周生期ホルモン曝露による標的器官への不可逆的影響の分子メカニズム

2008 Fiscal Year Annual Research Report

• Project/Area Number: 19370027
• Research Institution: National Institutes of Natural Sciences Okazaki Research Facilities
• Principal Investigator: 井口 泰泉 National Institutes of Natural Sciences Okazaki Research Facilities, 岡崎統合バイオサイエンスセンター, 教授 (90128588)
• Keywords: ホルモン / 曝露影響 / エピジェネティクス / 不可逆的影響

Research Abstract

女性ホルモンであるエストロゲンは、生殖をはじめとした様々な局面で重要な機能を果たしているが、ひとたびその制御システムが破たんをきたした場合、乳がんや子宮内膜症、不妊や骨粗鬆症などを引き起こすことが知られている。こうしたエストロゲンの制御システムの破たんの要因の1つとして、胎児期や幼若期におけるエストロゲン曝露による影響が懸念されている。本研究は、このエストロゲンによる制御システムの破たんの分子メカニズムを明らかにすることを目的としている。このモデルとして、不適切な時期(周生期)におけるエストロゲン曝露を行い、その成熟期における影響について解析を進めてきている。新生児期曝露を行ったマウスでは、成熟期の膣においてエストロゲン非依存的な細胞増殖が観察される。そこで、新生児期(生後5日まで)にエストロゲン曝露した群と成熟期(生後10週)にエストロゲン曝露した群を作製し、成熟期にマウス膣からRNAを抽出し、それぞれの遺伝子発現プロファイルを取得した。これらの遺伝子発現プロファイルの解析により、新生児期曝露に特異的に発現が変化した遺伝子をリストアップした。また、クロマチン免疫沈降法により、それぞれの遺伝子の制御領域を含むゲノム領域の構造についてエピジェネティックな観点から解析を進めている。特に、抗修飾ヒストン抗体、抗メチル化シトシン抗体を用いてゲノム断片を沈降させ、ゲノムワイドに解析を行うことにより、ゲノムが修飾を受ける領域を明らかにし、遺伝子発現変化、不可逆的影響との関連の解明を進めている。

Research Products

• [Journal Article] Effects of diethylstilbestrol on ovarian follicle development in neonatal mice (2009)
  • Author(s): H. Kim, S. Hayashi, P. Chambon, H. Watanabe, T. Iguchi, T. Sato
  • Journal Title: Reprod. Toxicol. 27 Pages: 55-62
  • Peer Reviewed
• [Journal Article] Sexual re-programming and estrogenic sensitization in wild fish exposed to ethinylestradiol (2009)
  • Author(s): A. Lange, G. C. Paull, T. S. Coe, Y. Katsu, H. Urushitani, T. Iguchi, C. R. Tyler
  • Journal Title: Environ. Sci. Technol. 43 Pages: 1219-1225
  • Peer Reviewed
• [Journal Article] Environmental health impacts of equine estrogens derived from hormone replacement therapy (2009)
  • Author(s): C. R. Tyler, A. L. Filby, L. K. Bickley, R. I. Cumming, R. Gibson, P. Labadie, Y. Katsu, K. E. Liney, J. A. Shears, V. Silva-Castros, H. Urushitani, A. Lange, M. J. Winter, T. Iguchi, E. M. Hill
  • Journal Title: Enviorn. Sci. Technol. (in press)
  • Peer Reviewed
• [Journal Article] Thyroid histopathology assessments for the amphibian metamorphosis assay to detect thyroid-active substances (2009)
  • Author(s): K. C. Grim, M. Wolfe, T. B raunbeck, T. Iguchi, Y. Ohta, O. Tooi, L. Touart, C. D ouglas, D. C. Wolf, J. Tietge
  • Journal Title: Tox. Pathol. (in press)
  • Peer Reviewed
• [Journal Article] Genetic integrations of the androgen and Wnt/beta-catenin pathways for the masculinization of external genitalia (2009)
  • Author(s): S. Miyagawa, Y. Satoh, R. Haraguchi, K. Suzuki, T. Iguchi, M. M. Taketo, N. Nakagata, T. Matsumoto, K. Takeyama, S. Kato, G. Yamada
  • Journal Title: Mol. Endocrinol. (in press)
  • Peer Reviewed
• [Journal Article] Why public health agencies cannot depend upon 'good laboratory practices' as a criterion for selecting data : The case of bisphenol A (2009)
