Microscopic analysis based on the quantitative behavioral tests in rodents for identification of the molecular target of developmental neurotoxicity

• Project/Area Number: 21671002
• Research Category: Grant-in-Aid for Young Scientists (S)
• Allocation Type: Single-year Grants
• Research Field: Risk sciences of radiation/Chemicals
• Research Institution: Nagasaki University (2013); The University of Tokyo (2009-2012)
• Principal Investigator: KAKEYAMA Masaki 長崎大学, 医歯薬学総合研究科(医学系), 准教授 (30353535)
• Project Period (FY): 2009 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥102,960,000 (Direct Cost: ¥79,200,000、Indirect Cost: ¥23,760,000); Fiscal Year 2013: ¥17,680,000 (Direct Cost: ¥13,600,000、Indirect Cost: ¥4,080,000); Fiscal Year 2012: ¥20,800,000 (Direct Cost: ¥16,000,000、Indirect Cost: ¥4,800,000); Fiscal Year 2011: ¥20,800,000 (Direct Cost: ¥16,000,000、Indirect Cost: ¥4,800,000); Fiscal Year 2010: ¥20,800,000 (Direct Cost: ¥16,000,000、Indirect Cost: ¥4,800,000); Fiscal Year 2009: ¥22,880,000 (Direct Cost: ¥17,600,000、Indirect Cost: ¥5,280,000)
• Keywords: 有害化学物質 / 神経科学 / 解剖学 / 行動学 / 環境政策

Research Abstract

The aim of this study is to develop the microscopic analysis methodology, and identify the molecular marker for developmental neurotoxicity of environmental chemicals. We found that perinatal exposure to a low dose of dioxin induces abnormal behaviors, including behavioral inflexibility, compulsive repetitive behavior, and low social dominance in mice. Immuhohistochemical analysis validated that hypoactivation of the medial prefrontal cortex (mPFC) and hyperactivation of the amygdala are the potential biological basis for these behavioral abnormalities.

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Research Products

• [Journal Article] Disruption of paired-associate learning in rat offspring perinatally exposed to dioxins. (2014)
  • Author(s): Kakeyama M, Endo T, Zhang Y, Miyazaki W, Tohyama C.
  • Journal Title: Arch Toxicol. Volume: 88(10-1007/s00204-013-1161-y.) Pages: 789-798
  • NAID: 120006986679
  • Peer Reviewed
• [Journal Article] Upregulation of colonic luminal polyamines produced by intestinal microbiota delays senescence in mice. (2014)
  • Author(s): Kibe R, Kurihara S, Sakai Y, Suzuki H, Ooga T, Sawaki E, Muramatsu K, Nakamura A, Yamashita A, Kitada Y, Kakeyama M. Benno Y. Matsumoto M.
  • Journal Title: Sci Rep. Volume: 4 Issue: 1 Pages: 4548-4548
  • DOI: 10.1038/srep04548
  • Peer Reviewed
• [Journal Article] In utero and lactational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin modulates dysregulation of the lipid metabolism in mouse offspring fed a high-calorie diet. (2014)
  • Author(s): Sugai E, Yoshioka W, Kakeyama M, Ohsako S. Tohyama C.
