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Understanding of molecular mechanisms of chemically-induced toxicities and risk evaluation using zebrafish

Research Project

Project/Area Number 15H05334
Research Category

Grant-in-Aid for Young Scientists (A)

Allocation TypeSingle-year Grants
Research Field Risk sciences of radiation and chemicals
Research InstitutionObihiro University of Agriculture and Veterinary Medicine

Principal Investigator

Kubota Akira  帯広畜産大学, 畜産学部, 准教授 (60432811)

Project Period (FY) 2015-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥21,450,000 (Direct Cost: ¥16,500,000、Indirect Cost: ¥4,950,000)
Fiscal Year 2018: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
Fiscal Year 2017: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000)
Fiscal Year 2016: ¥8,970,000 (Direct Cost: ¥6,900,000、Indirect Cost: ¥2,070,000)
Fiscal Year 2015: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000)
Keywordsトキシコロジー / ゼブラフィッシュ / 細胞内受容体 / 発生毒性 / 内分泌撹乱 / 環境汚染物質 / エストロゲン受容体 / シトクロムP450 / ビスフェノール類 / in silico解析 / リン酸エステル系難燃剤 / 化学物質 / CYP
Outline of Final Research Achievements

The present study aimed at understanding biological effects of a variety of chemicals and their molecular mechanisms, with particular emphasis on signaling pathways involving cellular receptors, using zebrafish as a model organism. Some of the biological effects identified include cytochrome P450 induction, cardiovascular toxicity, and endocrine disruption, through the cellular receptors such as pregnane X receptor (PXR), aryl hydrocarbon receptor type 2 (AHR2) and estrogen receptors (ERs). The current study also suggest that in silico simulations of interaction between chemicals and ER subtypes can predict in vivo potency of the ER-mediated response by untested chemical substances.

Academic Significance and Societal Importance of the Research Achievements

動物愛護の観点から、化学物質の有害性評価において動物実験代替法の利用を促進する活動が拡大する中で、ゼブラフィッシュを用いた本研究の成果は、動物愛護に寄与し多数の化学物質をハイスループットに評価したものとして学術的・社会的意義は大きい。さらに本研究の成果は、細胞内受容体を介した作用が疑われる医薬品等の安全性評価や環境汚染物質の生態毒性試験法として発展的に活用することも期待され、医療・環境分野における化学物質リスク評価の指針となるだけでなく、わが国の化学物質管理政策にも資すると考えられる。

Report

(5 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Annual Research Report
  • 2016 Annual Research Report
  • 2015 Annual Research Report
  • Research Products

    (46 results)

All 2019 2018 2017 2016 2015 Other

All Int'l Joint Research (6 results) Journal Article (9 results) (of which Int'l Joint Research: 5 results,  Peer Reviewed: 8 results,  Open Access: 2 results) Presentation (29 results) (of which Int'l Joint Research: 13 results,  Invited: 4 results) Remarks (2 results)

  • [Int'l Joint Research] Woods Hole Oceanographic Institution(米国)

    • Related Report
      2018 Annual Research Report
  • [Int'l Joint Research] University of Antwerp(ベルギー)

    • Related Report
      2018 Annual Research Report
  • [Int'l Joint Research] Woods Hole Oceanographic Institution(米国)

    • Related Report
      2017 Annual Research Report
  • [Int'l Joint Research] Chinese Academy of Fishery Sciences(中国)

    • Related Report
      2017 Annual Research Report
  • [Int'l Joint Research] ウッズホール海洋研究所(米国)

    • Related Report
      2016 Annual Research Report
  • [Int'l Joint Research] カロリンスカ研究所(スウェーデン)

    • Related Report
      2016 Annual Research Report
  • [Journal Article] Transcriptional profiling of cytochrome P450 genes in the liver of adult zebrafish, <i>Danio rerio</i>2019

    • Author(s)
      Akira Kubota, Yusuke K. Kawai, Natsumi Yamashita, Jae Seung Lee, Daisuke Kondoh, Shuangyi Zhang, Yasunobu Nishi, Kazuyuki Suzuki, Takio Kitazawa, Hiroki Teraoka
    • Journal Title