  • Author(s): J. P. Myers, F. S. vom Saal, B. T. Akingbemi, K. Arizono, S. Belcher, T. Colborn, I. Chahoud, D. A. Crain, F. Farabollini, L. J. Guillette, Jr., T. Hassold, S. -M. Ho, P. A. Hunt, T. Iguchi, S. Jobling, J. Kanno, H. Laufer, M. Marcus, J. A. McLachlan, A. Nadal, J. Oehlmann, N. Olea, P. Palanza, S. Parmigiani, B. S. Rubin, G. S choenfelder, C. Sonnenschein, A. M. Soto, C. E. Talsness, J. A. Taylor, L. N. Vanden berg, J. G. Vandenbergh, S. Vogel, C. S. Watson, W. V. Welshons, R. T. Zoeller
  • Journal Title: Environ. Health Perspect. 117 Pages: 309-315
  • Peer Reviewed
• [Journal Article] Novel approaches for the study of vertebrate steroid hormone receptors (2009)
  • Author(s): S. Kohno, Y. Katsu, T. Iguchi, L. J. Guillette Jr.
  • Journal Title: Integ. Comp. Biol. (in press)
  • Peer Reviewed
• [Journal Article] Molecular cloning and characterization of estrogen, androgen and progesterone nuclear receptors from a freshwater turtule (Pseudemys nelsoni) (2008)
  • Author(s): Y. Katsu, R. Ichikawa, T. Ikeuchi, S. Kohno, L. J. Guillette Jr., T. Iguchi
  • Journal Title: Endocrinology 149 Pages: 161-173
  • Peer Reviewed
• [Journal Article] Molecular cloning and sexually dimorphic expression of DM-domain genes in Daphnia magna (2008)
  • Author(s): Y. Kato, K. Kobayashi, S. Oda, J. K. Colbourne, N. Tatarazako, H. Watanabe, T. Iguchi
  • Journal Title: Genomics 91 Pages: 94-101
  • Peer Reviewed
• [Journal Article] Vacuolar degeneration of skeletal muscle in transgenic mice overexpressing ORP150 (2008)
  • Author(s): T. Kobayashi, Y. Takita, A. Suzuki, Y. Katsu, T. Iguchi, Y. Ohta
  • Journal Title: J. Vet. Med. Sci. 70 Pages: 115-118
  • Peer Reviewed
• [Journal Article] Gene expression analyses on the embryonic external genitalia : identification of regulatory genes possibly involved in masculinization processes (2008)
  • Author(s): H. Nishida, S. Miyagawa, D. Matsumaru, Y. Wada, Y. Satoh, Y. Ogino, T. Iguchi S Fukuda, T. Taga, G. Yamada
  • Journal Title: Congen. Anorm. 48 Pages: 63-67
  • Peer Reviewed
• [Journal Article] Increased post hatching mortality and loss of sexually dimorphic gene expression in alligators (Alligator mississippiensis) from a contaminated environment (2008)
  • Author(s): M. R. Milnes, T. A. Bryan, Y. Katsu, S. Kohno, B. C. Moore, T. Iguchi, L. J. Jr. Guillette
  • Journal Title: Biol. Reprod 78 Pages: 932-938
  • Peer Reviewed
• [Journal Article] Linking molecular and population stress responses in Daphnia magna exposed to cadmium (2008)
  • Author(s): R. Connon, H. L. Hooper, R. M. Sibly, F. L. Lim, L. H. Heckmann, D. J. Moore, H. Watanabe, A. Soetaert, K. Cook, S. J. Maund, T. H. Hutchinson, J. Moggs, W. De Coen, T. Iguchi, A. Callaghan
  • Journal Title: Environ. Sci. Technol. 42 Pages: 2181-2188
  • Peer Reviewed
• [Journal Article] Effect of atrazine on metamorphosis and sexual differentiation in Xenopus laevis (2008)
  • Author(s): T. Oka, O. Tooi, N. Mitsui, M. Miyahara, Y. Ohnishi, M. Takase, A. Kashiwagi, T. Shinkai, N. Santo, T. Iguchi