  • Journal Title: J Appl Toxicol Volume: 34 Issue: 3 Pages: 296-306
  • DOI: 10.1002/jat.2881
  • Peer Reviewed
• [Journal Article] Disruption of paired-associate learning in rat offspring perinatally exposed to dioxins (2013)
  • Author(s): Kakeyama M, Endo T, Zang Y, Miyazaki Y, Tohyama C
  • Journal Title: Archives of Toxicology Volume: 88 Pages: 789-98
  • DOI: 10.1007/s00204-013-1161-y
  • NAID: 120006986679
  • Peer Reviewed
• [Journal Article] Prenatal exposure to a polychlorinated biphenyl (PCB) congener influences fixation duration on biological motion at 4-months-old : a preliminary study (2013)
  • Author(s): Doi H, Nishitani S, Fujisawa TX, Nagai T, Kakeyama M, Maeda T, Shinohara K
  • Journal Title: PLoS One Volume: 8 Issue: 3 Pages: e59196-e59196
  • DOI: 10.1371/journal.pone.0059196
  • NAID: 120006985955
  • Peer Reviewed
• [Journal Article] Vesicular nucleotide transporter is involved in ATP storage of secretory lysosomes in astrocytes. (2013)
  • Author(s): Manami Oya
  • Journal Title: Biochemical Biophysical Research Communications. Volume: 438 Issue: 1 Pages: 145-151
  • DOI: 10.1016/j.bbrc.2013.07.043
  • Peer Reviewed
• [Journal Article] Executive Function Deficits and Social-Behavioral Abnormality in Mice Exposed to a Low Dose of Dioxin In Utero and via Lactation (2012)
  • Author(s): Endo T, Kakeyama M, Uemura Y, Haijima A, Okuno H, Bito H, Tohyama C
  • Journal Title: PLOS ONE Volume: 7 Issue: 12 Pages: e50741-e50741
  • DOI: 10.1371/journal.pone.0050741
  • Peer Reviewed
• [Journal Article] Fluorescence laser microdissection reveals a distinct pattern of gene activation in the mouse hippocampal region (2012)
  • Author(s): Yoshioka W, Endo N, Kurashige A, Haijima A, Endo T, Shibata T, Nishiyama R,Kakeyama M, Tohyama C
  • Journal Title: Scientific Reports Volume: 2 Issue: 1 Pages: 783-783
  • DOI: 10.1038/srep00783
  • Peer Reviewed
• [Journal Article] The small GTPase Cdc42 modulates the number of exocytosis-competentdense-core vesicles in PC12 cells (2012)
  • Author(s): Sato M, Kitaguchi T, Numano R, Ikematsu K, Kakeyama M, Murata M, Sato K, Tsuboi T
  • Journal Title: Biochemical and Biophysical Research Communications Volume: (印刷中)(掲載確定) Issue: 2 Pages: 417-421
  • DOI: 10.1016/j.bbrc.2012.03.010
  • Peer Reviewed
• [Journal Article] Schema-dependent gene activation and memory encoding in neocortex (2011)
  • Author(s): Tse, D ; Takeuchi, T ; Kakeyama, M ; Kajii, Y ; Okuno, H ; Tohyama, C ; Bito, H, Morris, RGM.
  • Journal Title: Science Volume: 333 Issue: 6044 Pages: 891-895
  • DOI: 10.1126/science.1205274
  • Peer Reviewed
• [Journal Article] Automated test of behavioral flexibility in mice using a behavioral sequencing task in Intelli Cage (2011)
  • Author(s): Endo T, Maekawa F, Voikar V, Haijima A, Uemura Y, Zhang Y, Miyazaki W, Suyama S, Shimazaki K, Wolfer DP, Yada T, Tohyama C, Lipp HP, Kakeyama M.
  • Journal Title: Behav Brain Res Volume: 221 Issue: 1 Pages: 172-181
  • DOI: 10.1016/j.bbr.2011.02.037
  • Peer Reviewed
• [Journal Article] Development of novel behavioral toxicity tests in rodents aimed for application to health risks in humans (2011)
  • Author(s): 掛山正心
  • Journal Title: Japanese Journal of Animal Psychology Volume: 61 Issue: 1 Pages: 33-42
  • DOI: 10.2502/janip.61.1.11
  • NAID: 130000780092
  • ISSN: 0916-8419, 1880-9022
  • Peer Reviewed
• [Journal Article] Automated test of behavioral flexibility in mice using a hehavioral sequencing task in IntelliCage. (2011)
  • Author(s): Endo T, Maekawa F, Voikar V, Haijima A, Uemura Y, Zhang Y, Miyazaki W, Suyama S, Shimazaki K, Wolfer DR, Yada T, Tohyama C, Lipp HR, Kakeyama M.
