Postnatal carcinogenic risks of fetal stage exposure to environmental pollutants and its epigenetic molecular mechanism

• Project/Area Number: 20380168
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Applied veterinary science
• Research Institution: The University of Tokyo
• Principal Investigator: OHSAKO Seiichiroh The University of Tokyo, 大学院・医学系研究科, 准教授 (00274837)
• Co-Investigator(Kenkyū-buntansha): MIYABARA Yuichi 信州大学, 山岳科学総合研究所, 准教授 (80311330)
• Research Collaborator: TAKEDA Makio 残留農薬研究所, 毒性部, 室長
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥18,980,000 (Direct Cost: ¥14,600,000、Indirect Cost: ¥4,380,000); Fiscal Year 2010: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2009: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2008: ¥8,060,000 (Direct Cost: ¥6,200,000、Indirect Cost: ¥1,860,000)
• Keywords: 有害化学物質 / ゲノム / 発生・分化 / 環境 / 薬剤反応性 / エピジェネティクス

Research Abstract

Recently much attention is focused to the hypothesis that the fetal stage environments can influence health and disease after birth. Laboratory animals exposed to dioxin in the fetal stage are prone to cancer when they are administered carcinogens such as benzo[a]pyrene in adulthood. In the present study using mice, we demonstrated that the epigenetic memory including DNA methylation of the gene for CYP1A1 enzyme responsible for metabolic activation of carcinogens was altered by perinatal exposure to dioxin and revealed a part of molecular mechanism causing this alteration.

Research Products

• [Journal Article] Perinatal exposure to environmental chemicals induce epigenomic changes in offspring. (2011)
  • Author(s): Ohsako S.
  • Journal Title: Genes and Environment Volume: 掲載確定(印刷中)
  • Peer Reviewed
• [Journal Article] Di (n-butyl) phthalate induces vimentin filaments disruption in rat Sertoli cells : A possible relation with spermatogenic cell apoptosis. (2010)
  • Author(s): Alam MS., Ohsako S., Tay TW., Tsunekawa N., Kanai N., Kurohmaru M.
  • Journal Title: Anatomia Histologia Embryologia 39 Pages: 189-193
  • Peer Reviewed
• [Journal Article] Comparative contribution of the aryl hydrocarbon receptor gene to perinatal stage development and dioxin-induced toxicity between the urogenital complex and testis in the mouse. (2010)
  • Author(s): Ohsako S., Fukuzawa N., Ishimura R., Kawakami T., Wu Q., Nagano R., Zaha H., Sone H., Yonemoto J., Tohyama C.
  • Journal Title: Biol Reprod 82 Pages: 636-643
  • Peer Reviewed
• [Journal Article] Induction of spermatogenic cell apoptosis in prepubertal rat testes irrespective of testicular steroidogenesis : A possible estrogenic effect of di (n-butyl) phthalate. (2010)
  • Author(s): Alam MS., Ohsako S., Matsuwaki T., Zhu XB., Tsunekawa N., Kanai Y., Sone H., Tohyama C., Kurohmaru M.
  • Journal Title: Reproduction 139 Pages: 427-437
  • Peer Reviewed
• [Journal Article] Profiles of Chemical Effects on Cells (pCEC) : a toxicogenomics database with a toxicoinformatics system for risk evaluation and toxicity prediction of environmental chemicals. (2010)
  • Author(s): Sone H, Okura M, Zaha H, Fujibuchi W, Taniguchi T, Akanuma H, Nagano R, Ohsako S, Yonemoto J.
  • Journal Title: J Toxicol Sci 35 Pages: 115-123
  • NAID: 10025983541
  • Peer Reviewed
• [Journal Article] When does the sex ratio of offspring of the paternal 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) exposure decrease : In the spermatozoa stage or at fertilization? (2010)
  • Author(s): Ishihara K, Ohsako S, Tasaka K, Harayama H, Miyake M, Warita K, Tanida T, Mitsuhashi T, Nanmori T, Tabuchi Y, Yokoyama T, Kitagawa H, Hoshi N.