  • Journal Title: Aquat. Toxicol. 87 Pages: 215-226
  • Peer Reviewed
• [Journal Article] Activation of steroid and xenobiotic receptor (SXR, NR112) and its orthologs in laboratory, toxicological, and genome model species (2008)
  • Author(s): M. R. Milnes, A. Garcia, E. Grossman, F. Grun, J. Shiotsugu, M. M. Tabb, Y. Kawashima, Y. Katsu, H. Watan abe, T. Iguchi, B. Blumberg
  • Journal Title: Eviron. Health Perspect. 116 Pages: 880-885
  • Peer Reviewed
• [Journal Article] Gene expression patterns in juvenile American alligators (Alligator mississippiensis) exposed to environmental contaminants (2008)
  • Author(s): S. Kohno, D. Bermudez, Y. Katsu, T. Iguchi, L. J. Guillette Jr.
  • Journal Title: Aquat. Toxicol. 88 Pages: 95-101
  • Peer Reviewed
• [Journal Article] Altered sexual development in roach (Rutilus rutilus) exposed to environmental concentrations of the pharmaceutical 17beta-ethinylestradiol and associated expression dynamics of aroma tases and estrogen receptors (2008)
  • Author(s): A. Lange, Y. Katsu, R. Ichikawa, G. C. Paull, L. L. Chidgey, T. S. Coe, T. Iguchi, C. R. Tyler
  • Journal Title: Tox. Sci. 106 Pages: 113-123
  • Peer Reviewed
• [Journal Article] Estrogen receptor subtypes selectively mediate female mouse reproductive abnormalities induced by neonatal exposure to estrogenic chemicals (2008)
  • Author(s): T. Nakamura, Y. Katsu, H. Watanabe, T. Iguchi
  • Journal Title: Toxicology 253 Pages: 117-124
  • Peer Reviewed
• [Journal Article] The influence of non-toxic concentrations of DDT and DDE on the old world vulture estrogen receptor (2008)
  • Author(s): V. Naido, Y. Katsu, T. Iguchi
  • Journal Title: Gen. Comp. Endocrinol 159 Pages: 188-195
  • Peer Reviewed
• [Journal Article] Transcriptome profiling in crustaceans as a tool for ecotoxico genomics (2008)
  • Author(s): H. Watanabe, K. Kobayashi, Y. Kato, S. Oda, R. Abe, N. Tatarazako, T. Iguchi
  • Journal Title: Cell Biol. Toxicol. 24 Pages: 641-647
  • Peer Reviewed
• [Journal Article] Molecular cloning, characterization and evolutionary analysis of estrogen receptors from phylogenetically ancient fish (2008)
  • Author(s): Y. Katsu, S. Kohno, S. Hyodo, S. Ijiri, A. Hara, L. J. Guillette Jr., T. Iguchi
  • Journal Title: Endocrinology 149 Pages: 6300-6310
  • Peer Reviewed
• [Journal Article] Developmental effects : estrogen induced vaginal changes and organotin induced adipogenesis (2008)
  • Author(s): T. Iguchi, H. Watanabe, Y. Ohta, B. Blumberg
  • Journal Title: Int. J. Androl. 31 Pages: 263-268
  • Peer Reviewed
• [Journal Article] Female reproductive disruption : The roles of endocrine disrupting compounds and developmental timing (2008)
  • Author(s): D. A. Crain, S. J. Janssen, T. M. Edwards, J. Heindel, S. -M. Ho, P. Hunt, T. Iguchi, A. Juul, J. A. McLachlan, J. Schwartz, N. Skakkebaek, A. M. Soto, S. Swan, C. Walker, T. Woodruff. T. Woodruff, L. C. Giudice, L. J. Guillette, Jr.