  • Journal Title: Behav Brain Res. Volume: 221 Pages: 172-181
  • Peer Reviewed
• [Journal Article] Use of live imaging analysis for evaluation of cytotoxic chemicals that induce apoptotic cell death. (2010)
  • Author(s): Koike-Kuroda T, Kakeyama M, Fujimaki H, Tsukahara S
  • Journal Title: Toxicol In Vitro Volume: 20 Pages: 2012-2020
  • Peer Reviewed
• [Journal Article] In utero and lactational exposure to low doses of chlorinated and brominated dioxins induces deficits in the fear memory of male mice (2010)
  • Author(s): Haijima A, Endo T, Zhang Y, Miyazaki W, Kakeyama M, Tohyama C
  • Journal Title: Neurotoxicology (掲載確定(印刷中))
  • Peer Reviewed
• [Presentation] Serotonin Reduction Impairs Executive Function and Induces Submissive-Like Behavior in Mice : A Validation Study of a New Cognitive Test for Chemical Risk Assessment. (2014)
  • Author(s): Endo T, Benner S, Ling W, Endo N, Kimura E, Tohyama C, Kakeyama M
  • Organizer: 53th Annual Meeting of Society of Toxicology
  • Place of Presentation: Arizona, USA
  • Year and Date: 2014-03-23
• [Presentation] 周産期TCDD曝露モデルマウスにおけるストレス応答系への発達毒性影響 (2013)
  • Author(s): ベナー聖子、井下太貴、丁雲潔、掛山正心、遠山千春
  • Organizer: 日本内分泌撹乱化学物質学会第16回研究発表会
  • Place of Presentation: 東京大学(東京)
  • Year and Date: 2013-12-12
• [Presentation] NPrenatal exposure to polychlorinated biphenyl (PCB) congener impairs socio-cognitive ability in human four-month-olds. (2013)
  • Author(s): Doi H, Nishitani S, Nagai T, Fujisawa T, Kakeyama M, Maeda T. Shinohara K.
  • Organizer: 11th World Congress of Biological Psychiatry
  • Place of Presentation: 京都際会館(京都府)
  • Year and Date: 2013-06-24
• [Presentation] マウスにおける行動柔軟性 : 包括的解析のための新規ハイスループット試験系の開発 (2013)
  • Author(s): 遠藤俊裕、ベナー聖子、遠藤のぞみ、古瀬民生、若菜茂晴、梶井靖、DP Wolfer、H-P Lipp、遠山千春、掛山正心
  • Organizer: 第36回日本神経科学大会
  • Place of Presentation: 幕張メッセ(千葉県)
  • Year and Date: 2013-06-22
• [Presentation] 環胎生期PCB曝露が乳児期バイオロジカルモーション知覚発達に及ぼす影響 (2013)
  • Author(s): 土居裕和、西谷正太、永井知子、藤澤隆史、掛山正心、前田隆浩、篠原一之
  • Organizer: 第36回日本神経科学大会
  • Place of Presentation: 幕張メッセ(千葉県)
  • Year and Date: 2013-06-22
• [Presentation] 周産期化学物質曝露による神経発達毒性・高次脳機能異常の検出手法の開発 (2013)
  • Author(s): 掛山正心、遠山千春
  • Organizer: 第40回日本毒性学会
  • Place of Presentation: 幕張メッセ(千葉県)
  • Year and Date: 2013-06-18
  • Invited
• [Presentation] 環境毒性 : 低用量の環境汚染物質への曝露の影響をどのように評価するか (2013)
  • Author(s): 掛山正心
  • Organizer: 日本毒性学会第14回生涯教育講習会
  • Place of Presentation: 幕張メッセ(千葉県)(招待)
  • Year and Date: 2013-06-16
• [Presentation] 環境毒性 : 低用量の環境汚染物質への曝露の影響をどのように評価するか (2013)
  • Author(s): 掛山正心
  • Organizer: 日本毒性学会第14回生涯教育講習会
  • Place of Presentation: 幕張メッセ(千葉県)
  • Year and Date: 2013-06-16
  • Invited
• [Presentation] げっ歯類を用いた高次脳機能評価法開発と環境化学物質の神経毒性評価への適用 (2013)
  • Author(s): 掛山正心
  • Organizer: 第83回日本衛生学会学術総会
  • Place of Presentation: 金沢大学、(日本衛生学会奨励賞受賞者講演)(招待)
  • Year and Date: 2013-03-26
• [Presentation] 乳仔期環境とマウス社会性 : ダイオキシン胎仔期曝露影響との共通性 (2013)
