2014 Fiscal Year Annual Research Report
多元的オミックス解析による化学物質ー細胞内受容体シグナル伝達撹乱の種差の解明
Project/Area Number |
26220103
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Research Institution | Ehime University |
Principal Investigator |
岩田 久人 愛媛大学, 沿岸環境化学研究センター, 教授 (10271652)
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Co-Investigator(Kenkyū-buntansha) |
田辺 信介 愛媛大学, 沿岸環境化学研究センター, 教授 (60116952)
国末 達也 愛媛大学, 沿岸環境化学研究センター, 教授 (90380287)
野見山 桂 愛媛大学, 沿岸環境化学研究センター, 講師 (30512686)
阿草 哲郎 愛媛大学, 沿岸環境化学研究センター, 研究員 (50403853)
中田 晴彦 熊本大学, 自然科学研究科, 准教授 (60311875)
久保田 彰 帯広畜産大学, 畜産学部, 准教授 (60432811)
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Project Period (FY) |
2014-05-30 – 2019-03-31
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Keywords | 感受性 / 細胞内受容体 / オミックス / シトクロムP450 / トランスクリプトーム / ホモロジーモデル |
Outline of Annual Research Achievements |
今年度の実績の概要は以下の通りである。 1)ビスフェノール類(BPs)の分析法を確立し、一部のBPsは衣類中に高濃度に含まれ、洗濯排水が主要な環境汚染源になっている可能性を示した。また、GCxGC-HRTOFMSを用いた多環芳香族炭化水素の同定法を確立し、アルキル化ベンゾ[a]アントラセン・クリセンの一部異性体が環境中で難分解であることを明らかにした。さらに、動物組織を対象とした12種のリン酸エステル系難燃剤の新規分析法開発を試み、10種の高精度分析に成功した。 2)鳥類3種のダイオキシン受容体AHRのin silicoホモロジーモデルを構築し、AHR1とダイオキシン類との結合には、ニワトリAHR1の324Ileと380Serに相当するアミノ酸残基の分子動力学シミュレーションによって説明できることを明らかにした。また、バイカルアザラシのシトクロムP450(CYP)のin vitro発現系および in silicoホモロジーモデルを構築し、CYP1A2は進化の過程でヘム近傍のスレオニンがプロリンに変異したため代謝能が失われたことを示した。 3)バイカルアザラシを対象に、PCBsとその水酸化代謝物(OH-PCBs)の蓄積濃度とトランスクリプトームの関係を解析した。その結果、PCBs・OH-PCBs曝露によって活性化されたAHRを介して慢性肝炎が誘導され、脱ヨウ素化酵素によるT4からT3への代謝経路が撹乱されている可能性が示された。また北太平洋産ミンククジラを対象にしたトランスクリプトーム解析でも、ダイオキシン様PCBsの曝露によってビタミンD受容体シグナル伝達系の抑制や内因性AHRリガンドであるキヌレニンの合成促進が示唆された。 4)プレグネノロン曝露したゼブラフィッシュ胚を用いて、核内受容体PXR発現依存的に100を超える遺伝子の発現量が増加することがわかった。さらに、ダイオキシンに対して感受性の異なるマウス2系統を用いて感受性規定因子を探索し、hnRNP-A2/B1を同定することに成功した。
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Current Status of Research Progress |
Current Status of Research Progress
2: Research has progressed on the whole more than it was originally planned.