  • Journal Title: Reprod Toxicol 29 Pages: 68-73
  • Peer Reviewed
• [Journal Article] Di(n-butyl) phthalate induces vimentin filaments disruption in rat Sertoli cells : A possible relation with spermatogenic cell apoptosis. (2010)
  • Author(s): Alam MS., Ohsako S., Tay TW., Tsunekawa N., Kanai N., Kurohmaru M.
  • Journal Title: Anatomia Histologia Embryologia Volume: 39 Pages: 189-193
  • Peer Reviewed
• [Journal Article] Comparative contribution of the aryl hydrocarbon receptor gene to perinatal stage development and dioxin-induced toxicity between the urogenital complex and testis in the mouse. (2010)
  • Author(s): Ohsako S., Fukuzawa N., Ishimura R., Kawakami T., Wu Q., Nagano R., Zaha H., Sone H., Yonemoto J., Tohyama C.
  • Journal Title: Biology of Reproduction Volume: 82 Pages: 636-643
  • Peer Reviewed
• [Journal Article] Induction of spermatogenic cell apoptosis in prepubertal rat testes irrespective of testicular steroidogenesis : A possible estrogenic effect of di(n-butyl) phthalate. (2010)
  • Author(s): Alam MS., Ohsako S., Matsuwaki T., Zhu XB., Tsunekawa N., Kanai Y., Sone H., Tohyama C., Kurohmaru M.
  • Journal Title: Reproduction Volume: 139 Pages: 427-437
  • Peer Reviewed
• [Journal Article] When does the sex ratio of offspring of the paternal 2,3,7,8-tetrachlorodibenzo p-dioxin (TCDD) exposure decrease : In the spermatozoa stage or at fertilization? (2010)
  • Author(s): Ishihara K, Ohsako S, Tasaka K, Harayama H, Miyake M, Warita K, Tanida T, Mitsuhashi T, Namnori T, Tabuchi Y, Yokoyama T, Kitagawa H, Hoshi N.
  • Journal Title: Reproductive Toxicology Volume: 29 Pages: 68-73
  • Peer Reviewed
• [Journal Article] Di(n-butyl)phthalate induces vimentin filaments disruption in rat Sertoli cells : A possible relation with spermatogenic cell apoptosis. (2010)
  • Author(s): Alam MS., Ohsako S., Tay TW., Tsunekawa N., Kanai N., Kurohmaru M.
  • Journal Title: Anatomia Histologia Embryologia (in press)(印刷中,掲載確定)
  • Peer Reviewed
• [Journal Article] Comparative contribution of the aryl hydrocarbon receptor gene to perinatal stage development and dioxin-induced toxicity between the urogenital complex and testis in the mouse. (2010)
  • Author(s): Ohsako S., Fukuzawa N., Ishimura R., Kawakami T., Wu Q., Nagano R., Zaha H., Sone H., Yonemoto J., Tohyama C.
  • Journal Title: Biol Reprod (in press)(印刷中, 掲載確定)
  • Peer Reviewed
• [Journal Article] Induction of spermatogenic cell apoptosis in prepubertal rat testes irrespective of testicular steroidogenesis : A possible estrogenic effect of di(n-butyl)phthalate. (2010)
  • Author(s): Alam MS., Ohsako S., Matsuwaki T., Zhu XB., Tsunekawa N., Kanai Y., Sone H., Tohyama C., Kurohmaru M.
  • Journal Title: Reproduction 139 Pages: 427-437
  • Peer Reviewed
• [Journal Article] Profiles of Chemical Effects on Cells(pCEC) : a toxicogenomics database with a toxicoinformatics system for risk evaluation and toxicity prediction of environmental chemicals. (2010)
  • Author(s): Sone H, Okura M, Zaha H, Fujibuchi W, Taniguchi T, Akanuma H, Nagano R, Ohsako S, Yonemoto J.
  • Journal Title: J Toxicol Sci 35 Pages: 115-123
  • NAID: 10025983541
  • Peer Reviewed
• [Journal Article] When does the sex ratio of offspring of the paternal 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin(TCDD)exposure decrease : In the spermatozoa stage or at fertilization? (2010)
  • Author(s): Ishihara K, Ohsako S, Tasaka K, Harayama H, Miyake M, Warita K, Tanida T, Mitsuhashi T, Nanmori T, Tabuchi Y, Yokoyama T, Kitagawa H, Hoshi N.
