title: Inorganic arsenic causes cell apoptosis in mouse cerebrum through an oxidative stress-regulated signaling pathway.
abstract: Arsenic pollution is a major public health problem worldwide. Inorganic arsenic (iAs) is usually more harmful than organic ones. iAs pollution increases the risk of human diseases such as peripheral vascular disease and cancer. However, the toxicological effects of iAs in the brain are mostly unclear. Here, we investigated the toxic effects and possible mechanisms of iAs in the cerebrum of mice after exposure to iAs (0.5 and 5 ppm (mg/l) As(2)O(3), via the drinking water), which was the possible human exposed dose via the ingestion in iAs-contaminated areas, for 6 consecutive weeks. iAs dose-dependently caused an increase of LPO production in the plasma and cerebral cortex. iAs also decreased the reduced glutathione levels and the expressions of NQO1 and GPx mRNA in the cerebral cortex. These impairments in the cerebral cortex caused by iAs exposure were significantly correlated with the accumulation of As. Moreover, iAs induced the production of apoptotic cells and activation of caspase-3, up-regulation of Bax and Bak, and down-regulation of Mcl-1 in the cerebral cortex. Exposure to iAs also triggered the expression of ER stress-related genes, including GRP78, GRP94, and CHOP. Meanwhile, an increase of p38 activation and dephosphorylation of ERK1/2 were shown in the cerebral cortex as a result of iAs-exposed mice. These iAs-induced damages and apoptosis-related signals could be significantly reversed by NAC. Taken together, these results suggest that iAs-induced oxidative stress causes cellular apoptosis in the cerebrum, signaling of p38 and ERK1/2, and ER stress may be involved in iAs-induced cerebral toxicity.
authors.affiliation: Department of Occupational Safety and Health, College of Health Care and Management, Chung Shan Medical University, Taichung, 40201, Taiwan.
authors.forename: Cheng Chien
authors.initials: CC
authors.lastname: Yen
authors.forename: Tsung Jung
authors.initials: TJ
authors.lastname: Ho
authors.forename: Chin Ching
authors.initials: CC
authors.lastname: Wu
authors.forename: Chun Fang
authors.initials: CF
authors.lastname: Chang
authors.forename: Chin Chuan
authors.initials: CC
authors.lastname: Su
authors.forename: Ya Wen
authors.initials: YW
authors.lastname: Chen
authors.forename: Tzyy Rong
authors.initials: TR
authors.lastname: Jinn
authors.forename: Tien Hui
authors.initials: TH
authors.lastname: Lu
authors.forename: Po Wen
authors.initials: PW
authors.lastname: Cheng
authors.forename: Yi Chang
authors.initials: YC
authors.lastname: Su
authors.forename: Shing Hwa
authors.initials: SH
authors.lastname: Liu
authors.forename: Chun Fa
authors.initials: CF
authors.lastname: Huang
mesh_terms: D000111:Acetylcysteine / Q000627:therapeutic use; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D020261:Arsenic Poisoning / Q000097:blood / Q000378:metabolism* / Q000473:pathology; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D000091342:Endoplasmic Reticulum Chaperone BiP; D004785:Environmental Pollutants / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000235:genetics / Q000378:metabolism; D008054:Lipid Peroxides / Q000097:blood / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000627:therapeutic use; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D010087:Oxides / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity*; D012333:RNA, Messenger / Q000378:metabolism; D011897:Random Allocation
chemical_list: D051017:Apoptosis Regulatory Proteins; D001152:Arsenicals; D000091342:Endoplasmic Reticulum Chaperone BiP; D004785:Environmental Pollutants; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; D008054:Lipid Peroxides; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D010087:Oxides; D012333:RNA, Messenger; D005979:Glutathione Peroxidase; D016660:NAD(P)H Dehydrogenase (Quinone); C491732:Nqo1 protein, mouse; D005978:Glutathione; D000077237:Arsenic Trioxide; D000111:Acetylcysteine