Neurotoxicity of organotins via nuclear respiratory factor-1 (NRF-1) inhibition

• Project/Area Number: 15H02826
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Risk sciences of radiation and chemicals
• Research Institution: Hiroshima University
• Principal Investigator: KOTAKE Yaichiro 広島大学, 大学院医歯薬保健学研究科(薬), 教授 (20335649)
• Co-Investigator(Kenkyū-buntansha): 太田 茂 広島大学, 医歯薬保健学研究科(薬), 名誉教授 (60160503)
• Project Period (FY): 2015-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥16,900,000 (Direct Cost: ¥13,000,000、Indirect Cost: ¥3,900,000); Fiscal Year 2018: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000); Fiscal Year 2017: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2016: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2015: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
• Keywords: 有機スズ / 核呼吸因子-1 / 神経毒性 / グルタミン酸受容体

Outline of Final Research Achievements

We revealed details about Nuclear Respiratory Factor-1 (NRF-1) inhibition by tributyltin, and clarified that suppressed NRF-1 expression is caused by hypermethylation of the NRF-1 promoter region. NRF-1 knockdown causes compensatory induction of lysosomal proteins, probably via suppression of lysosomal functions.

Academic Significance and Societal Importance of the Research Achievements

有機スズの神経毒性メカニズムは以前から報告されていたものの、そのメカニズムはほとんど明らかになっていなかった。今回低濃度有機スズの毒性メカニズムの一端に、NRF-1という転写因子の低下が関与すること、またなぜNRF-1が低下するのかを明らかにしたことは、環境中に広く存在する化学物質の毒性を明らかにし、その毒性を抑制する方法を考える上で興味深い知見である。

Research Products

• [Journal Article] Low-Concentration Tributyltin Decreases GluR2 Expression via Nuclear Respiratory Factor-1 Inhibition (2017)
  • Author(s): Ishida Keishi、Aoki Kaori、Takishita Tomoko、Miyara Masatsugu、Sakamoto Shuichiro、Sanoh Seigo、Kimura Tomoki、Kanda Yasunari、Ohta Shigeru、Kotake Yaichiro
  • Journal Title: International Journal of Molecular Sciences Volume: 18 Issue: 8 Pages: 1754-1754
  • DOI: 10.3390/ijms18081754
  • Peer Reviewed / Open Access
• [Journal Article] Lead-Induced ERK Activation Is Mediated by GluR2 Non-containing AMPA Receptor in Cortical Neurons (2017)
  • Author(s): Ishida K, Kotake Y, Sanoh S, Ohta S.
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 40 Issue: 3 Pages: 303-309
  • DOI: 10.1248/bpb.b16-00784
  • NAID: 130005398478
  • ISSN: 0918-6158, 1347-5215
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Mild MPP(+) exposure impairs autophagic degradation through a novel lysosomal acidity-independent mechanism. (2016)
  • Author(s): Miyara M, Kotake Y, Tokunaga W, Sanoh S, Ohta S
  • Journal Title: J Neurochem Volume: 139 Issue: 2 Pages: 294-308
  • DOI: 10.1111/jnc.13700
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Perfluorooctane sulfonate induces neuronal vulnerability by decreasing GluR2 expression. (2016)
  • Author(s): Ishida K., Tsuyama Y., Sanoh S., Ohta S., Kotake Y.
  • Journal Title: Arch. Toxicol. Volume: 未定 Issue: 2 Pages: 885-895
  • DOI: 10.1007/s00204-016-1731-x
  • Peer Reviewed
• [Presentation] 核呼吸因子-1発現減少による網羅的な遺伝子発現変動 (2018)
  • Author(s): 齊木崇史，石田慶士，太田 茂，古武弥一郎
  • Organizer: 第45回日本毒性学会学術年会
• [Presentation] 低濃度トリブチルスズによるニューロン脆弱化機構の解明 (2015)
  • Author(s): 石田慶士、古武弥一郎、青木香織、瀧下智子、木村朋紀、諫田泰成、太田 茂
  • Organizer: メタルバイオサイエンス研究会2015
  • Place of Presentation: 名古屋市
  • Year and Date: 2015-08-27
• [Presentation] 有機スズ神経毒性に関与する核呼吸因子-1 (NRF-1) 阻害機構の解明 (2015)
  • Author(s): 石田慶士、古武弥一郎、青木香織、瀧下智子、木村朋紀、諫田泰成、太田 茂
  • Organizer: 第42回日本毒性学会学術年会
  • Place of Presentation: 金沢市
  • Year and Date: 2015-06-29