  • Journal Title: Reprod Toxicol 29 Pages: 68-73
  • Peer Reviewed
• [Journal Article] Gene expression signatures of environmental chemicals in cancer and in developmental disorders. (2010)
  • Author(s): Sone H, Imanishi S, Akanuma H, Nagano R, Fukuda T, Ohsako S.
  • Journal Title: In "The roles of free radicals in biology and medicine", MEDIMOND SRL Publ. Pages: 45-52
• [Journal Article] Possible Involvement of arylhydrocarbon receptor variants in TCDD-induced thymic atrophy and XRE-dependent transcriptional activity in Wistar Hannover GALAS rats. (2009)
  • Author(s): Kawakami T, Ito T, Ohsako S, Shiizakia K, Murakami Y, Hirowatarid K, Sato M, Tohyama C.
  • Journal Title: J Toxicol Sci 34 Pages: 209-220
  • Peer Reviewed
• [Journal Article] Dioxin-induced toxicity on vascular remodeling of the placenta. (2009)
  • Author(s): Ishimura R, Kawakami T, Ohsako S, Tohyama C.
  • Journal Title: Biochemical Pharmacol 77 Pages: 660-669
  • Peer Reviewed
• [Journal Article] (2009)
  • Author(s): 大迫誠一郎
  • Journal Title: 科学「プログラムされる"病"の新たな仮説-環境化学物質による代謝系遺伝子の次世代エピゲノム変化」(岩波書店) Pages: 984-988
• [Journal Article] Dioxin-induced toxicity on vascular remodeling of the placenta. (2009)
  • Author(s): Ishimura R, Kawakami T, Ohsako S, and Tohyama C.
  • Journal Title: Biochemical Pharmacol 77 Pages: 660-669
  • Peer Reviewed
• [Journal Article] Possible Involvement of arylhydrocarbon receptor variants in TCDD-induced thymic atrophy and XRE-dependent transcriptional activity in Wistar Hannover GALAS rats. (2009)
  • Author(s): Kawakami T, Ito T, Ohsako S, Shiizakia K, Murakami Y, Hirowatarid K, Sato M, and Tohva C.
  • Journal Title: J Toxicol Sci 34 Pages: 209-220
  • Peer Reviewed
• [Journal Article] Omeprazole alleviates benzo[a]-pyrene cytotoxicity by inhibition of CYP1A1 activity in human and mouse hepatoma cells. (2008)
  • Author(s): Shiizaki K, Ohsako S, Kawanishi M, Yagi T.
  • Journal Title: Basic Clinical Pharmacol Toxicol 103 Pages: 468-475
  • Peer Reviewed
• [Journal Article] Differences in gene expression and benzo[a]-pyrene-induced DNA adduct formation in the liver of three strains of female mice with identical AhRb2 genotype treated with 2, 3, 7,8-tetrachlorodibenzo-p-dioxin and/or benzo [a]pyrene. (2008)
  • Author(s): Wu Q., Suzuki J.S., Zaha H., Lin T-M., Peterson R.E., Tohyama C., Ohsako S.
  • Journal Title: J Appl Toxicol 28 Pages: 724-733
  • Peer Reviewed
• [Journal Article] Omeprazole alleviates benzo[a]pyrene cytotoxicity by inhibition of CYPlAl activity in human and mouse hepatoma cells. (2008)
  • Author(s): Shiizaki K, Ohsako S, Kawanishi M, and Yagi T.
  • Journal Title: Basic Clinical Pharmacol Toxicol 103 Pages: 468-475
  • Peer Reviewed
• [Journal Article] Perinatal exposure to environmental chemicals induces epigenomic changes in offspring.
  • Author(s): Ohsako S.
  • Journal Title: Genes Environ 印刷中(掲載確定)
  • Peer Reviewed
• [Presentation] マウスおよびヒトES細胞を用いた神経分化培養系におけるメチル水銀の毒性影響評価. (2010)
  • Author(s): 大迫誠一郎, 永野麗子, 何小明, 今西哲、藤渕航, 赤沼宏美, 曽根秀子.
