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Research on methylmercury-induced selective cytotoxicity focusing on reactive sulfur species

Research Project

Project/Area Number 19K16368
Research Category

Grant-in-Aid for Early-Career Scientists

Allocation TypeMulti-year Fund
Review Section Basic Section 47030:Pharmaceutical hygiene and biochemistry-related
Research InstitutionNational Institute for Minamata Disease

Principal Investigator

Unoki Takamitsu  国立水俣病総合研究センター, その他部局等, 主任研究員 (00742868)

Project Period (FY) 2019-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2020: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2019: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Keywordsメチル水銀 / 活性イオウ分子 / レドックスホメオスタシス / レドックスバイオロジー
Outline of Research at the Start

水俣病に象徴されるメチル水銀による健康影響は現代でも世界的な懸念事項である。メチル水銀曝露による中枢神経系への傷害は部位・発達段階で異なるが、その理由を説明できる知見は少ない。本研究は高い求核性・抗酸化性によりメチル水銀毒性防御に寄与する活性イオウ分子の中枢神経系での存在量を時空間的に解析し、その差異がメチル水銀による傷害に特異性をもたらす因子かを明らかとし、メチル水銀毒性の根本的な謎解明に挑む。

Outline of Final Research Achievements

Brain sensitivity to methylmercury (MeHg) is developmentally and site-specific in both humans and rodents, but the mechanism is not well understood. Reactive sulfur species (RSS) are known to react with MeHg to form a less toxic metabolite, bismethylmercury sulfide, which exerts cytoprotective effects. In this study, we evaluated changes in RSS contents in rat brains and their relationships to sensitivity to MeHg. Analysis of fetal and juvenile rat brains revealed that RSS content was low in early development. Site-specific analysis of adult rat brains revealed that RSS levels in the cerebellum were lower than those in the hippocampus. In the cerebellum, the RSS levels in the granule cell layer were lower than those in the molecular layer. Thus, lower RSS levels corresponded to brain regions vulnerable to MeHg. Taken together with the result that brain RSS is consumed during MeHg exposure, RSS is a factor that defines the specificity of MeHg vulnerability in the brain.

Academic Significance and Societal Importance of the Research Achievements

メチル水銀による中枢神経系の細胞傷害は部位・細胞種や発達段階で異なるが、その特異性が生じる要因については全容の解明には至っていない。本研究は、活性イオウ分子を介したレドックスバランス制御の観点からこの疑問にアプローチすることで、メチル水銀毒性機序の解明を通とリスク評価への寄与が期待される。また、近年急速に発展しつつあるイオウ生物学において、活性イオウ分子の有する生理的意義付けに新たな知見を提供できる。

Report

(5 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Research-status Report
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (11 results)

All 2022 2021 2020 2019

All Journal Article (4 results) (of which Peer Reviewed: 4 results,  Open Access: 4 results) Presentation (7 results)

  • [Journal Article] Spatio-temporal distribution of reactive sulfur species during methylmercury exposure in the rat brain2022

    • Author(s)
      Unoki Takamitsu、Akiyama Masahiro、Shinkai Yasuhiro、Kumagai Yoshito、Fujimura Masatake
    • Journal Title

      The Journal of Toxicological Sciences

      Volume: 47 Issue: 1 Pages: 31-37

    • DOI

      10.2131/jts.47.31

    • NAID

      130008139752

    • ISSN
      0388-1350, 1880-3989
    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Nrf2 Activation and Its Coordination with the Protective Defense Systems in Response to Electrophilic Stress2020

    • Author(s)
      Unoki Takamitsu、Akiyama Masahiro、Kumagai Yoshito
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 21 Issue: 2 Pages: 545-545

    • DOI

      10.3390/ijms21020545

    • NAID

      120007132700

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Environmental Electrophile-Mediated Toxicity in Mice Lacking Nrf2, CSE, or Both2019

    • Author(s)
      Akiyama Masahiro、Unoki Takamitsu、Shinkai Yasuhiro、Ishii Isao、Ida Tomoaki、Akaike Takaaki、Yamamoto Masayuki、Kumagai Yoshito
    • Journal Title

      Environmental Health Perspectives

      Volume: 127 Issue: 6 Pages: 067002-067002

    • DOI

      10.1289/ehp4949

    • NAID

      120007133174

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Adaptive Responses to Electrophilic Stress and Reactive Sulfur Species as their Regulator Molecules2019

    • Author(s)
      Kumagai Yoshito、Akiyama Masahiro、Unoki Takamitsu
    • Journal Title

      Toxicological Research

      Volume: 35 Issue: 4 Pages: 303-310

    • DOI

      10.5487/tr.2019.35.4.303

    • NAID

      120007127813

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] RSS産生酵素CSEはマウスへのメチル水銀曝露による脳中水銀蓄積と中毒症状を抑制する2021

    • Author(s)
      鵜木隆光, 秋山雅博, 新開泰弘, 石井功, 熊谷嘉人
    • Organizer
      第48回 日本毒性学会学術年会
    • Related Report
      2021 Research-status Report
  • [Presentation] メチル水銀曝露による脳中水銀蓄積と中毒症状は活性イオウ分子産生酵素CSEにより抑制される2021

    • Author(s)
      鵜木隆光, 秋山雅博, 新開泰弘, 石井功, 熊谷嘉人
    • Organizer
      フォーラム2021 衛生薬学・環境トキシコロジー
    • Related Report
      2021 Research-status Report
  • [Presentation] 活性イオウ分子を介した親電子ストレス防御2020

    • Author(s)
      鵜木隆光, 秋山雅博, 新開泰弘, 熊谷嘉人, 藤村成剛
    • Organizer
      第47回 日本毒性学会学術年会
    • Related Report
      2020 Research-status Report
  • [Presentation] 活性イオウ分子の脳内分布とメチル水銀感受性の連関2020

    • Author(s)
      鵜木隆光, 秋山雅博, 熊谷嘉人, 藤村成剛
    • Organizer
      生命金属に関する合同年会2020 (メタルバイオサイエンス研究会2020)
    • Related Report
      2020 Research-status Report
  • [Presentation] メチル水銀の細胞傷害特異性に対する含イオウ求核低分子の影響2019

    • Author(s)
      鵜木隆光, 秋山雅博, 熊谷嘉人, 藤村成剛
    • Organizer
      第46回日本毒性学会学術年会
    • Related Report
      2019 Research-status Report
  • [Presentation] メチル水銀の細胞傷害特異性に対する活性イオウ分子の影響2019

    • Author(s)
      鵜木隆光, 秋山雅博, 熊谷嘉人, 藤村成剛
    • Organizer
      第42回日本分子生物学会年会
    • Related Report
      2019 Research-status Report
  • [Presentation] メチル水銀の細胞傷害特異性に対する活性イオウ分子の影響2019

    • Author(s)
      鵜木隆光
    • Organizer
      環境省「重金属等による健康影響に関する総合的研究」メチル水銀研究ミーティング
    • Related Report
      2019 Research-status Report

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Published: 2019-04-18   Modified: 2024-01-30  

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