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内分泌撹乱物質の人体汚染における次世代への影響とリスク評価

Research Project

Project/Area Number 13027210
Research Category

Grant-in-Aid for Scientific Research on Priority Areas

Allocation TypeSingle-year Grants
Review Section Science and Engineering
Research InstitutionChiba University

Principal Investigator

森 千里  千葉大学, 大学院・医学研究院, 教授 (90174375)

Co-Investigator(Kenkyū-buntansha) 長田 久夫  千葉大学, 医学部附属病院, 講師 (30233505)
外山 芳郎  千葉大学, 大学院・医学研究院, 講師 (70009637)
小宮山 正敏 (小宮山 政敏)  環境健康都市園芸フィールド科学教育研究センター, 講師 (70175339)
深田 秀樹  千葉大学, 大学院・医学研究院, 助教授 (00359598)
原 寿郎  九州大学, 大学院・医学研究院, 教授 (40150445)
足達 哲也  千葉大学, 大学院・医学研究院, 助手 (60345014)
高田 秀重  東京農工大学, 農学部, 助教授 (70187970)
磯野 協一  千葉大学, 遺伝子実験施設, 助手 (90323435)
Project Period (FY) 2001 – 2003
Project Status Completed (Fiscal Year 2003)
Budget Amount *help
¥50,000,000 (Direct Cost: ¥50,000,000)
Fiscal Year 2003: ¥9,100,000 (Direct Cost: ¥9,100,000)
Fiscal Year 2002: ¥14,600,000 (Direct Cost: ¥14,600,000)
Fiscal Year 2001: ¥26,300,000 (Direct Cost: ¥26,300,000)
Keywords内分泌撹乱物質 / ダイオキシン / 植物エストロゲン / ヒト臍帯 / 精子形成 / バイオマーカー / DNAメチル化 / リスクコミュニケーション / 遺伝子発現 / DNAマイクロアレイ / 遺伝子 / 環境 / 生体機能利用 / 発生分化 / マイクロアレイ / 内分泌攪乱物質 / 胎児曝露
Research Abstract

新生児の臍帯血に含まれる植物エストロゲンについて検討した結果、genisteinとdaidzeinがほとんどの胎児から検出され、母親より濃度が高く、equolは約半数から検出され母親の方が高濃度であること、またcoumestrolは検出限界以下であることが判明した。エピジェネティック解析からのリスク評価を目指し、DNAメチル化状態を網羅的に解析できるRLGS法を用いて、マウス新生仔期ジエチルスチルベストロール(DES)曝露の影響を調べたところ、精巣上体や子宮におけるDNAメチル化状態が長期的、濃度依存的、かつ臓器特異的パターンで変化することが判明した。メチル化が変化する遺伝子のいくつかについてクローニングを行った。これら化学物質曝露によるメチル化の変化は、過去の曝露履歴を表すマーカーになると考えられた。エストラジオール、ビスフェノールA、フルタミド等へのマウス新生仔期曝露により、精子頭部に奇形の生じることが明らかになり、作用メカニズムとしてセルトリ細胞・精子細胞間の特殊接合装置への影響が判明した。また、複数の化学物質への複合曝露の場合、低濃度域における影響が増強される現象を見出した。ヒト臍帯血、母体血、乳児血、成人血の単核球におけるそれぞれの基礎的遺伝子発現および3MCを用いた誘導による発現の比較により、単核球の種類によりその特徴的な違いが明らかになった。母親での曝露量や蓄積量を減らすことで胎児の複合曝露を減ずることが可能であると判明したため、母親の曝露状況改善のための環境教育やリスクコミュニケーションの活用と、体内蓄積量の削減方法の開発を行った。

Report

(3 results)
  • 2003 Annual Research Report
  • 2002 Annual Research Report
  • 2001 Annual Research Report
  • Research Products

    (41 results)

All Other

All Publications (41 results)

