ER stress and ER stress-mediated apoptosis are involved in manganese-induced neurotoxicity in the rat striatum in vivo.
Manganese (Mn) is an essential trace element found in many enzymes, however, excessive Mn-exposure can result in manganism which is similar to Parkinson's movement disorder. The mechanisms of manganism are not well-known. The present in vivo study was carried out to determine whether endoplasmic reticulum stress (ER stress) and ER stress-mediated apoptosis are involved in manganese-induced neurotoxicity. Sixty-four SD rats were randomly divided into four groups and were administered intraperitoneally with normal saline (NS, as control) or MnCl₂ (7.5, 15 and 30 mg/kg body weight, respectively) for 4 weeks. We found that MnCl₂ dose-dependently accumulate in striatal. HE staining and TUNEL assay results indicated that MnCl₂ induced striatal neurocytes apoptosis in both male and female rats. The alterations of ultrastructures showed that MnCl₂ resulted in chromatin condensation, mitochondria and ER tumefaction in rat striatal neurocytes. Furthermore, MnCl₂ increased the expressions of p-IRE-1, ATF-6α, PERK, GRP78, Sigma-1R, CHOP, Bim, Bax, caspase-12 and caspase-3, and decreased the expression of Bcl-2 in rat striatal neurocytes. In conclusion, MnCl₂ could induce ER stress and ER stress-mediated apoptosis in rat striatal neurocytes, which might be one of the important mechanisms of Mn-induced neurotoxicity.
Department of Toxicology, School of Public Health, Peking University Health Science Center, Beijing 100191, PR China; Beijing Key Laboratory of Toxicological Research and Risk Assessment for Food Safety, School of Public Health, Peking University Health Science Center, Beijing 100191, PR China; The seventh people hospital of Zhengzhou, Zhengzhou Henan 450000, China.
Ting
T
Wang
Department of Toxicology, School of Public Health, Peking University Health Science Center, Beijing 100191, PR China; Beijing Key Laboratory of Toxicological Research and Risk Assessment for Food Safety, School of Public Health, Peking University Health Science Center, Beijing 100191, PR China.
Xuehui
X
Li
Department of Toxicology, School of Public Health, Peking University Health Science Center, Beijing 100191, PR China.
Dongxu
D
Yang
Department of Toxicology, School of Public Health, Peking University Health Science Center, Beijing 100191, PR China; Beijing Key Laboratory of Toxicological Research and Risk Assessment for Food Safety, School of Public Health, Peking University Health Science Center, Beijing 100191, PR China.
Hongtao
H
Zhang
Department of Toxicology, School of Public Health, Peking University Health Science Center, Beijing 100191, PR China; Beijing Key Laboratory of Toxicological Research and Risk Assessment for Food Safety, School of Public Health, Peking University Health Science Center, Beijing 100191, PR China.
Peng
P
Zhao
Department of Toxicology, School of Public Health, Peking University Health Science Center, Beijing 100191, PR China.
Juanling
J
Fu
Department of Toxicology, School of Public Health, Peking University Health Science Center, Beijing 100191, PR China; Beijing Key Laboratory of Toxicological Research and Risk Assessment for Food Safety, School of Public Health, Peking University Health Science Center, Beijing 100191, PR China. Electronic address: yaoby@bjmu.edu.cn.
Biyun
B
Yao
Department of Toxicology, School of Public Health, Peking University Health Science Center, Beijing 100191, PR China. Electronic address: zhouzc@bjmu.edu.cn.
Zongcan
Z
Zhou
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D002712:Chlorides / Q000633:toxicity*; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005260:Female; D008297:Male; D017895:Manganese Compounds; D020149:Manganese Poisoning / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
D051017:Apoptosis Regulatory Proteins; D002712:Chlorides; D017895:Manganese Compounds; C025340:manganese chloride
Apoptosis; Endoplasmic reticulum stress; Manganese; Neurotoxicity; Striatum