  • Author(s): 掛山正心, 他
  • Organizer: 第83回日本衛生学会学術総会
  • Place of Presentation: 金沢大学(招待)
  • Year and Date: 2013-03-25
• [Presentation] 高次脳機能評価系としてのラット・マウス行動テストのイノベーション (2012)
  • Author(s): 掛山正心
  • Organizer: 第24回日本生物学的精神医学会・アボット・ジャパン共催ランチョンセミナー
  • Place of Presentation: 神戸国際会議場(招待)
  • Year and Date: 2012-09-30
• [Presentation] 認知・行動毒性学 : マウスにおける認知機能と社会行動の定量化 (2012)
  • Author(s): 掛山正心, 他
  • Organizer: 第39回日本毒性学会
  • Place of Presentation: 仙台国際会議場(招待)
  • Year and Date: 2012-07-17
• [Presentation] マウス行動試験法を用いた発達期ストレスの社会性影響評価 (2012)
  • Author(s): ベナー聖子、掛山正心、遠山千春
  • Organizer: 第82回日本衛生学会学術総会
  • Place of Presentation: 京都大学(京都府)
  • Year and Date: 2012-03-25
• [Presentation] IN UTERO AND LACTATIONAL EXPOSURE TO DIOXIN ALTERS GENE EXPRESSION IN THE DEVELOPING MOUSE BRAIN (2012)
  • Author(s): Kimura E, Miyazaki W, Endo T, Hosaka R, Yoshioka W, Kakeyama M, Tohyama C
  • Organizer: 51st Annual Meeting of Society of Toxicology
  • Place of Presentation: Moscone Convention Centerサンフランシスコ(アメリカ)
  • Year and Date: 2012-03-14
• [Presentation] Effects of maternal chemical exposure on social anxiety and learning (2011)
  • Author(s): Kakeyama M, Endo T
  • Organizer: Workshop on Neurobehavioral Mechanisms of Affiliative Behavior and Cooperation : Prospects for Translational Advances for Psychiatric Disorders
  • Place of Presentation: Atlanta(招待、Endo T が代理講演)
  • Year and Date: 2011-10-23
• [Presentation] Effects of maternal chemical exposure on social anxiety and learning (2011)
  • Author(s): Endo T, Kakeyama M
  • Organizer: Workshop on Neurobehavioral Mechanisms of Affiliative Behavior and Cooperation : Prospects for Translational Advances for Psychiatric Disorders
  • Place of Presentation: Emory Universityアトランタ(アメリカ)(招待講演)
  • Year and Date: 2011-10-23
• [Presentation] ASSESSMENT OF ADVANCED COGNITIVE BEHAVIORS IN RODENTS : MATERNAL EXPOSURE TO DIOXIN CAUSES PSYCHOBEHAVIORAL ABNORMALITY AND LEARNING DEFICITS (2011)
  • Author(s): Tohyama C, Kakeyama M
  • Organizer: the 7th Congress of the Federations of Asian and Oceanian Physiological Societies (FAOPS)
  • Place of Presentation: NTUH Convention Center台北(台湾)(招待講演)
  • Year and Date: 2011-09-13
• [Presentation] 実験動物高次脳機能評価法の今後の展開 (2010)
  • Author(s): 掛山正心
  • Organizer: 第13回日本環境ホルモン学会・特別シンポジウム
  • Place of Presentation: 東京大学(招待)
  • Year and Date: 2010-12-16
• [Presentation] 実験動物高次脳機能評価法の今後の展開 (2010)
  • Author(s): 掛山正心・遠山千春
  • Organizer: 環境ホルモン学会第13回研究発表会
  • Place of Presentation: 東京
  • Year and Date: 2010-12-16
• [Presentation] Corridor shuttling spatial learning task[1] : Automated analysis of behavioral flexibility and reversal learning-set in mice using IntelliCage system. 2010/10, San Diego. (2010)
  • Author(s): Endo T, Maekawa F, Voikar V, Haijima A, Uemura Y, Zhang Y, Miyazaki W, Suyama S, Shimazaki K, Wofler DP, Yada T, Tohyama C, Lipp HP, Kakeyama M.
