Spatiotemporal analysis of the UPR transition induced by methylmercury in the mouse brain
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 unc...
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| Veröffentlicht in: | Archives of toxicology 2021-04, Vol.95 (4), p.1241-1250 |
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| creator | Hiraoka, Hideki Nomura, Ryosuke Takasugi, Nobumasa Akai, Ryoko Iwawaki, Takao Kumagai, Yoshito Fujimura, Masatake Uehara, Takashi |
| description | 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. |
| doi_str_mv | 10.1007/s00204-021-02982-9 |
| format | Article |
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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.</description><identifier>ISSN: 0340-5761</identifier><identifier>EISSN: 1432-0738</identifier><identifier>DOI: 10.1007/s00204-021-02982-9</identifier><identifier>PMID: 33454823</identifier><language>eng</language><publisher>Berlin/Heidelberg: Springer Berlin Heidelberg</publisher><subject>Apoptosis ; Biomedical and Life Sciences ; Biomedicine ; Brain ; Cell death ; Dimethylmercury ; Drinking water ; Endoplasmic reticulum ; Environmental Health ; Exposure ; Inorganic Compounds ; Mercury (metal) ; Methylmercury ; Neuropathy ; Neurotoxicity ; Occupational Medicine/Industrial Medicine ; Oxidative stress ; Pharmacology/Toxicology ; Protein folding ; Therapeutic targets ; Toxicants ; Transgenic mice</subject><ispartof>Archives of toxicology, 2021-04, Vol.95 (4), p.1241-1250</ispartof><rights>The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature 2021</rights><rights>The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature 2021.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c485t-66ef5f2c4fa8ee2e64679c7d9a53abf1aeba36a3dca232d346342bdf43f45d543</citedby><cites>FETCH-LOGICAL-c485t-66ef5f2c4fa8ee2e64679c7d9a53abf1aeba36a3dca232d346342bdf43f45d543</cites><orcidid>0000-0002-6562-2957</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s00204-021-02982-9$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s00204-021-02982-9$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,780,784,27923,27924,41487,42556,51318</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33454823$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hiraoka, Hideki</creatorcontrib><creatorcontrib>Nomura, Ryosuke</creatorcontrib><creatorcontrib>Takasugi, Nobumasa</creatorcontrib><creatorcontrib>Akai, Ryoko</creatorcontrib><creatorcontrib>Iwawaki, Takao</creatorcontrib><creatorcontrib>Kumagai, Yoshito</creatorcontrib><creatorcontrib>Fujimura, Masatake</creatorcontrib><creatorcontrib>Uehara, Takashi</creatorcontrib><title>Spatiotemporal analysis of the UPR transition induced by methylmercury in the mouse brain</title><title>Archives of toxicology</title><addtitle>Arch Toxicol</addtitle><addtitle>Arch Toxicol</addtitle><description>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.</description><subject>Apoptosis</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Brain</subject><subject>Cell death</subject><subject>Dimethylmercury</subject><subject>Drinking water</subject><subject>Endoplasmic reticulum</subject><subject>Environmental Health</subject><subject>Exposure</subject><subject>Inorganic Compounds</subject><subject>Mercury (metal)</subject><subject>Methylmercury</subject><subject>Neuropathy</subject><subject>Neurotoxicity</subject><subject>Occupational Medicine/Industrial Medicine</subject><subject>Oxidative stress</subject><subject>Pharmacology/Toxicology</subject><subject>Protein folding</subject><subject>Therapeutic targets</subject><subject>Toxicants</subject><subject>Transgenic mice</subject><issn>0340-5761</issn><issn>1432-0738</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNp9kD1PwzAQhi0EoqXwBxiQJeaA7XM-PKKKLwkJBHRgspzYpqnyhZ0M-fe4TYGN4XTDPfee7kHonJIrSkh67QlhhEeE0VAiY5E4QHPKgUUkhewQzQlwEsVpQmfoxPsNIZRlAo7RDIDHPGMwRx9vnerLtjd11zpVYdWoavSlx63F_drg1csr7p1qfBmoBpeNHgqjcT7i2vTrsaqNKwY3hsEOr9vBG5w7VTan6MiqypuzfV-g1d3t-_Ihenq-f1zePEUFz-I-ShJjY8sKblVmDDMJT1JRpFqoGFRuqTK5gkSBLhQDpoEnwFmuLQfLYx1zWKDLKbdz7ddgfC837eDCG16ymAhBMipEoNhEFa713hkrO1fWyo2SErm1KSebMtiUO5tyu3Sxjx7y2ujflR99AYAJ8GHUfBr3d_uf2G_TQYEM</recordid><startdate>20210401</startdate><enddate>20210401</enddate><creator>Hiraoka, Hideki</creator><creator>Nomura, Ryosuke</creator><creator>Takasugi, Nobumasa</creator><creator>Akai, Ryoko</creator><creator>Iwawaki, Takao</creator><creator>Kumagai, Yoshito</creator><creator>Fujimura, Masatake</creator><creator>Uehara, Takashi</creator><general>Springer Berlin Heidelberg</general><general>Springer Nature B.V</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7T2</scope><scope>7TK</scope><scope>7U7</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>88I</scope><scope>8AO</scope><scope>8C1</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>M2P</scope><scope>MBDVC</scope><scope>PATMY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PYCSY</scope><scope>Q9U</scope><orcidid>https://orcid.org/0000-0002-6562-2957</orcidid></search><sort><creationdate>20210401</creationdate><title>Spatiotemporal analysis of the UPR transition induced by methylmercury in the mouse brain</title><author>Hiraoka, Hideki ; 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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.</abstract><cop>Berlin/Heidelberg</cop><pub>Springer Berlin Heidelberg</pub><pmid>33454823</pmid><doi>10.1007/s00204-021-02982-9</doi><tpages>10</tpages><orcidid>https://orcid.org/0000-0002-6562-2957</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Apoptosis Biomedical and Life Sciences Biomedicine Brain Cell death Dimethylmercury Drinking water Endoplasmic reticulum Environmental Health Exposure Inorganic Compounds Mercury (metal) Methylmercury Neuropathy Neurotoxicity Occupational Medicine/Industrial Medicine Oxidative stress Pharmacology/Toxicology Protein folding Therapeutic targets Toxicants Transgenic mice |
| title | Spatiotemporal analysis of the UPR transition induced by methylmercury in the mouse brain |
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