Reason
ビスフェノール類(BPs)や多環芳香族炭化水素(PAHs)・リン酸エステル系難燃剤の分析法を開発し、野生動物に蓄積した化学物質のエクスポゾーム解析を進めている。 また、アザラシやクジラの野生個体群やプレグネノロン曝露したゼブラフィッシュ胚のトランスクリプトーム解析をおこない、化学物質曝露濃度と遺伝子発現プロファイルとの関係についても検証できた。 さらに、鳥類ダイオキシン受容体AHRの感受性を規定するアミノ酸残基(ニワトリAHR1の324Ileと380Serに相当するアミノ酸残基)や、マウスのダイオキシン感受性規定因子(hnRNP-A2/B1)の同定に成功した。 以上の結果は、初年度の研究成果としては十分で、想定し得る範囲であることから、研究は予定通り順調に進んでいると判断した。
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Strategy for Future Research Activity |
代表的環境動物種の各臓器・組織に残留するエクスポゾームの解析は継続しておこなう。同定・定量が難しい化学物質の分析法の開発も進める。また一部の化学物質およびその代謝物に関しては、トキシコキネティクス解析も実施する。 エクスポゾームと受容体の相互作用を網羅的に解析するため、まず環境試料から検出された化学物質を対象に、in vitroレポーター遺伝子アッセイ系により各受容体の転写活性化能を測定する。さらに代表的環境動物種の各受容体やシトクロムP450(CYP)タンパク質との結合モードをin silicoでシミュレーションし、相互作用に関与するアミノ酸残基の同定を試みる。 ビスフェノールA(BPA)は、低用量で生体にエストロゲン作用などの内分泌かく乱を引き起こすことが知られているが、その詳細なメカニズムについては不明な点が多い。そこで今後は、魚類・鳥類・哺乳類を対象に、BPAの胎児期曝露による次世代(出生仔)への影響とそのメカニズムの解明を目指して研究を遂行する。具体的には、ゼブラフィッシュ卵やニワトリ卵・妊娠ラットにBPAおよび陽性対照としてのエストラジオール(E2)を投与した後、孵化した仔魚や雛・仔ラットからRNAを抽出・精製し、トランスクリプトーム解析を実施する。また同じ試料のプロテオーム解析も同時並行して進める。
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[Journal Article] In silico analysis of the interaction of avian aryl hydrocarbon receptors and dioxins to decipher isoform-, ligand-, and species-specific activations.2015
Author(s)
Hirano, M., Hwang, J.H., Park, H.J., Bak, S.M., Iwata, H., Kim, E.Y.
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Journal Title
Environmental Science and Technology
Volume: 49(6)
Pages: 3795-3804
DOI
Peer Reviewed / Acknowledgement Compliant
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[Journal Article] Residue profiles of organohalogen compounds in human serum from e-waste recycling sites in North Vietnam: association with thyroid hormone levels.2015
Author(s)
Eguchi, A., Nomiyama, K., Tue, N.M., Trang, P.T. K., Viet, P.H., Takahashi, S., Tanabe, S.
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Journal Title
Environmental Research
Volume: 137
Pages: 440-449
DOI
Peer Reviewed
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[Journal Article] Organohalogens and their hydroxylated metabolites in the blood of pigs from an open waste dumping site in south India: association with hepatic cytochrome P4502015
Author(s)
Mizukawa, H., Nomiyama, K., Kunisue, T., Watanabe, M.X., Subramanian, A., Iwata, H., Ishizuka, M., Tanabe, S.
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Journal Title
Environmental Research
Volume: 138
Pages: 255-263
DOI
Peer Reviewed / Acknowledgement Compliant
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[Journal Article] Comprehensive determination of pharmaceuticals, personal care products, benzotriazole UV stabilizers and organophosphorus flame retardants in environmental water samples using SPE coupled with UHPLC-MS/MS.2015
Author(s)
Kim, J.W., Isobe, T., Tanoue, R., Chang, K.H., Tanabe, S.
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Journal Title
Current Analytical Chemistry
Volume: 11
Pages: 138-149
DOI
Peer Reviewed
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[Journal Article] HP genotyping of Vietnamese: global distribution of HPdel, complete deletion allele of the haptoglobin gene2015
Author(s)
Soejima, M., Agusa, T., Iwata, H., Fujihara, J., Kunito, T., Takeshita, H., Lan, V.T.M., Minh, T.B., Takahashi, S., Trang, P.T.K., Viet, P.H., Tanabe, S., Koda, Y.
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Journal Title
Legal Medicine
Volume: 17
Pages: 14-16
DOI
Peer Reviewed
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[Journal Article] Role of pregnane X receptor and aryl hydrocarbon receptor in transcriptional regulation of pxr, CYP2, and CYP3 genes in developing zebrafish.2015
Author(s)
Kubota, A., Goldstone, J.V., Lemaire, B., Takata, M., Woodin, B.R., Stegeman, J.J.