  • Organizer: 40th Annual meeting of Society for Neuroscience.
  • Place of Presentation: San Diego, USA
  • Year and Date: 2010-10-17
• [Presentation] Corridor shuttling spatial learning task[2] : Chemically-induced emotional dysfunctions in group-housed mice as an animal model of perseveration and social anxiety. (2010)
  • Author(s): Kakeyama M, Endo T, Tohyama C.
  • Organizer: 40th Annual meeting of Society for Neuroscience
  • Place of Presentation: San Diego, USA
  • Year and Date: 2010-10-17
• [Presentation] Histological and behavioral analyses in CL3/CaMKIgamma-deficient mice, 2010/09, Kobe. (2010)
  • Author(s): Takemoto-Kimura S, Kamijo S,Horigane S, Suzuki K, Okuno H, Haijima A, Endo T, Takeuchi T, Abe M, Natsume R, Yamazaki M, Mori H, Tohyama C, Sakimura K, Mishina M, Kakeyama M, Bito H.
  • Organizer: The 33rd Aaaual Meeting of The Japan Neuroscience Society
  • Place of Presentation: 神戸国際会議場(兵庫県神戸市)
  • Year and Date: 2010-09-04
• [Presentation] ヒトへの外挿を目指した行動毒性試験の開発:ダイオキシンによる高次機能の撹乱 (2010)
  • Author(s): 掛山正心
  • Organizer: 日本動物心理学会第70回大会
  • Place of Presentation: 東京
  • Year and Date: 2010-08-29
• [Presentation] 認知学習試験,簡易試験,行動と分子をつなぐ試み (2010)
  • Author(s): 掛山正心
  • Organizer: 第37回日本トキシコロジー学会学術年会
  • Place of Presentation: 沖縄
  • Year and Date: 2010-06-17
• [Presentation] 新たな行動試験～ダイオキシンによる社会行動の異常 (2010)
  • Author(s): 掛山正心
  • Organizer: 第80回日本衛生学会学術総会
  • Place of Presentation: 仙台
  • Year and Date: 2010-05-10
• [Presentation] Perinatal TCDD exposure induce learning and affective behavioral deficits in adult male mice : Its low-dose specificity and the possible causal brain regions (2010)
  • Author(s): 遠藤俊裕, 遠山千春, 掛山正心
  • Organizer: 49^<th> Annual meeting of Society of Toxicology (SOT)
  • Place of Presentation: U.S.A., Salt lake city, The Salt Palace Convention Center
  • Year and Date: 2010-03-10
• [Presentation] 周産期ダイオキシン曝露による学習低下と異常行動:低用量特異的影響の免疫組織学的検証 (2009)
  • Author(s): 遠藤俊裕、掛山正心、遠山千春
  • Organizer: 環境ホルモン学会第12回研究発表会
  • Place of Presentation: 東京大学 東京都
  • Year and Date: 2009-12-08
• [Presentation] Fully Automated Analytic Apparatus of Rodent Behaviors Revealed Low Dose Specific Effects of Perinatal Dioxin Exposure on Learning and Affective Functions. (2009)
  • Author(s): 遠藤俊裕, 掛山正心, 遠山千春
