Spatiotemporal analysis of the UPR transition induced by methylmercury in the mouse brain

Archives of Toxicology (2021)Cite this article

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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Acknowledgements

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.).

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Affiliations

  1. Department of Medicinal Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, 700-8530, Japan

    Hideki Hiraoka, Ryosuke Nomura, Nobumasa Takasugi & Takashi Uehara

  2. Division of Cell Medicine, Department of Life Science, Medical Research Institute, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Kahoku, Ishikawa, 920-0293, Japan

    Ryoko Akai & Takao Iwawaki

  3. Environmental Biology Laboratory, Faculty of Medicine, University of Tsukuba, Ibaraki, 305-8575, Japan

    Yoshito Kumagai

  4. Department of Basic Medical Science, National Institute for Minamata Disease, Kumamoto, 867-0008, Japan

    Masatake Fujimura

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  1. Hideki Hiraoka
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  2. Ryosuke Nomura
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  3. Nobumasa Takasugi
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Correspondence to Takashi Uehara.

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Hiraoka, H., Nomura, R., Takasugi, N. et al. Spatiotemporal analysis of the UPR transition induced by methylmercury in the mouse brain. Arch Toxicol (2021). https://doi.org/10.1007/s00204-021-02982-9

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Keywords

  • Methylmercury
  • Neuronal cell death
  • ER stress
  • UPR
  • ERAI gene