  • Journal Title: Fertil. Steril. 90 Pages: 911-940
  • Peer Reviewed
• [Journal Article] Commonality and difference in mechanisms of endocrine disruption in various animal species (2008)
  • Author(s): T. Iguchi, Y. Katsu
  • Journal Title: BioScience 58 Pages: 1061-1067
  • Peer Reviewed
• [Journal Article] 内分泌かく乱物質が及ぼす発生、成長への影響 (2008)
  • Author(s): 井口泰泉、中村武志
  • Journal Title: ビオフィリア 4 Pages: 13-17
• [Journal Article] (2008)
  • Author(s): T. Iguchi, H. Watanabe, Y. Katsu
  • Journal Title: Toxicogenomics and ecotoxicogenomics : Studying chemical effects and basic biology in vertebrates and invertebrates." In : Toxicogenomics : A Powerful Tool for Toxicology Assessment(John Wiley & Sons) Pages: 143-158
• [Journal Article] (2008)
  • Author(s): H. Watanabe, K. Kobayashi, Y. Kato, S. Oda, R. Abe, N. Tatarazako, T. Iguchi
  • Journal Title: Genomic response in Daphnia to chemical pollutants." In : Interdis ciplinary Studies on Environmental Chemistry-Biological Response to Chemical Pollutants. Eds. Y. Murakami, K. Nakayama, S. -I. Kitamura, H. Iwata and S. Tanabe(TERAPUB) Pages: 133-142
• [Journal Article] (2008)
  • Author(s): 井口泰泉
  • Journal Title: 2. 13 乳腺・生殖器(女性)「からだと水の事典」佐々木成、石橋賢一(編集)(朝倉書店) Pages: 205-213
• [Presentation] Analysis of ligand-independent activation of the estrogen receptor in mouse vagina (2008)
  • Author(s): N. Kikuchi, H. Watanabe, T. Iguchi
  • Organizer: 第11回環境ホルモン学会
  • Place of Presentation: 東京
  • Year and Date: 20081213-20081214
• [Presentation] Molecular analysis of the csd gene from the water flea, Daphnia magna. (2008)
  • Author(s): Y. Kato, K. Kobayashi, S. Oda, N. Tatarazako, H. Watanabe, T. Iguchi
  • Organizer: 第11回環境ホルモン学会
  • Place of Presentation: 東京
  • Year and Date: 20081213-20081214
• [Presentation] Epigenetic effect of estrogen exposure in prenatal mice. (2008)
  • Author(s): S. Yoshida-Koide, H. Watanabe, T. Iguchi
  • Organizer: 第11回環境ホルモン学会
  • Place of Presentation: 東京
  • Year and Date: 20081213-20081214
• [Presentation] BPA投与により誘起した雌ラット卵管異常における網羅的遺伝子解析の試み (2008)
  • Author(s): 太田康彦, 生川亮一郎, 竹内崇師, 鈴木敦子, 加藤英男, 渡邉肇, 井口泰泉
  • Organizer: 第11回環境ホルモン学会
  • Place of Presentation: 東京
  • Year and Date: 20081213-20081214
• [Presentation] 外因性男性ホルモンにより誘導されるトゲウオ腎臓での特異的バイオマーカー(スピギン)と男性ホルモン受容体の遺伝子発現 (2008)
  • Author(s): 松尾昴, 坂井正, 征矢野清, 勝義直, 井口泰泉, 大久保伸幸, 松原孝博, I. Katsiadaki, A. P. Scott, 長江真樹
  • Organizer: 第11回環境ホルモン学会
  • Place of Presentation: 東京
  • Year and Date: 20081213-20081214
• [Presentation] Analysis of ligand-independent activation of the estrogen receptor in mouse vagina (2008)
  • Author(s): N. Kikuchi, H. Watanabe, T. Iguchi
  • Organizer: 7^<th> OIB Symposium, Frontiers of Biological Imaging, Synergy of the Advanced Techniques
  • Place of Presentation: Okazaki
  • Year and Date: 20081112-20081113
• [Presentation] Epigenetic effect of estrogen exposure in prenatal mice (2008)
  • Author(s): S. Yoshida-Koide, H. Watanabe, T. Iguchi
  • Organizer: 7^<th> OIB Symposium, Frontiers of Biological Imaging, Synergy of the Advanced Techniques
