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Effect of endocrine disruptors on nuclear receptor superfamily.

Research Project

Project/Area Number 14370764
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Environmental pharmacy
Research InstitutionOsaka University

Principal Investigator

NISHIKAWA Jun-ichi  Osaka University, Graduate School of Pharmaceutical Sciences, Associate Professor, 薬学研究科, 助教授 (90218131)

Co-Investigator(Kenkyū-buntansha) SHIRAISHI Fujio  National Institute for Environmental Studies, Senior Research Scientist, 環境ホルモンダイオキシン研究グループ, 主任研究員 (30113476)
今川 正良  名古屋市立大学, 薬学部, 教授 (20136823)
Project Period (FY) 2002 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥13,800,000 (Direct Cost: ¥13,800,000)
Fiscal Year 2004: ¥2,500,000 (Direct Cost: ¥2,500,000)
Fiscal Year 2003: ¥2,500,000 (Direct Cost: ¥2,500,000)
Fiscal Year 2002: ¥8,800,000 (Direct Cost: ¥8,800,000)
Keywordsendocrine disrupter / environmental hormone / nuclear receptor / reproductive toxicity / estrogen / retinoid / imposex / organotin / レチノイン酸
Research Abstract

Nuclear receptors play important roles in the maintenance of the endocrine system, regulation of organ differentiation and fetal development. Endocrine disruptors exert their adverse effects by disrupting the endocrine system via various mechanisms. Many naturally occurring and synthetic compounds, including DDT and its metabolites, PCBs, and some alkylphenols have hormonal activities. Although the levels of natural hormones are precisely regulated metabolically in intact organisms, synthetic chemicals elude this regulation to stimulate organs by mechanisms different from those of natural hormones. Nuclear receptors are the likely targets of endocrine disruptors, because their intrinsic ligands are fat-soluble, low-molecular weight agents, as are the environmental pollutants. To evaluate the effects of numerous synthetic chemicals on many nuclear receptors, we developed the CoA-BAP system, a high-throughput method for identifying activators of nuclear receptors. Using this system, we f … More ound that several compounds possess agonistic activities for multiple receptors simultaneously. Butyl benzyl phthalate, hexachlorocyclohexane, maneb, mancozeb, and alkylphenols were weakly agonistic for multiple receptors including estrogen receptor. One intriguing finding was that the effect of organotins (TBT and TPT) on retinoid X receptor(RXR) was as strong as that of its endogenous ligand, 9-cis retinoic acid (9-cis RA). Organotins are potent inducers of imposex (a superimposition of male genital tracts, such as penis and vas deferens, on females) in marine gastropods. Cloning of the RXR homolog from wild rock shell (Thais clavigera) revealed that the ligand-binding domain of rock shell RXR was very similar to vertebrate RXR and bound to both 9-cis RA and to organotins. Further, injection of 9-cis RA into females of Thais clavigera induced the development of imposex. These data provide strong evidence that RXR plays an important role in inducing the development of imposex, namely the differentiation and growth of male genital tracts in female gastropods. Less

Report

(4 results)
  • 2004 Annual Research Report   Final Research Report Summary
  • 2003 Annual Research Report
  • 2002 Annual Research Report
  • Research Products

    (24 results)

All 2005 2004 Other

All Journal Article (18 results) Publications (6 results)

  • [Journal Article] Organotin compounds promote adipocyte differentiation as agonists of the PPARγ/RXR pathway.2005

    • Author(s)
      Kanayama, T. et al.
    • Journal Title

      Molecular Pharmacology 67

      Pages: 766-774

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Some organotin compounds enhance histone acetyltransferase activity.2005

    • Author(s)
      Osada, S. et al.
    • Journal Title

      Toxicology Letters 155

      Pages: 329-335

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Organotin compounds promote adipocyte differentiation as agonists of the peroxisome proliferator-activated receptor(PPAR) γ/retinoid X receptor(RXR) pathway.2005

    • Author(s)
      Kanayama, T., Kobayashi, N., Mamiya, S., Nakanishi, T., Nishikawa J.
    • Journal Title

      Mol.Pharmacol. 67

      Pages: 766-774

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Some organotin compounds enhance histoneacetyltransferase activity.2005

    • Author(s)
      Osada, S., Nishikawa, J., Nakanishi, T., Tanaka, K., Nishihara, T.
    • Journal Title

      Toxicol.Lett. 155

      Pages: 329-335

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Organotin compounds promote adipocyte differentiation as agonists of the peroxisome proliferator-activated receptor γ/ retinoid X receptor pathway.2005

    • Author(s)
      Kanayama, T. et al.
    • Journal Title

      Molecular Pharmacology Vol.67

      Pages: 766-774

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Some organotin compounds enhance histone acetyltransferase activity.2005