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Journal Title
Toxicological Sciences
Volume: 143
Pages: 398-407
DOI
Peer Reviewed
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[Journal Article] Enzymatic characterization of in vitro-expressed Baikal seal cytochrome P450 (CYP) 1A1, 1A2, and 1B1: Implication of low metabolic potential of CYP1A22015
Author(s)
Iwata, H., Yamaguchi, K., Takeshita, Y., Kubota, A., Hirakawa, S., Isobe, T., Hirano, M., Kim, E.Y.
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Journal Title
Aquatic Toxicology
Volume: 162
Pages: 138-151
DOI
Peer Reviewed / Acknowledgement Compliant
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[Journal Article] Blood levels of polychlorinated biphenyls and their hydroxylated metabolites in Baikal seals (Pusa sibirica): Emphasis on interspecies comparison, gender difference and association with blood thyroid hormone levels.2014
Author(s)
Imaeda, D., Nomiyama, K., Kunisue, T., Iwata, H., Tsydenova, O., Amano, M., Petrov, E. A., Batoev, V. B., Tanabe, S.
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Journal Title
Chemosphere
Volume: 114
Pages: 1-8
DOI
Peer Reviewed / Acknowledgement Compliant
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[Journal Article] Occurrence of perchlorate and thiocyanate in human serum from e-waste recycling and reference sites in Vietnam: association with thyroid hormone and iodide levels.2014
Author(s)
Eguchi, A., Kunisue, T., Wu, Q., Trang, P. T. K., Viet, P. H., Kannan, K., Tanabe, S.
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Journal Title
Archives of Environmental Contamination and Toxicology
Volume: 67
Pages: 29-41
DOI
Peer Reviewed
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[Journal Article] Involvement of COX2-thromboxane pathway in TCDD-induced precardiac edema in developing zebrafish.2014
Author(s)
Teraoka, H., Okuno, Y., Nijoukubo, D., Yamakoshi, A., Peterson, R.E., Stegeman, J.J., Kitazawa, T., Hiraga, T., Kubota, A.
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Journal Title
Aquatic Toxicology
Volume: 154
Pages: 19-26
DOI
Peer Reviewed
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[Journal Article] Transient suppression of AHR activity in early red seabream embryos does not prevent the disruption of peripheral nerve projection by 2,3,7,8-tetrachlorodibenzo-p-dioxin.2014
Author(s)
Iida, M., Bak, S.M., Murakami, Y., Kim, E.Y., Iwata, H.
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Journal Title
Aquatic Toxicology
Volume: 154
Pages: 39-47
DOI
Peer Reviewed / Acknowledgement Compliant
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[Journal Article] Polycyclic aromatic hydrocarbons in oysters and sediments from the Yatsushiro Sea, Japan: Comparison of potential risks among PAHs, dioxins and dioxin-like compounds in benthic organisms.2014
Author(s)
Nakata, H., Uehara, K., Goto, Y., Fukumura, M., Shimasaki, H., Takikawa, K., Miyawaki, T.
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Journal Title
Environmental Safety and Ecotoxicology
Volume: 99
Pages: 61-68
DOI
Peer Reviewed
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[Journal Article] Exposure assessment of lead to workers and children in the battery recycling craft village, Dong Mai, Vietnam2014
Author(s)
Noguchi, T., Itai, T., Tue, N.M., Agusa, T., Ha, N.N., Horai, S., Trang, P.T.K., Viet, P.H., Takahashi, S., Tanabe, S.
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Journal Title
Journal of Material Cycles and Waste Management
Volume: 16
Pages: 46-51
DOI
Peer Reviewed
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[Journal Article] Human exposure to arsenic from drinking water in Vietnam2014
Author(s)
Agusa, T., Trang, P.T.K., Lan, V.M., Anh, D.H., Tanabe, S., Viet, P.H., Berg, M.
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Journal Title
Science of the Total Environment
Volume: 488-489
Pages: 562-569
DOI
Peer Reviewed
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[Journal Article] Aryl hydrocarbon receptor mediated activities in road dust from a metropolitan area, Hanoi-Vietnam: Concentration of polycyclic aromatic hydrocarbons (PAHs) and human risk assessment.2014
Author(s)
Tuyen, L.H., Tue, N.M., Suzuki, G., Misaki, K., Viet, P.H., Takahashi, S., Tanabe, S.
