ID | 61401 |
FullText URL | |
Author |
Hiraoka, Hideki
Department of Medicinal Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
Nomura, Ryosuke
Department of Medicinal Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
Takasugi, Nobumasa
Department of Medicinal Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
Akai, Ryoko
Division of Cell Medicine, Department of Life Science, Medical Research Institute, Kanazawa Medical University
Iwawaki, Takao
Division of Cell Medicine, Department of Life Science, Medical Research Institute, Kanazawa Medical University
Kumagai, Yoshito
Environmental Biology Laboratory, Faculty of Medicine, University of Tsukuba
Fujimura, Masatake
Department of Basic Medical Science, National Institute for Minamata Disease
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Abstract | Methylmercury (MeHg), an environmental toxicant, induces neuronal cell death and injures a specific area of the brain. MeHg-mediated neurotoxicity is believed to be caused by oxidative stress and endoplasmic reticulum (ER) stress but the mechanism by which those stresses lead to neuronal loss is unclear. Here, by utilizing the ER stress-activated indicator (ERAI) system, we investigated the signaling alterations in the unfolded protein response (UPR) prior to neuronal apoptosis in the mouse brain. In ERAI transgenic mice exposed to MeHg (25 mg/kg, S.C.), the ERAI signal, which indicates activation of the cytoprotective pathway of the UPR, was detected in the brain. Interestingly, detailed ex vivo analysis showed that the ERAI signal was localized predominantly in neurons. Time course analysis of MeHg exposure (30 ppm in drinking water) showed that whereas the ERAI signal was gradually attenuated at the late phase after increasing at the early phase, activation of the apoptotic pathway of the UPR was enhanced in proportion to the exposure time. These results suggest that MeHg induces not only ER stress but also neuronal cell death via a UPR shift. UPR modulation could be a therapeutic target for treating neuropathy caused by electrophiles similar to MeHg.
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Keywords | Methylmercury
Neuronal cell death
ER stress
UPR
ERAI gene
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Note | This is a post-peer-review, pre-copyedit version of an article published in Archives of Toxicology. The final authenticated version is available online at: http://dx.doi.org/10.1007/s00204-021-02982-9.
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Published Date | 2021-01-16
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Publication Title |
Archives of Toxicology
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Volume | volume95
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Issue | issue4
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Publisher | Springer
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Start Page | 1241
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End Page | 1250
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ISSN | 0340-5761
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NCID | AA00548865
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Content Type |
Journal Article
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language |
English
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OAI-PMH Set |
岡山大学
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File Version | author
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PubMed ID | |
DOI | |
Web of Science KeyUT | |
Related Url | isVersionOf https://doi.org/10.1007/s00204-021-02982-9
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Funder Name |
Ministry of Education, Culture, Sports, Science and Technology
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助成番号 | 18H02579
19K22498
18H05293
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