  • Organizer: 第13回日本外因性内分泌撹乱化学物質学会
  • Place of Presentation: 東京大学山上会館(東京)
  • Year and Date: 2010-12-16
• [Presentation] 胎生プログラミング異常を検出するためのマルチプロファイリング技術の確立. (2010)
  • Author(s): 赤沼宏美, 永野麗子, 座波ひろ子, 大迫誠一郎, 曽根秀子.
  • Organizer: 第13回日本外因性内分泌撹乱化学物質学会
  • Place of Presentation: 東京大学山上会館(東京)
  • Year and Date: 2010-12-16
• [Presentation] マウスES細胞を用いた神経系分化系におけるメチル水銀の毒性影響評価. (2010)
  • Author(s): 何小明, 永野麗子, 赤沼宏美, 座波ひろ子, 遠山千春, 曽根秀子, 大迫誠一郎.
  • Organizer: 第36回日本トキシコロジー学会
  • Place of Presentation: 沖縄コンベンションセンター(沖縄)
  • Year and Date: 2010-06-17
• [Presentation] ダイオキシンの胎生期曝露による生後の化学発癌感受性亢進とエピゲノム変化 (2009)
  • Author(s): 大迫誠一郎
  • Organizer: 第38回日本環境変異原学会、シンポジウム「エピジェネティクス-環境変異原研究の新しい展開-」
  • Place of Presentation: 清水テルサ、静岡
  • Year and Date: 2009-11-27
• [Presentation] ダイオキシンの胎生期曝露による生後の化学発癌感受性亢進とエピゲノム変化. (2009)
  • Author(s): 大迫誠一郎
  • Organizer: 第38回日本環境変異原学会
  • Place of Presentation: 静岡テルサ(静岡)
  • Year and Date: 2009-11-27
• [Presentation] Perinatal exposure to dioxins alters the epigenomic program that influences the susceptibility to carcinogens exposed in adulthood. (2009)
  • Author(s): 大迫誠一郎
  • Organizer: Horiba Conference/CDBIM Symposium, 21^<st> Century Advances in the Molecular Toxicology of Environmental Chemicals and Pathogenesis of Disease
  • Place of Presentation: 東京大学、東京
  • Year and Date: 2009-10-27
• [Presentation] Perinatal exposure to dioxins alters the epigenomic program that influences the susceptibility to carcinogens exposed in adulthood. (2009)
  • Author(s): Ohsako S
  • Organizer: Horiba Conference/CDBIM Symposium, 21^<st> Century Advances in the Molecular Toxicology of Environmental Chemicals and Pathogenesis of Disease
  • Place of Presentation: 東京大学医学部鉄門講堂(東京)
  • Year and Date: 2009-10-27
• [Presentation] ダイオキシンの胎生期曝露による肝臓エピゲノム変化 (2009)
  • Author(s): 大迫誠一郎
  • Organizer: 第82回日本生化学会、シンポジウム「化学物質による遺伝子修飾と毒性発現」
  • Place of Presentation: 神戸国際センター、神戸
  • Year and Date: 2009-10-24
• [Presentation] ダイオキシンの胎生期曝露による肝臓エビゲノム変化 (2009)
  • Author(s): 大迫誠一郎
  • Organizer: 第82回日本生化学会
  • Place of Presentation: 神戸国際会議場(神戸)
  • Year and Date: 2009-10-24
• [Presentation] Reduction of methylation frequency in the matured mouse hepatic CYPIA1 promoter region by perinatal dioxin exposure. (2009)
  • Author(s): Ohsako S., Tohyama C
  • Organizer: The 50^<th> International Congress of Asian Society of Toxicology
  • Place of Presentation: 台北退役軍人病院(Taipci)中国
  • Year and Date: 2009-09-11
• [Presentation] 環境汚染物質の胎生期曝露影響は生後の肝臓においてエピジェネティックメモリーとして残る (2009)
  • Author(s): 大迫誠一郎
  • Organizer: 第3回日本エピジェネティクス研究会