  • Place of Presentation: Okazaki
  • Year and Date: 20081112-20081113
• [Presentation] Molecular analysis of csd gene from the water flea, Daphnia magna. (2008)
  • Author(s): Y. Kato, K. Kobayashi, S. Oda, N. Tatarazako, H. Watanabe, T. Iguchi
  • Organizer: 7^<th> OIB Symposium, Frontiers of Biological Imaging, Synergy of the Advanced Techniques
  • Place of Presentation: Okazaki
  • Year and Date: 20081112-20081113
• [Presentation] Comparative responsiveness and sensitivity of fish estrogen receptor to steroid estrogens and other environmental estrogens (2008)
  • Author(s): Y. Katsu, A. Lange, C. R. Tyler, T. Iguchi
  • Organizer: 7^<th> OIB Symposium, Frontiers of Biological Imaging, Synergy of the Advanced Techniques
  • Place of Presentation: Okazaki
  • Year and Date: 20081112-20081113
• [Presentation] Ecotoxicogenomics, transactivation assays as tools for studying endocrine active chemicals in aquatic animals (2008)
  • Author(s): T. Iguchi
  • Organizer: Korean Society of Toxicogenomics
  • Place of Presentation: Incheon, Korea
  • Year and Date: 20081106-20081108
• [Presentation] Development and application of molecular tools for establishing mechanistic information on chemical effect pathways (2008)
  • Author(s): A. Lange, Y. Katsu, T. Iguchi, C. R. Tyler
  • Organizer: The 10th Annual Scientific Workshop on Research into Environmental Endocrine Disrupting Chemicals
  • Place of Presentation: Bovey Castle. Devon
  • Year and Date: 20081005-20081008
• [Presentation] Comparative responsiveness and sensitivity of fish estrogen receptors to steroid estrogens and estrogen mimics mimicks (2008)
  • Author(s): Y. Katsu, A. Lange, C. R. Tyler, T. Iguchi
  • Organizer: The 10th Annual Scientific Workshop on Research into Environmental Endocrine Disrupting Chemicals
  • Place of Presentation: Bovey Castle, Devon
  • Year and Date: 20081005-20081008
• [Presentation] Estrogen receptor expression in American alligator oviduct (2008)
  • Author(s): Y. Ohta, Y. Katsu, T. Iguchi, S. Kohno, B. Moore, L. J. Jr. Guillette
  • Organizer: The 10th Annual Scientific Workshop on Research into Environmental Endocrine Disrupting Chemicals
  • Place of Presentation: Bovey Castle, Devon
  • Year and Date: 20081005-20081008
• [Presentation] Embryo toxicity in Japanese medaka and zebrafish exposed to endocrine disruptors, pesticides, and PPCPs (2008)
  • Author(s): N. Tatarazako, N. Hirai, T. Iguchi
  • Organizer: The 10th Annual Scientific Workshop on Research into Environmental Endocrine Disrupting Chemicals
  • Place of Presentation: Bovey Castle, Devon
  • Year and Date: 20081005-20081008
• [Presentation] Sexual re-programming and oestrogenic sensitization in wild fish exposed to ethinylestradiol (2008)
  • Author(s): A. Lange. G. C. Paull, Y. Katsu, H. Urushitani, R. Ichikawa, T. S. Coe, T. Iguchi, C. R. Tyler
  • Organizer: The 10th Annual Scientific Workshop on Research into Environmental Endocrine Disrupting Chemicals
  • Place of Presentation: Bovey Castle, Devon
  • Year and Date: 20081005-20081008
• [Presentation] 古代魚のエストロゲン受容体の単離 (2008)