    • Author(s)
      Osada, S. et al.
    • Journal Title

      Toxicology Letters Vol.155

      Pages: 329-335

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Involvement of the retinoid X receptor in the development of imposex caused by organotins in gastropod.2004

    • Author(s)
      Nishikawa, J. et al.
    • Journal Title

      Environmental Science and Technology 38

      Pages: 6271-6276

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] 1-Chloro-2,4-dinitrobenzene stimulates the estrogenic activity in MCF-7 cells.2004

    • Author(s)
      Jung, J. et al.
    • Journal Title

      Journal of Health Science 50

      Pages: 581-587

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Development of standardized in vitro assay system for estrogen receptor and species specificity of binding of 4-nonylphenol and p-octylphenol.2004

    • Author(s)
      Nishizuka, M. et al.
    • Journal Title

      Journal of Health Science 50

      Pages: 511-517

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Development of a competitive enzyme immunoassay for detection of capacity of chemicals to bind quail estrogen receptor α and β.2004

    • Author(s)
      Maekawa, S. et al.
    • Journal Title

      Journal of Health Science 50

      Pages: 25-32

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Involvement of the retinoid X receptor in the development of imposex caused by organotins in gastropod.2004

    • Author(s)
      Nishikawa, J., Mamiya, S., Kanayama, T., Nishikawa, T., Shiraishi, F., Horiguchi, T.
    • Journal Title

      Environ.Sci.Technol. 38

      Pages: 6271-6276

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] 1-Chloro-2,4-dinitrobenzene stimulates the estrogenic activity in MCF-7 cells.2004

    • Author(s)
      Jung, J., Ishida, K., Osada, S., Nishikawa, J., Nishihara, T.
    • Journal Title

      J.Health Sci. 50

      Pages: 581-587

    • NAID

      110003666006

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Development of standardized in vitro assay system for estrogen receptors and species specificity of binding ability of 4-nonylphenol and p-octylphenol.2004

    • Author(s)
      Nishizuka, M., Heitaku, S., Maekawa, S., Nishikawa, J., Imagawa, M.
    • Journal Title

      J.Health Sci. 50

      Pages: 511-517

    • NAID

      110003609196

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Development of a competitive enzyme immunoassay for detection of capacity of chemicals to bind quail estrogen receptor α and β.2004

    • Author(s)
      Maekawa, S., Nishizuka, M., Heitaku, S., Kunimoto, M., Nishikawa, J., Ichikawa, K., Shimada, K., Imagawa, M.
    • Journal Title

      J.Health Sci. 50

      Pages: 25-32

    • NAID

      110003609124

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Involvement of the retinoid X receptor in the development of imposex caused by organotins in gastropod.2004

    • Author(s)
      Nishikawa, J. et al.
    • Journal Title

      Environmental Science and Technology Vol.38

      Pages: 6271-6276

    • Related Report
      2004 Annual Research Report
  • [Journal Article] 1-Chloro-2,4-dinitrobenzene stimulates the estrogenic activity in MCF-7 cells.2004

    • Author(s)
      Jung, J. et al.
    • Journal Title

      Journal of Health Science Vol.50

      Pages: 581-587

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Development of standardized in vitro assay system for estrogen receptors and species specificity of binding of 4-nonylphenol and p-Otylphenol.2004

    • Author(s)
      Nishizuka, M. et al.
    • Journal Title

      Journal of Health Science Vol.50

      Pages: 511-517

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Development of a competitive enzyme immunoassay for detection of capacity of chemicals to bind quail estrogen receptor α and β.2004

    • Author(s)
      Maekawa, S. et al.
    • Journal Title

      Journal of Health Science Vol.50

      Pages: 25-32

    • Related Report
      2004 Annual Research Report
  • [Publications] Kanayama, T. et al.: "Basis of a high-throughput method for nuclear receptor ligands"Journal of Biochemistry. Vol.133. 791-797 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Mikamo, E. et al.: "Endocrine disruptors induce cytochrome P450 by affecting transcriptional regulation via pregnane X receptor"Toxicology and Applied Pharmacology. Vol.193. 66-72 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Nishikawa, J. et al.: "Effect of suspected endocrine disruptors on various kinds of nuclear hormone receptors"Journal of Environmental Biotechnology. Vol.3. 37-42 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Shiraishi, F. et al.: "Estrogenic and thyroid hormone activity of a series of hydroxy-polychlorinated biphenyls"Chemosphere. Vol.52. 33-42 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Mikamo, E. et al.: "Methoxychlor induces CYP2C11 to convert itself into hormonally active metabolites"Journal of Health Science. Vol.49. 229-232 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kawamura, Y. et al.: "Estrogenic activities of UV stabilizers used in food contact plastics and benzophenone derivatives tested by the Yeast two-hybrid assay"Journal of Health Science. Vol.49. 205-212 (2003)

    • Related Report
      2003 Annual Research Report

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Published: 2002-04-01   Modified: 2016-04-21  

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