Imaging analysis for toxicity mechanisms using aryl hydrocarbon receptor dynamics

• Project/Area Number: 17K12826
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Risk sciences of radiation and chemicals
• Research Institution: National Institute for Environmental Studies
• Principal Investigator: Kimura Eiki 国立研究開発法人国立環境研究所, 環境リスク・健康研究センター, JSPS特別研究員 (90710054)
• Project Period (FY): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2018: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: イメージング解析 / アリール炭化水素受容体 / ニューロン / 脳 / ダイオキシン / マウス / 蛍光免疫染色法 / 内分泌かく乱化学物質

Outline of Final Research Achievements

The aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, is essential for dioxin toxicities, such as cancer, reproductive toxicity, and neurotoxicity. In the present study, we examined expression of AhR in the mouse brain, and found neuronal expression of AhR in the locus coeruleus (LC). In addition, we revealed that the amount of AhR in the nucleus was significantly increased in LC neurons of dioxin-exposed mice compared with that in vehicle-treated mice. Furthermore, impaired micromorphology of neurons that express active form of AhR was observed in the mouse brain. Our findings show the expression of AhR in brain neurons and nuclear translocation of AhR in a dioxin-dependent manner. These results suggest that overactivation of AhR may disrupt neural circuit structure.

Academic Significance and Societal Importance of the Research Achievements

ダイオキシンの受容体として機能するAhRを発現している細胞集団を同定することは、ダイオキシン毒性メカニズムを解明する上で必須となるが、これまで脳におけるAhRの発現を組織学的に捉え、ダイオキシン依存的なAhRの核移行量を定量的に解析した研究はほぼ皆無であった。本研究では、マウス脳の組織切片を用いてAhRを発現しているニューロンを同定したこと、そしてイメージング解析の利点を活かしてAhRの細胞内分布パターンを定量的に調べることに成功した点に学術的意義がある。今後はダイオキシン以外の化学物質曝露影響の解明においてもイメージング解析を活用し、毒性メカニズムに迫る研究を発展させていきたい。

Research Products

• [Journal Article] Impaired dendritic growth and positioning of cortical pyramidal neurons by activation of aryl hydrocarbon receptor signaling in the developing mouse (2017)
  • Author(s): Eiki Kimura, Ken-ichiro Kubo, Toshihiro Endo, Wenting Ling, Kazunori Nakajima, Masaki Kakeyama, Chiharu Tohyama
  • Journal Title: PLoS One Volume: 12 (8) Issue: 8 Pages: e0183497-e0183497
  • DOI: 10.1371/journal.pone.0183497
  • Peer Reviewed / Open Access
• [Presentation] マウス脳におけるアリール炭化水素受容体の発現パターン (2018)
  • Author(s): 木村栄輝、前川文彦、遠山千春
  • Organizer: 第45回日本毒性学会学術年会
• [Presentation] Expression pf aryl hydrocarbon receptor in the developing mouse brain (2018)
  • Author(s): Eiki Kimura, Fumihiko Maekawa, Chiharu Tohyama
  • Organizer: The 54th Congress of the European Societies of Toxicology
• [Presentation] Excessive activation of AhR signaling reduces dendritic growth in the developing mouse brain (2017)
  • Author(s): Eiki Kimura, Yunjie Ding, Chiharu Tohyama
  • Organizer: DIOXIN 2017
  • Int'l Joint Research
• [Presentation] かたちと動きから解き明かす化学物質曝露の毒性メカニズム (2017)
  • Author(s): 木村栄輝
  • Organizer: 行動 2017
  • Invited
• [Presentation] 仔の鳴き声から探るダイオキシン曝露影響と毒性メカニズム (2017)
  • Author(s): 木村栄輝、前川文彦、遠山千春
  • Organizer: 第187回 日仏生物学会例会