  • Author(s): 勝義直, 井口泰泉
  • Organizer: 日本動物学会第79回福岡大会
  • Place of Presentation: 福岡
  • Year and Date: 20080905-20080907
• [Presentation] The novel field of ecotoxicogenomics in the study of endocrine disruption in non-mammalian models (2008)
  • Author(s): T. Iguchi
  • Organizer: The Endocrine Society 90th Annual Meeting
  • Place of Presentation: San Francisco, CA, USA
  • Year and Date: 20080615-20080618
• [Presentation] Cloning and characterization of DM domain genes from the water flea, Daphnia magna. (2008)
  • Author(s): Y. Kato, K. Kobayashi, J. K. Colbourne, H. Watanabe, T. Iguchi
  • Organizer: Cordon Research Conference on Environmental Endocrine Disruptors
  • Place of Presentation: Waterville Valley Resort, NH, USA
  • Year and Date: 20080608-20080613
• [Presentation] Current situation of endocrine disruptor issue in Japan (2008)
  • Author(s): T. Iguchi
  • Organizer: Gordon Research Conference on Environmental Endocrine Disruptors
  • Place of Presentation: Waterville, Valley Resort, NH, USA
  • Year and Date: 20080608-20080613
• [Presentation] Sex determination mechanisms of fish food, Daphnia magna. (2008)
  • Author(s): T. Iguchi
  • Organizer: Sex Determination and Gametegenesis in Fish : Current Status and Future Directions
  • Place of Presentation: Honolulu, Hawaii, USA
  • Year and Date: 20080530-20080601
• [Presentation] Achievements of UK Japan collaboration (2008)
  • Author(s): T. Iguchi, O. Tooi
  • Organizer: DEFRA meeting : Endocrine Disruption in Aquatic Environments : Lessons for Taking the Science Forward in Support of Chemic al Management
  • Place of Presentation: UK
  • Year and Date: 20080513-20080514
• [Presentation] Activities in OECD and Japan (2008)
  • Author(s): T. Iguchi
  • Organizer: NERC International Workshop on Fish Toxi cogenomics : Moving into Monitoring and Regulation
  • Place of Presentation: Vancouver, Canada
  • Year and Date: 20080421-20080423
• [Presentation] New concepts in environmental endocrine signaling (2008)
  • Author(s): T. Iguchi
  • Organizer: e. hormone
  • Place of Presentation: Tulane University, New Orleans. LA. USA
  • Year and Date: 20080413-20080416
• [Presentation] 内分泌かく乱物質の作用メカニズム (2008)
  • Author(s): 井口泰泉
  • Organizer: 第9回比較3学会合同シンポジウム
  • Place of Presentation: 東京医科歯科大学
  • Year and Date: 2008-08-26
• [Book] Novel approaches for the study of vertebrate steroid hormone receptors (2009)
  • Author(s): S. Kohno, Y. Katsu, T. Iguchi, L. J. Guillette Jr.
  • Publisher: Integ. Comp. Biol. (in press)
• [Book] Genes to ecosystems : viviparous fishes and endocrine disruption (2009)
  • Author(s): T. M. Edwards, T. Iguchi, L. J. Guillette, Jr.
  • Publisher: Viviparous Fishes II. Carmen, M. ed. (in press)
• [Book] Modern genetics of reproductive biology. In Environmental Impacts on Reproductive Health and Fertility (2009)
  • Author(s): T. Iguchi, T. Sudo
  • Publisher: Cambridge University Press, Woodruff, T., Guillette, L. J. Jr. (Eds.)(in press)
• [Remarks]
  • URL: http://www.nibb.ac.jp/bioenvl/index-j.html