      The Journal of Toxicological Sciences

      Volume: 44 Issue: 5 Pages: 347-356

    • DOI

      10.2131/jts.44.347

    • NAID

      130007642915

    • ISSN
      0388-1350, 1880-3989
    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The evolution of UDP-glycosyl/glucuronosyltransferase 1E (UGT1E) genes in bird lineages is linked to feeding habits but UGT2 genes is not.2018

    • Author(s)
      Yusuke K. Kawai, Yoshinori Ikenaka, Mayumi Ishizuka, Akira Kubota
    • Journal Title

      PLoS One

      Volume: 13 Issue: 10 Pages: 1-13

    • DOI

      10.1371/journal.pone.0205266

    • NAID

      120006540774

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] 十勝の台風被害による飼料用トウモロコシサイレージおよび牧草サイレージのかび毒汚染の実態2018

    • Author(s)
      川島千帆、久保田彰
    • Journal Title

      北海道畜産草地学会報

      Volume: 6 Pages: 29-34

    • NAID

      40021519058

    • Related Report
      2017 Annual Research Report
  • [Journal Article] Ecotoxicology of Dioxins in Wild Avian Species2017

    • Author(s)
      久保田 彰
    • Journal Title

      Japanese Journal of Zoo and Wildlife Medicine

      Volume: 22 Issue: 4 Pages: 63-67

    • DOI

      10.5686/jjzwm.22.63

    • NAID

      130006731441

    • ISSN
      1342-6133, 2185-744X
    • Year and Date
      2017-12-22
    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Dexamethasone-induced hepatomegaly and steatosis in larval zebrafish2017

    • Author(s)
      Guojun Yin, Liping Cao, Jinliang Du, Rui Jia, Takio Kitazawa, Akira Kubota, Hiroki Teraoka
    • Journal Title

      The Journal of Toxicological Sciences

      Volume: 42 Issue: 4 Pages: 455-459

    • DOI

      10.2131/jts.42.455

    • NAID

      130005765960

    • ISSN
      0388-1350, 1880-3989
    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Biological effects of 6-formylindolo[3,2-b]carbazole (FICZ) in vivo are enhanced by loss of CYP1A function in an Ahr2-dependent manner2016

    • Author(s)
      Wincent, E., Kubota, A., Timme-Laragy, A. R., J&ouml;nsson, M. E., Hahn, M. E. and Stegeman, J. J.
    • Journal Title

      Biochemical Pharmacology

      Volume: 110-111 Pages: 117-129

    • DOI

      10.1016/j.bcp.2016.04.012

    • Related Report
      2016 Annual Research Report 2015 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Protective effect of prostacyclin against pre-cardiac edema caused by 2,3,7,8-tetrachlorodibenzo-p-dioxin and a thromboxane receptor agonist in developing zebrafish2016

    • Author(s)
      Nijoukubo, D., Tanaka, Y., Okuno, Y., Yin, G., Kitazawa, T., Peterson, R. E., Kubota, A. and Teraoka, H.
    • Journal Title

      Chemosphere

      Volume: 156 Pages: 111-117

    • DOI

      10.1016/j.chemosphere.2016.04.107

    • Related Report
      2016 Annual Research Report 2015 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Cytochrome P450 20A1 in zebrafish: Cloning, regulation and potential involvement in hyperactivity disorders2016

    • Author(s)
      Benjamin Lemaire, Akira Kubota, Conor M. O'Meara, David C. Lamb, Robert L. Tanguay, Jared V. Goldstone, John J. Stegeman
    • Journal Title

      Toxicology and Applied Pharmacology

      Volume: 296 Pages: 73-84

    • DOI

      10.1016/j.taap.2016.02.001

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Functional characterization of zebrafish cytochrome P450 1 family proteins expressed in yeast2015

    • Author(s)
      Stegeman, J. J., Behrendt, L., Woodin, B. R., Kubota, A., Lemaire, B., Pompon, E., Goldstone, J. V. and Urban, P.
    • Journal Title

