cell cytotoxicity, caspase-3/-7 activity, and JNK and ERK1/2 activation. Additionally, exposure of Neuro-2a cells to iAs triggered endoplasmic reticulum (ER) stress identified through several key molecules (GRP 78, CHOP, XBP-1, and caspase-12), which was prevented by NAC. Transfection with GRP 78- and CHOP-specific si-RNA dramatically suppressed GRP 78 and CHOP expression, respectively, and attenuated the activations of caspase-12, -7, and -3 in iAs-exposed cells. Therefore, these results indicate that iAs induces ROS causing neuronal cell death via both JNK/ERK-mediated mitochondria-dependent and GRP 78/CHOP-triggered apoptosis pathways.
authors.affiliation: Department of Physiology, and Graduate Institute of Basic Medical Science, College of Medicine, China Medical University, Taichung 404, Taiwan.
authors.forename: Tien-Hui
authors.initials: TH
authors.lastname: Lu
authors.forename: To-Jung
authors.initials: TJ
authors.lastname: Tseng
authors.forename: Chin-Chuan
authors.initials: CC
authors.lastname: Su
authors.forename: Feng-Cheng
authors.initials: FC
authors.lastname: Tang
authors.forename: Cheng-Chieh
authors.initials: CC
authors.lastname: Yen
authors.forename: Yu-Yun
authors.initials: YY
authors.lastname: Liu
authors.forename: Ching-Yao
authors.initials: CY
authors.lastname: Yang
authors.forename: Chin-Ching
authors.initials: CC
authors.lastname: Wu
authors.forename: Kuo-Liang
authors.initials: KL
authors.lastname: Chen
authors.forename: Dong-Zong
authors.initials: DZ
authors.lastname: Hung
authors.forename: Ya-Wen
authors.initials: YW
authors.lastname: Chen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001151:Arsenic / Q000633:toxicity*; D000091342:Endoplasmic Reticulum Chaperone BiP; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D006360:Heat-Shock Proteins / Q000502:physiology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000502:physiology*; D009474:Neurons / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D051742:Transcription Factor CHOP / Q000502:physiology*
chemical_list: C497250:Ddit3 protein, mouse; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D017382:Reactive Oxygen Species; D051742:Transcription Factor CHOP; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D001151:Arsenic
keywords: Apoptosis; Arsenic; C/EBP homologue protein; CHOP; ER stress; ERK; Endoplasmic reticulum stress (ER stress); GRP; JNK; MAPKs; MMP; Mitogen-activated protein kinases (MAPKs); N-acetylcysteine; NAC; Neurotoxicity; Nrf2; PARP; ROS; Reactive oxygen species (ROS); X-box binding protein-1; XBP-1; c-Jun N-terminal kinase; endoplasmic reticulum stress; extracellular signal-related kinase; glucose-regulated protein; mitochondrial membrane potential; mitogen-activated protein kinases; nuclear-factor-E2-related factor 2; poly (ADP-ribose) polymerase; reactive oxygen species; si-RNA; small interference RNA