  • [Publications] Matsuno, Yoshiharu: "Association of testicular undescent induced by prenatal flutamide treatment with thickening of the cremaster muscle in rats."Reproductive Medicine and Biology. 2. 109-113 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Adachi, Tetsuya: "ADAM7 (a disintegrin and metalloprotease 7) mRNA is suppressed in mouse epididymis by neonatal exposure to diethylstilbestrol."Molecular Reproduction and Development. 64. 414-421 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Mori, Chisato: "Application of toxicogenomic analysis to risk assessment of delayed long-term effects of multiple chemicals including endocrine disruptors in human fetuses."Environmental Health Perspectives. 111. 803-809 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Adachi, Tetsuya: "Toxicogenomic difference between diethylstilbestrol and 17β-estradiol in mouse testicular gene expression by neonatal exposure."Molecular Reproduction and Development. 67. 19-25 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Yamamoto, Junko: "Characteristic expression of aryl hydrocarbon receptor repressor gene in human tissues : organs-specific distribution and variable induction patterns in mononuclear cells."Life Sciences. 74・8. 1039-1049 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Sakurai, Kenichi: "Bisphenol A affects to glucose transport in mouse 3T3-F442A adipocytes."British Journal of Pharmacology. (In press). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Matsuno, Yoshiharu: "Effect of neonatal exposure to diethylstilbestrol on testicular gene expression in adult mouse : comprehensive analysis with cDNA subtraction method."International Journal of Andrology. (In press). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Adachi, Tetsuya: "Long-term alteration of gene expression without morphological change in testis after neonatal exposure to genistein in mice : toxicogenomic analysis using cDNA microarray."Food Chem Toxicol. (In press). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] 森 千里: "胎児の複合汚染状況の情報開示と次世代環境健康学の創成について"産婦人科の実際. 52. 2363-2371 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 森 千里: "ヒト胎児の複合曝露に対する新しい影響評価法の開発-トキシコゲノミクスを用いて"医学のあゆみ. 204. 954-958 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 森 千里: "化学物質による胎児の複合汚染.ハイリスクグループの存在と,「次世代環境健康学」創生の必要性"科学. 74. 38-42 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] 森 千里: "ヒトへの影響. アプローチ環境ホルモン-その基礎と水環境における最前線(社団法人日本水環境学会関西支部編)"技報堂出版,東京. 16 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 櫻井健一: "ヒトの臍帯(血)中の内分泌撹乱物質.環境ホルモンの最新動向と測定・試験・機器開発(井口泰泉監修)"シーエムシー出版,東京. 5 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 小宮山政敏: "マウス雄性生殖系に対する影響の評価法.環境ホルモンの最新動向と測定・試験・機器開発(井口泰泉監修)"シーエムシー出版,東京. 4 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Mori, Chisato: "Application of toxicogenomic analysis to risk assessment of delayed long-term effects of multiple chemicals including endocrine disruptors in human fetuses"Environ. Health Perspect. Toxicogenomics. 111・1T. 7-13 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Uchida, Kaoru: "Bisphanol-A administration during pregnancy results in fetal exposure in mice and monkeys"J. Health Sci.. 48・6. 579-582 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Tobe, Toyofusa: "Embryonic myosin heavy chain and troponin T isoforms remain in cremaster muscle of adult cryptorchid rats induced with flutamide"Arch. Histol. Cytol.. 65・3. 279-290 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Yang, Ya-Gai: "Immunohistochemical changes of androgen receptor and estrogen receptors alpha and beta in the gubernaculum of cryptorchid rats during testicular descent"Acta Histochem. Cytochem.. 35・4. 281-286 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Mori, Chisato: "Temporal changes in testis-weight during the last 50 years in Japan"Anatomical Science International. 77. 109-116 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Todaka, Emiko: "Necessity to establish new risk assessment and risk communication for human fetal exposure to multiple endocrine disruptors in Japan"Congenital Anomalies. 42. 87-93 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Adachi, Tetsuya: "Toxicogenomic effects of neonatal exposure to diethylstilbestrol on mouse testicular gene expression in the long term : a study using cDNA microarray analysis"Mol. Reprod. Dev.. 63. 17-23 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Adachi, Tetsuya: "ADAM7 (a disintegrin and metalloprotease 7) mRNA is suppressed in mouse epididymis by neonatal exposure to diethylstilbestrol"Mol. Reprod. Dev.. 64・4. 414-421 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Hosoi, I.: "Development of the blood-testis barrier in the mouse is delayed by neonatally administered diethylstilbestrol but not by β-estradiol 3-benzoate"Andrologia. 34. 255-262 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Takano, Kaiya: "Alteration of androgen receptor immunoexpression by neonatal DES-treatment in mouse epididymis"Congenital Anomalies. 42. 36-37 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 足達 哲也: "実験講座マイクロアレイの使い方:内分泌撹乱物質による遺伝子発現変化のモニタリング"ゲノム医学. 2. 399-405 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 小宮山 政敏: "胎児複合曝露の影響評価"医学のあゆみ. 201. 137-142 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Komiyama, Masatoshi: "Analysis of toxicogenomic response to endocrine disruptors in the mouse testis. In : Toxicogenomics. T.Inoue and W.D.Pennie(eds)"Springer-Verlag Tokyo. 7 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] 森 千里: "胎児の複合汚染"中央公論新社. 204 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 森 千里: "環境ホルモン〜ヒトへの影響と対策の方向性"Journal of Endocrine Disruptor. 1. 203-212 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] 足達 哲也: "植物エストロゲンおよび内分泌撹乱物質の精子形成への影響評価に対するDNAマイクロアレイを用いた判定法の開発"千葉医学雑誌. 77. 151-158 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Mori, Chisato: "Possible effects of endocrine disruptors on male reproductive function"Acta Anatomica Nipponica. 76. 361-368 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Shibayama, Takako: "Neonatal exposure to genistein reduces expression of estrogen receptor alpha and androgen receptor in testes of adult mice"Endocrine Journal. 48. 655-663 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Toyama, Yoshiro: "Neonatally administered diethylstilbestrol retards the development of the blood-testis barrier in the rat"Journal of Andrology. 22. 413-423 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Toyama, Yoshiro: "β-Estradiol 3-benzoate affects spermatogenesis in the adult mouse"Molecular and Cellular Endocrinology. 178. 161-168 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] 森 千里: "内分泌撹乱物質の次世代や男性生殖器への影響とその評価に関する新しい試み"最新医学. 57. 236-242 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Mori, Chisato: "Temporal changes in testis-weight during the last 50 years in Japan"Anatomical Science International. (In press). (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] 小宮山 政敏: "胎児複合曝露の影響評価"医学のあゆみ. 201(印刷中). (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Takano, Kaiya: "Alteration of androgen receptor immunoexpression by neonatal DES-treatment in mouse"Congenital Anomalies. 42(In press). (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Rockett, J.C.: "The effects of hyperthermia on spermatogenesis, apoptosis, gene expression and fertility in adult male mice"Biology of Reproduction. 65. 229-239 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] 森 千里: "新女性医学体系 11 リプロダクティブヘルス 妊孕性に関わる諸問題 環境因子と生殖"中山書店. 15 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Komiyama, Masatoshi: "Analysis of toxicogenomic response to endocrine disruptors in the mouse tesits. In : Toxicogenomics"Springer-Verlag (In press). (2002)

    • Related Report
      2001 Annual Research Report

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Published: 2001-04-01   Modified: 2018-03-28  

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