      Biochimica et Biophysica Acta

      Volume: 1850(11) Issue: 11 Pages: 2340-2352

    • DOI

      10.1016/j.bbagen.2015.07.010

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Presentation] In vivo measurement and in silico prediction of estrogen-like potency of bisphenol A and its analogues in zebrafish2019

    • Author(s)
      Akira Kubota, Jae Seung Lee, Yumi Wakayama, Michiko Nakamura, Yuka Yoshinouchi, Hisato Iwata, Masashi Hirano, Haruhiko Nakata, Yusuke Kawai
    • Organizer
      SOT 58th Annual Meeting and ToxExpo
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] In vivo measurement and in silico prediction of estrogenic and anti-estrogenic potency of bisphenol A and its analogues in zebrafish2019

    • Author(s)
      Akira Kubota, Jae Seung Lee, Yumi Wakayama, Michiko Nakamura, Yuka Yoshinouchi, Hisato Iwata, Masashi Hirano, Yusuke Kawai
    • Organizer
      International Chemical Hazard Symposium in Hokkaido
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Assessment of estrogenic and anti-estrogenic potency of bisphenol A replacement in zebrafish2018

    • Author(s)
      Jae Seung Lee, Yumi Wakayama, Michiko Nakamura, Yuka Yoshinouchi, Hisato Iwata, Masashi Hirano, Haruhiko Nakata, Yusuke Kawai, Akira Kubota
    • Organizer
      第27回環境化学討論会
    • Related Report
      2018 Annual Research Report
  • [Presentation] ゼブラフィッシュを用いた生態毒性試験について2018

    • Author(s)
      久保田彰
    • Organizer
      第12回生態影響試験実習セミナー
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] ゼブラフィッシュを用いたビスフェノールA代替物質の内分泌攪乱作用の評価2018

    • Author(s)
      久保田彰、Jae Seung Lee、若山裕己、中村倫子、川合佑典、芳之内結加、岩田久人、平野将司、中田晴彦
    • Organizer
      第45回日本毒性学会学術年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 十勝の台風被害による飼料用トウモロコシサイレージのかび毒汚染の実態2018

    • Author(s)
      久保田 彰、Jae Seung Lee、川島千帆
    • Organizer
      第45回日本毒性学会学術年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Evaluating estrogenic and anti-estrogenic potency of bisphenol A analogues in vivo and in silico using zebrafish2018

    • Author(s)
      Akira Kubota, Yumi Wakayama, Jae Seung Lee, Michiko Nakamura, Yusuke Kawai, Yuka Yoshinouchi, Hisato Iwata, Masashi Hirano, Haruhiko Nakata
    • Organizer
      38th International Symposium on Halogenated Persistent Organic Pollutants
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] タンチョウにおける異物代謝関連遺伝子の同定と定量2018

    • Author(s)
      川合佑典、伊藤究、坂本梨果子、吉野智生、飯間裕子、松本文雄、久保田彰
    • Organizer
      第161回日本獣医学会学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] In silico prediction and in vivo measurement of estrogenic activity of bisphenol analogues in zebrafish2018

    • Author(s)
      Akira Kubota, Yumi Wakayama, Michiko Nakamura, Yusuke Kawai, Yuka Yoshinouchi, Hisato Iwata, Masashi Hirano, Haruhiko Nakata
    • Organizer
      57th Society of Toxicology Annual Meeting
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] ゼブラフィッシュ胚を用いたin silicoおよびin vivo解析によるビスフェノール類のエストロゲン様作用の評価2017

    • Author(s)
      川合佑典、中村倫子、若山裕己、森田友理、芳之内結加、平野将司、中田晴彦、岩田久人、久保田 彰
    • Organizer
      第26回環境化学討論会
    • Related Report
      2017 Annual Research Report
  • [Presentation] In vivo and in silico assessment of estrogen-like effects of bisphenol analogues in zebrafish2017

