2004 Fiscal Year Final Research Report Summary
Effect of endocrine disruptors on nuclear receptor superfamily.
| Project/Area Number |
14370764
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Environmental pharmacy
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| Research Institution | Osaka University |
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Principal Investigator |
NISHIKAWA Jun-ichi Osaka University, Graduate School of Pharmaceutical Sciences, Associate Professor, 薬学研究科, 助教授 (90218131)
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| 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)
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| Project Period (FY) |
2002 – 2004
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| Keywords | endocrine disrupter / environmental hormone / nuclear receptor / reproductive toxicity / estrogen / retinoid / imposex / organotin |
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| 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
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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
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Research Products
(12 results)
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[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.
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Journal Title
Environ.Sci.Technol. 38
Pages: 6271-6276
Description
「研究成果報告書概要(欧文)」より
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[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.
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Journal Title
J.Health Sci. 50
Pages: 581-587
Description
「研究成果報告書概要(欧文)」より
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[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.
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Journal Title
J.Health Sci. 50
Pages: 25-32
Description
「研究成果報告書概要(欧文)」より
