TY - JOUR
T1 - Spatiotemporal analysis of the UPR transition induced by methylmercury in the mouse brain
AU - Hiraoka, Hideki
AU - Nomura, Ryosuke
AU - Takasugi, Nobumasa
AU - Akai, Ryoko
AU - Iwawaki, Takao
AU - Kumagai, Yoshito
AU - Fujimura, Masatake
AU - Uehara, Takashi
N1 - Funding Information:
We thank Y. Okamoto, H. Nakai, and M. Matsumoto for technical assistance. This work was supported in part by Grants-in-Aid for Scientific Research (B) (18H02579), Challenging Exploratory Research (19K22498) (to T.U.), and Scientific Research (S) (18H05293) (to Y.K.) from the Ministry of Education, Culture, Sports and Technology (MEXT) of Japan and Study of the Health Effects of Heavy Metals Organized by Ministry of the Environment, Japan (to T.U.).
Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.
PY - 2021/4
Y1 - 2021/4
N2 - 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.
AB - 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.
KW - ER stress
KW - ERAI gene
KW - Methylmercury
KW - Neuronal cell death
KW - UPR
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U2 - 10.1007/s00204-021-02982-9
DO - 10.1007/s00204-021-02982-9
M3 - Article
C2 - 33454823
AN - SCOPUS:85100188577
VL - 95
SP - 1241
EP - 1250
JO - Archiv fur Toxikologie
JF - Archiv fur Toxikologie
SN - 0003-9446
IS - 4
ER -