    • Author(s)
      Yumi Wakayama, Michiko Nakamura, Yuri Morita, Yuka Yoshinouchi, Hisato Iwata, Masashi Hirano, Haruhiko Nakata, Yusuke Kawai, Akira Kubota
    • Organizer
      19th International Symposium on Pollutant Responses in Marine Organisms
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Evolution of avian UGT family genes in relation to feeding habit2017

    • Author(s)
      Yusuke Kawai, Yoshinori Ikenaka, Mayumi Ishizuka, Akira Kubota
    • Organizer
      19th International Symposium on Pollutant Responses in Marine Organisms
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] ゼブラフィッシュをモデルとしたin vivoおよびin silico解析によるビスフェノール類のエストロゲン様作用の評価2017

    • Author(s)
      中村倫子、若山裕己、芳之内結加、森田友理、岩田久人、川合佑典、久保田 彰
    • Organizer
      第44回日本毒性学会学術年会
    • Related Report
      2017 Annual Research Report
  • [Presentation] 有機リン系難燃剤およびその代謝物による発達期ゼブラフィッシュに対する影響2017

    • Author(s)
      森田友理、若山裕己、芳之内結加、岩田久人、川合佑典、久保田 彰
    • Organizer
      第44回日本毒性学会学術年会
    • Related Report
      2017 Annual Research Report
  • [Presentation] In silico prediction and in vivo measurement of estrogenic activity of bisphenol analogues in zebrafish2017

    • Author(s)
      Akira Kubota, Yumi Wakayama, Michiko Nakamura, Yusuke Kawai, Yuka Yoshinouchi, Hisato Iwata, Masashi Hirano, Haruhiko Nakata
    • Organizer
      20th International Conference on Cytochrome P450
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] ゼブラフィッシュをモデルとしたin silicoおよびin vivo解析によるビスフェノール類のエストロゲン様作用の評価2017

    • Author(s)
      久保田 彰、若山裕己、中村倫子、川合佑典、芳之内結加、岩田久人、平野将司、中田晴彦
    • Organizer
      環境ホルモン学会 第20回研究発表会
    • Related Report
      2017 Annual Research Report
  • [Presentation] Biological effects of a dysfunctional CYP1A/AHR2 feedback loop in developing zebrafish2016

    • Author(s)
      Akira Kubota, Alicia Timme-Laragy, Maria Jonsson, Mark E. Hahn, John J. Stegeman, Emma Wincent
    • Organizer
      環境ホルモン学会 第19回研究発表会
    • Place of Presentation
      文部科学省 研究交流センター(茨城県つくば市)
    • Year and Date
      2016-12-08
    • Related Report
      2016 Annual Research Report
  • [Presentation] Reciprocal cross-talk between Ahr2 and Pxr signaling in response to PCB126 and pregnenolone in developing zebrafish2016

    • Author(s)
      Akira Kubota, Jared Goldstone, John Stegeman
    • Organizer
      The 9th International PCB Workshop
    • Place of Presentation
      神戸国際会議場(兵庫県・神戸市)
    • Year and Date
      2016-10-09
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 発達期ゼブラフィッシュにおけるCYP1A/AHRフィードバック機構攪乱の影響2016

    • Author(s)
      久保田彰,Emma Wincent,John Stegeman
    • Organizer
      第22回日本環境毒性学会研究発表会
    • Place of Presentation
      愛媛大学(愛媛県・松山市)
    • Year and Date
      2016-09-06
    • Related Report
      2016 Annual Research Report
  • [Presentation] Characterization of a Pxr-null zebrafish2016

    • Author(s)
      Matthew C. Salanga, Akira Kubota, Benjamin Lemaire, Rachel Harbeitner, Daniel Gusenleitner, Stefano Monti, John J. Stegeman, Jared V. Goldstone
    • Organizer
      55th Annual Meeting of Society of Toxicology
    • Place of Presentation
      ニューオーリンズ(米国)
    • Year and Date
      2016-03-13
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 発達期ゼブラフィッシュをモデルとした化学物質の毒性発現機構の解析2016

    • Author(s)
      久保田彰
    • Organizer
      第7回LaMer特別講演会
    • Place of Presentation
      愛媛大学(愛媛県・松山市)
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] ゼブラフィッシュにおける薬物代謝酵素の網羅的解析:魚類とヒト健康影響のモデル動物の観点から2016