  • Organizer: HORIBA/CDBIM Symposium
  • Place of Presentation: 東京大学 東京都
  • Year and Date: 2009-10-26
• [Presentation] Effects of prenatal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin on emotional and social behaviors in mice. (2009)
  • Author(s): Higo S, Endo T, Sakamoto T, Haijima A, Tohyama C, Kakeyama M, Ogawa S
  • Organizer: HORIBA/CDBIM Symposium
  • Place of Presentation: 東京大学 東京都
  • Year and Date: 2009-10-26
• [Presentation] Perinatal exposure to a low-dose of dioxin induces deficits in fear conditioning in mice. (2009)
  • Author(s): Haijima A., Endo T., Zhang Y., Kakeyama M., Tohyama C
  • Organizer: 29th International Symposium on Halogenated Persistent Organic Pollutants
  • Place of Presentation: Beijing China
  • Year and Date: 2009-08-23
• [Presentation] 蛍光免疫染色標本からの遺伝子発現解析 (2009)
  • Author(s): 掛山正心
  • Organizer: 第34回組織細胞化学講習会
  • Place of Presentation: 徳島大学 徳島県
  • Year and Date: 2009-07-31
• [Presentation] 認知・行動毒性学：マウスにおける認知機能と社会行動の定量化
  • Author(s): 掛山正心、遠山千春
  • Organizer: 第39回日本毒性学会
  • Place of Presentation: 仙台国際会議場（宮城県）
  • Invited
• [Presentation] 高次脳機能評価系としてのラット・マウス行動テストのイノベーション
  • Author(s): 掛山正心
  • Organizer: 第24回日本生物学的精神医学会・ランチョンセミナー
  • Place of Presentation: 神戸国際会議場（兵庫県）
  • Invited
• [Presentation] 乳仔期環境とマウス社会性： ダイオキシン胎仔期曝露影響との共通性
  • Author(s): 掛山正心、遠山千春
  • Organizer: 第83回日本衛生学会学術総会
  • Place of Presentation: 金沢大学（石川県）
  • Invited
• [Presentation] げっ歯類を用いた高次脳機能評価法開発と 環境化学物質の神経毒性評価への適用（奨励賞受賞者講演）
  • Author(s): 掛山正心
  • Organizer: 第83回日本衛生学会学術総会
  • Place of Presentation: 金沢大学（石川県）
  • Invited
• [Book] 毒性の科学 : 分子・細胞から人間集団まで (2013)
  • Author(s): 熊谷嘉人・姫野誠一郎・渡辺知保編著
  • Publisher: 東京大学出版会
• [Book] 毒性の科学 : 分子・細胞から人間集団まで(3.6節高次脳機能の行動試験法) (2013)
  • Author(s): 熊谷嘉人・姫野誠一郎・渡辺知保編(掛山正心)
  • Total Pages: 4
  • Publisher: 東京大学出版会
• [Book] 3.6節 高次脳機能の行動試験法
  • Author(s): 掛山正心
• [Remarks]
  • URL: http://www.med.nagasakiu.ac.jp/physlgy2/
• [Remarks] Todai Research「生体組織の蛍光標識微細断片における遺伝子発現量測定の新技術」
  • URL: http://www.u-tokyo.ac.jp/ja/todai-research/research-news/gene-micro-determination-in-micro-dissected-tissue/
• [Remarks] Todai Research「環境化学物質が子どものこころの健康に影響」
  • URL: http://www.u-tokyo.ac.jp/ja/todai-research/research-news/environmental-chemicals-may-affect-childrens-minds/