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Journal Title
Science of the Total Environment
Volume: 491-492
Pages: 246-254
DOI
Peer Reviewed
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[Journal Article] Dioxin-related compounds in breast milk of women from Vietnamese e-waste recycling sites: Levels, toxic equivalents and relevance of non-dietary exposure.2014
Author(s)
Tue, N.M., Katsura, K., Suzuki, G., Tuyen, L.H., Takasuga, T., Takahashi, S., Viet, P.H., Tanabe, S.
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Journal Title
Ecotoxicology and Environmental Safety
Volume: 106
Pages: 220-225
DOI
Peer Reviewed
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[Journal Article] Effects of persistent organochlorine exposure on the liver transcriptome of the common minke whale (Balaenoptera acutorostrata) from the North Pacific.2014
Author(s)
Niimi, S., Imoto, M., Kunisue, T., Watanabe, M.X., Kim, E.Y., Nakayama, K., Yasunaga, G., Fujise, Y., Tanabe, S., Iwata, H.
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Journal Title
Ecotoxicology and Environmental Safety
Volume: 108
Pages: 95-105
DOI
Peer Reviewed / Acknowledgement Compliant
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[Journal Article] Simultaneous determination of polar pharmaceuticals and personal care products in biological organs and tissues.2014
Author(s)
Tanoue, R., Nomiyama, K., Nakamura, H., Hayashi, T., Kim, J. W., Isobe, T., Shinohara, R., Tanabe, S.
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Journal Title
Journal of Chromatography A.
Volume: 1355
Pages: 193-205
DOI
Peer Reviewed
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[Journal Article] Methylated and unsubstituted polycyclic aromatic hydrocarbons in street dust from Vietnam and India: Occurrence, distribution and in vitro toxicity evaluation.2014
Author(s)
Tuyen, L.H., Tue, N.M., Takahashi, S., Suzuki, G., Viet, P.H., Subramanian, An., Bulbule, K.A., Parthasarathy, P., Ramanathan, A.,Tanabe, S.
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Journal Title
Environmental Pollution
Volume: 194
Pages: 272-280
DOI
Peer Reviewed
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[Journal Article] Toxicological assessment of polychlorinated biphenyls and their metabolites in the liver of Bikal seal (Pusa sibirica).2014
Author(s)
Nomiyama, K., Hirakawa, S., Eguchi, A., Kanbara, C., Imaeda, D., Yoo, J., Kunisue, T., Kim, E.Y., Iwata, H., Tanabe, S.
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Journal Title
Environmental Science and Technology
Volume: 48(22)
Pages: 13530-13539
DOI
Peer Reviewed / Acknowledgement Compliant
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[Journal Article] Novel role of hnRNP-A2/B1 in modulating aryl hydrocarbon receptor ligand sensitivity.2014
Author(s)
Cho, S.W., Suzuki, K., Miura, Y., Miyazaki, T., Nose, M., Iwata, H., Kim, E.Y.
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Journal Title
Archives of Toxicology
Volume: 1
Pages: 1-12
DOI
Peer Reviewed / Acknowledgement Compliant
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[Presentation] Relationship between mRNA expression level and SNPs of AS3MT in residents from arsenic-contaminated areas in Vietnam2015
Author(s)
Agusa, T., Kunito, T., Tue, N. M., Lan, V. T., Minh, T. B., Trang, P. T., Fujihara, J., Takeshita, H., Takahashi, S., Viet, P. H., Tanabe, S., Iwata, H.
Organizer
Society of Toxicology (SOT) 54th Annual Meeting
Place of Presentation
サンディエゴ, アメリカ
Year and Date
2015-03-25
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[Presentation] Strain-differences in the proteome of dioxin-sensitive and -resistant mice treated with 2,3,7,8-tetrabromodibenzo-p-dioxin2015
Author(s)
Nguyen, T., Lauan, M., Yoo, J., Iida, M., Agusa, T., Kim, E., Miyazaki, T., Nose, M., Iwata, H.