    • Author(s)
      久保田彰
    • Organizer
      環境リスク・健康研究センター特別講演会
    • Place of Presentation
      国立環境研究所(茨城県つくば市)
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] 魚類におけるPXR・AHRを介したシトクロムP450発現制御機構の特徴2015

    • Author(s)
      久保田 彰, Jared V. Goldstone, John J. Stegeman
    • Organizer
      第21回日本環境毒性学会研究発表会
    • Place of Presentation
      東洋大学白山キャンパス(東京都・文京区)
    • Year and Date
      2015-09-02
    • Related Report
      2015 Annual Research Report
  • [Presentation] 魚類におけるシトクロムP450の発現制御機構と代謝特性2015

    • Author(s)
      久保田 彰, John J. Stegeman
    • Organizer
      第42回日本毒性学会学術年会
    • Place of Presentation
      石川県立音楽堂、金沢市アートホテル、ホテル日航金沢(石川県・金沢市)
    • Year and Date
      2015-06-29
    • Related Report
      2015 Annual Research Report
  • [Presentation] ゼブラフィッシュのリガンド依存性転写因子とシトクロムP4502015

    • Author(s)
      久保田 彰, Jared V. Goldstone, Emma Wincent, John J. Stegeman
    • Organizer
      第42回日本毒性学会学術年会
    • Place of Presentation
      石川県立音楽堂、金沢市アートホテル、ホテル日航金沢(石川県・金沢市)
    • Year and Date
      2015-06-29
    • Related Report
      2015 Annual Research Report
  • [Presentation] Role of pregnane X receptor and aryl hydrocarbon receptor in transcriptional regulation of PXR, CYP2, and CYP3 genes in developing zebrafish2015

    • Author(s)
      Akira Kubota, Jared V. Goldstone, Benjamin Lemaire, John J. Stegeman
    • Organizer
      19th International Conference on Cytochrome P450
    • Place of Presentation
      国立オリンピック記念青少年総合センター(東京都・渋谷区)
    • Year and Date
      2015-06-12
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Differences in responses to putative PXR agonists associated with PXR alleles in zebrafish embryos2015

    • Author(s)
      Akira Kubota, Jared V. Goldstone, Benjamin Lemaire, Rachel Harbeitner, Lauren Salay, John J. Stegeman
    • Organizer
      18th International symposium on Pollutant Responses in Marine Organisms
    • Place of Presentation
      トロンハイム(ノルウェー)
    • Year and Date
      2015-05-24
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Reciprocal cross-talk between PXR and AHR2 signaling in response to their putative agonists in developing zebrafish2015

    • Author(s)
      Akira Kubota, Jared V. Goldstone, Benjamin Lemaire, Matthew Takata, Bruce R. Woodin, John J. Stegeman
    • Organizer
      18th International symposium on Pollutant Responses in Marine Organisms
    • Place of Presentation
      トロンハイム(ノルウェー)
    • Year and Date
      2015-05-24
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] The PXR “gene battery” in zebrafish2015

    • Author(s)
      Jared V. Goldstone, Rachel Harbeitner, Akira Kubota, Benjamin Lemaire, John J. Stegeman
    • Organizer
      18th International symposium on Pollutant Responses in Marine Organisms
    • Place of Presentation
      トロンハイム(ノルウェー)
    • Year and Date
      2015-05-24
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Remarks] 帯広畜産大学獣医学研究部門基礎獣医学分野 毒性学研究室ホームページ

    • URL

      http://www.obihiro.ac.jp/~toxicology/index.html

    • Related Report
      2018 Annual Research Report 2017 Annual Research Report
  • [Remarks] 帯広畜産大学 獣医学研究部門基礎獣医学分野 毒性学研究室 ホームページ

    • URL

      http://www.obihiro.ac.jp/~toxicology/index.html

    • Related Report
      2016 Annual Research Report

URL: 

Published: 2015-04-16   Modified: 2020-03-30  

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