Elucidation of the mechanisms of vulnerability of neonatal kidney

• Project/Area Number: 16H05889
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: Risk sciences of radiation and chemicals
• Research Institution: Jikei University School of Medicine
• Principal Investigator: Yoshioka Wataru 東京慈恵会医科大学, 医学部, 講師 (80425496)
• Project Period (FY): 2016-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥23,790,000 (Direct Cost: ¥18,300,000、Indirect Cost: ¥5,490,000); Fiscal Year 2019: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2018: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2017: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2016: ¥7,410,000 (Direct Cost: ¥5,700,000、Indirect Cost: ¥1,710,000)
• Keywords: 水腎症 / 多尿 / 尿濃縮障害 / プロスタグランジン / phospholipase / プロスタグランジン合成酵素 / 有害化学物質 / ダイオキシン / 脂肪肝 / 生体分子 / 遺伝子 / 病理学 / 腎

Outline of Final Research Achievements

Arylhydrocarbon receptor (AhR) is a ligand-dependent transcription factor that is responsible for dioxin toxicity. The mechanisms linking AhR and dioxin toxicity has been largely unknown. In this study, we found that a phospholipase cPLA2a has a potential to link AhR and dioxin toxicity. In addition, we found that an increase and dilution of urine is a direct mechanism of hydronephrosis, one of developmental-stage specific dioxin toxicity, and that the mechanism is not induced in adults. These findings offered important insights into the problem of developmental-stage specific toxicity of dioxins as well as mechanisms of vulnerability of neonatal kidney.

Academic Significance and Societal Importance of the Research Achievements

化学物質の生体影響について、発達段階のある時期には悪影響が生じて別の時期には影響が生じないことがある。このように発達段階特異性があることは化学物質の影響評価を困難にする問題であるが、その原因はよく分かっていない。本研究では、芳香族炭化水素類等がマウス新生子に引き起こす水腎症をモデルとして、発症機序をまず解明し、次いで水腎症が生じない時期にこの機序が作動しないことを明らかにした。機序を解明することで発達段階特異性が生じる原因が明らかにできることが示された。

Research Products

• [Journal Article] Significance of AHR nuclear translocation sequence in 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced cPLA2α activation and hydronephrosis (2019)
  • Author(s): Fujisawa Nozomi、Yoshioka Wataru、Yanagisawa Hiroyuki、Tohyama Chiharu
  • Journal Title: Archives of Toxicology Volume: 0 Issue: 5 Pages: 0-0
  • DOI: 10.1007/s00204-019-02414-9
  • Peer Reviewed
• [Journal Article] Mechanisms of Developmental Toxicity of Dioxins and Related Compounds (2019)
  • Author(s): Yoshioka Wataru、Tohyama Chiharu
  • Journal Title: International Journal of Molecular Sciences Volume: 20 Issue: 3 Pages: 617-617
  • DOI: 10.3390/ijms20030617
  • Peer Reviewed / Open Access
• [Journal Article] Roles of cytosolic phospholipase A2α in reproductive and systemic toxicities in 2,3,7,8-tetrachlorodibenzo-p-dioxin-exposed mice (2018)
  • Author(s): Nozomi Fujisawa, Wataru Yoshioka, Hiroyuki Yanagisawa, Chiharu Tohyama
  • Journal Title: Archives of Toxicology Volume: 92 Issue: 2 Pages: 789-801
  • DOI: 10.1007/s00204-017-2081-z
  • Peer Reviewed / Open Access
• [Journal Article] Polyuria-associated hydronephrosis induced by xenobiotic chemical exposure in mice. (2016)
  • Author(s): Yoshioka W, Kawaguchi T, Nishimura N, Akagi T, Fujisawa N, Yanagisawa H, Matsumura F, Tohyama C
  • Journal Title: American journal of physiology Renal physiology Volume: 311 Issue: 4 Pages: 752-762
  • DOI: 10.1152/ajprenal.00001.2016
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] ダイオキシン類が引き起こす授乳期・胎仔期水腎症の病態と原因遺伝子の 解明 (2019)
  • Author(s): 吉岡亘、遠山千春、柳澤裕之
  • Organizer: 第92回日本産業衛生学会
• [Presentation] Molecular basis of resistance to TCDD-induced hydronephrosis in adult mice. (2017)
  • Author(s): 35.Yoshioka W, Kawaguchi T, Nishimura N, Fujisawa N, Yanagisawa H, Tohyama C
  • Organizer: SOT2017 (The Annual Meeting of the Society of Toxicology)
  • Place of Presentation: Baltimore, USA
  • Year and Date: 2017-03-12
  • Int'l Joint Research