Methylmercury induced neuronal damage via M1-microglial activation

• Project/Area Number: 19K16345
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 47030:Pharmaceutical hygiene and biochemistry-related
• Research Institution: Tohoku University
• Principal Investigator: Toyama Takashi 東北大学, 薬学研究科, 助教 (50720918)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000); Fiscal Year 2019: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: メチル水銀 / 炎症性サイトカイン / ミクログリア / 活性酸素種 / TNF-α / 神経障害

Outline of Research at the Start

メチル水銀は魚介類の摂取を介して人体に蓄積し、中枢神経障害を惹起するが、その機構は不明である。最近申請者はメチル水銀を投与したマウスの大脳皮質において、脳内の免疫担当細胞であるミクログリアを活性化している可能性を見出した。これまで、活性化したミクログリアは 炎症性サイトカイン類の過剰産生を介して神経細胞死を誘導することで;、様々な神経疾患の発症に関わる可能性が示唆されている。そこで本研究では、1. メチル水銀による神経傷害へのミクログリア活性化の関与と、2. メチル水銀によるミクログリア活性化を介した神経傷害機構について解明を目指す。

Outline of Final Research Achievements

In this study, we newly established a mouse cerebral cortex slice culture that can evaluates inflammatory microglial activation. We also found that methylmercury induces inflammatory cytokine (tumor necrosis factor-alpha; TNF-α) in microglia in the mouse brain with the new methodology and in vivo experiments. Interestingly TNF-α is released out from microglia by methylmercury and induced neuronal cell death via TNFR1 on neurons. We further confirmed that methylmercury induced TNF-α　induction is dependent on mitochondrial ROS production and activation of its downstream ASK1/p38 signaling.
Hence the present study indicates inflammatory crosstalk between microglia and neurons are crucial for methylmercury-induced neuronal toxicity, and this could be an outstanding finding in the toxicology of methylmercury.

Academic Significance and Societal Importance of the Research Achievements

4年前、約150カ国の国と地域が参加する水俣条約が発行されており、メチル水銀の健康影響は現在世界的なホットトピックとなっている。しかし、水俣病の発生から現在まで60年以上にわたりメチル水銀毒性発現機構の研究が行われてきたが、中枢特異的な神経傷害機構解明には至っていない。また、神経疾患におけるミクログリア活性化の関与は現在ホットな研究領域となっている一方、メチル水銀による神経傷害とミクログリア活性化の両者の関連を示す研究は無い。すなわち本申請研究が示した知見は、これらを具体的に、in vitroからin vivoで横断的に示しており、メチル水銀の毒性発現機構を解明する上で意義深い成果である。

Research Products

• [Journal Article] Gefitinib initiates sterile inflammation by pomoting IL-1β and HMGB1 release via two distinct mechanisms (2021)
  • Author(s): Takuya Noguchi, Yuto Sekiguchi, Yuki Kudoh, Rio Naganuma, Tomohiro Kagi, Akiko Nishidate, Kazuhiro Maeda, Chizuru Ishii, Takashi Toyama, Yusuke Hirata, Gi-Wook Hwang, Atsushi Matsuzawa
  • Journal Title: Cell Death. Dis. Volume: 12 Issue: 1 Pages: 49-49
  • DOI: 10.1038/s41419-020-03335-7
  • Peer Reviewed / Open Access
• [Journal Article] Increased expression of TCF3, transcription factor 3, is a defense response against methylmercury toxicity in mouse neuronal C17.2 cells (2021)
  • Author(s): Toyama Takashi、Wang Yanjiao、Kim Min-Seok、Takahashi Tsutomu、Naganuma Akira、Hwang Gi-Wook
  • Journal Title: Toxicological Research Volume: 22 Issue: 4 Pages: 1-8
  • DOI: 10.1007/s43188-021-00087-0
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Methylmercury induces neuronal cell death by inducing TNF-α expression through the ASK1/p38 signaling pathway in microglia (2021)
  • Author(s): Toyama T, Hoshi T, Noguchi T, Saito Y, Matsuzawa A, Naganuma A, Hwang G. W.
  • Journal Title: Scientific Reports Volume: -
  • Peer Reviewed
• [Journal Article] Increased putrescine levels due to ODC1 overexpression prevents mitochondrial dysfunction-related apoptosis induced by methylmercury (2020)
  • Author(s): Sato Masayuki、Toyama Takashi、Kim Min-Seok、Lee Jin-Yong、Hoshi Takayuki、Miura Nobuhiko、Naganuma Akira、Hwang Gi-Wook
  • Journal Title: Life Sciences Volume: 256 Pages: 118031-118031
  • DOI: 10.1016/j.lfs.2020.118031
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Hydrogen Peroxide Causes Cell Death via Increased Transcription of HOXB13 in Human Lung Epithelial A549 Cells (2020)
  • Author(s): Endo Naoki、Toyama Takashi、Naganuma Akira、Saito Yoshiro、Hwang Gi-Wook
  • Journal Title: Toxics Volume: 8 Issue: 4 Pages: 78-78
  • DOI: 10.3390/toxics8040078
  • Peer Reviewed
• [Journal Article] Evaluation of M1-microglial activation by neurotoxic metals using optimized organotypic cerebral slice cultures (2019)
  • Author(s): Hoshi T, Toyama T, Shinozaki Y, Koizumi S, Lee JY, Naganuma A, Hwang GW.
  • Journal Title: The Journal of Toxicological Sciences Volume: 44 Issue: 7 Pages: 471-479
  • DOI: 10.2131/jts.44.471
  • NAID: 130007674444
  • ISSN: 0388-1350, 1880-3989
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Methylmercury causes neuronal cell death via M1-microglial activation in organotypic slices prepared from mouse cerebral cortex (2019)
  • Author(s): Takayuki Hoshi, Takashi Toyama, Akira Naganuma, Gi-Wook Hwang
  • Journal Title: Fundamental Toxicological Sciences Volume: 6 Issue: 5 Pages: 167-170
  • DOI: 10.2131/fts.6.167
  • NAID: 130007674519
  • ISSN: 2189-115X
  • Peer Reviewed / Open Access
• [Presentation] メチル水銀の炎症性サイトカイン類の発現誘導を介した脳神経傷害機構 (2020)
  • Author(s): 外山 喬士
  • Organizer: フォーラム2020 環境・衛生トキシコロジー
  • Invited
• [Presentation] Redox Regulation of Microglial Activation by Methylmercury (2019)
  • Author(s): Takashi Toyama
  • Organizer: Gordon Research Conference Oxygen Radicals
  • Int'l Joint Research
• [Presentation] Establishment of organotypic brain slice culture that can evaluate M1-microglial activation (2019)
  • Author(s): Takayuki Hoshi, Takashi Toyama, Akira Naganuma, Gi-Wook Hwang
  • Organizer: フォーラム2019衛生薬学・環境トキシコロジー
  • Int'l Joint Research