  • Place of Presentation: 一ツ橋学術総合センター、東京
  • Year and Date: 2009-05-23
• [Presentation] 環境汚染物質の胎生期曝露影響は生後の肝臓においてエビジェネティックメモリーとして残る (2009)
  • Author(s): 大迫誠一郎
  • Organizer: 第3回日本エビジェネティクス研究会
  • Place of Presentation: 一ツ橋学術総合センタ-(東京)
  • Year and Date: 2009-05-23
• [Presentation] 環境汚染物質の胎児期曝露によるゲノムのエピジェネティックな変化 (2009)
  • Author(s): 大迫誠一郎
  • Organizer: 第79回日本衛生学会 エピジェネティク研究会シンポジム
  • Place of Presentation: 北里大学、東京
  • Year and Date: 2009-03-31
• [Presentation] 環境汚染化学物質の胎児期曝露によるエピジェネティックな変化 (2008)
  • Author(s): 大迫誠一郎
  • Organizer: 第52回日本薬学会関東支部会、シンポジウム「環境化学物質の新たな分子標的」
  • Place of Presentation: 東京理科大学、千葉
  • Year and Date: 2008-10-04
• [Presentation] 胎生期ダイオキシン曝露により生じる生後発達の不可逆的変化について (2008)
  • Author(s): 大迫誠一郎
  • Organizer: 第48回日本先天異常学会
  • Place of Presentation: 聖路加看護大学、東京
  • Year and Date: 2008-06-29
• [Presentation] 胎生期ダイオキシン曝露により生じる生後発達の不可逆的変化について (2008)
  • Author(s): 大迫誠一郎
  • Organizer: 日本先天異常学会
  • Place of Presentation: 聖路加大学・東京
  • Year and Date: 2008-06-29
• [Presentation] ダイオキシンの胎児曝露による遺伝子メチル化の変異 (2008)
  • Author(s): 大迫誠一郎・菅井恵津子・阪田佳紀・松田佳奈・吉岡亘・掛山正心・遠山千春
  • Organizer: 第35回日本トキシコロジー学会
  • Place of Presentation: オリンピックセンター、東京
  • Year and Date: 2008-06-28
• [Presentation] 胎児期ダイオキシン曝露による生後の組織内ゲノムメチル化の変動 (2008)
  • Author(s): 大迫誠一郎
  • Organizer: 第19回環境ホルモン学会講演会
  • Place of Presentation: 江戸東京博物館、東京
  • Year and Date: 2008-06-10
• [Book] 分子予防環境医学(松島・酒井・遠山ら編)(エピジェネティクスと環境医学) (2010)
  • Author(s): 大迫誠一郎
  • Publisher: 本の泉社
• [Book] The roles of free radicals in biology and medicine MEDIMOND SRL Publ.(Gene expression signatures of environmental chemicals in cancer and in developmental disorders.) (2009)
  • Author(s): Sone H, Imanishi S, Akanuma H, Nagano R, Fukuda T, Ohsako S
• [Book] 科学(プログラムされる"病"の新たな仮説-環境化学物質による代謝系遺伝子の次世代エピゲノム変化) (2009)
  • Author(s): 大迫誠一郎
• [Book] Morita M.ed., Persistent organic Pollutants (POPS) Research in Asia(Does maternal exposure to 2,3,7,8-tetrachlorodibenzo-p- dioxin (TCDD) induce glutathione S- transferase-positive hepatic foci in adult rats?) (2008)
  • Author(s): Sone H, Miyabara Y, Fukuda T, Okura M, Ohsako S, Yonemoto J.
• [Remarks]
  • URL: http://env-health.m.u-tokyo.ac.jp/
• [Patent(Industrial Property Rights)] CpGメチル化頻度の変動をゲノムワイドに比較解析するためのDNA試料作成方法 (2010)
  • Inventor(s): 大迫誠一郎、栗田尚佳
  • Industrial Property Rights Holder: 東京大学
  • Filing Date: 2010
  • Overseas
• [Patent(Industrial Property Rights)] CpGメチル化頻度の変動をゲノムワイドに比較解析するためのDNA試料作成方法 (2010)
  • Inventor(s): 大迫誠一郎, 栗田尚佳
  • Industrial Property Rights Holder: 東京大学
  • Filing Date: 2010-03-04
  • Overseas