Organizer
Society of Toxicology (SOT) 54th Annual Meeting
Place of Presentation
サンディエゴ、アメリカ
Year and Date
2015-03-24
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[Presentation] Cytochrome P450 20A1: Diversity and potential functions of a major orphan P450s2015
Author(s)
Lemaire, B., Goldstone, J.V., Lam, D., Kubota, A., Nelson, D., Stegeman, J.J.
Organizer
Society of Toxicology (SOT) 54th Annual Meeting
Place of Presentation
サンディエゴ、アメリカ
Year and Date
2015-03-23
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[Presentation] RNA-Seq analysis of the mysid crustacean transcriptome treated with naturally occurring 1,3,7-tribromodibenzo-p-dioxin2015
Author(s)
Hirano, M., Uchida, M., Kusano, T., Arizono, K., Iwata, H.
Organizer
Society of Toxicology (SOT) 54th Annual Meeting
Place of Presentation
サンディエゴ、アメリカ
Year and Date
2015-03-23
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[Presentation] Effects of a naturally occurring dioxin, 1,3,7-tribromodibenzo-p-dioxin on the mysid transcriptome2014
Author(s)
Hirano, M., Uchida, M., Kusano, T., Arizono, K., Iwata, H.
Organizer
環境ホルモン学会 第17回研究発表会
Place of Presentation
東京都文京区、日本
Year and Date
2014-12-10
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[Presentation] Toxicological assessment of polychlorinated biphenyls (PCBs) and their metabolites (OH-PCBs) in the liver of wild Baikal seals (Pusa sibirica): Application of microarray and biochemical analysis.2014
Author(s)
Nomiyama, K., Hirakawa, S., Eguchi, A., Kanbara, C., Imaeda, D., Yoo, J., Kunisue, T., Kim, E.Y., Iwata, H., Tanabe, S.
Organizer
International Conference of Asian Environmental Chemistry 2014 (ICAEC2014)
Place of Presentation
バンコク、タイ
Year and Date
2014-11-25
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[Presentation] Atmospheric concentrations of persistent organic pollutants (POPs) using passive air sampler in Batam Island, Indonesia.2014
Author(s)
Sudaryanto, A., Ilyas, M., Riyadi, A.S., Isobe, T., Tanabe, S.
Organizer
International Conference of Asian Environmental Chemistry 2014 (ICAEC2014)
Place of Presentation
バンコク、タイ
Year and Date
2014-11-24 – 2014-11-26
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[Presentation] PCBs, PBDEs and their hydroxylated metabolites in the brain of free-ranging toothed and baleen whales.2014
Author(s)
Ochiai, M., Nomiyama, K., Isobe, T., Yamada, T.K., Tajima, Y., Makara, M., Amano, M., Matsuishi, T., Iwata, H., Tanabe, S.
Organizer
6th Bilateral Seminar Italy‐Japan on Physical and Chemical Impacts on Marine Organisms
Place of Presentation
パレルモ、イタリア
Year and Date
2014-11-19
Invited
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[Presentation] Temporal and spatial trends of PAHs and hopanes concentrations in bivalves and sediments after the Tsunami disaster in Tohoku coastal waters, Japan.2014
Author(s)
Izumida, H., Miyazaki, K., Nakata, H., Ueno, D., Miyawaki, T., Matsumura, T., Nakamura, M., Nakai, K.
Organizer
35th SETAC (Society of Environmental Toxicology and Chemistry) North America
Place of Presentation
バンクーバー、カナダ
Year and Date
2014-11-12
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[Presentation] Dioxin-related compounds and POPs in floor dust from ELV recycling sites in northern Vietnam: comparison with e-waste recycling sites.2014
Author(s)
Takahashi, S., Takayanagi, C., Tue, N.M., Tuyen, L.H., Suzuki, G., Viet, P.H., Sakai, S., Tanabe, S.
Organizer
End-of-Life Vehicle (ELV) Recycling Workshop 2014
Place of Presentation
東京都千代田区、日本
Year and Date
2014-09-10
Invited
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[Presentation] Ecological factors as pressure of natural selection of AhR genotypes in avian species2014
Author(s)
Hwang, J.H., Park, H.J., Park, J.Y., Bak, S.M., Park, Y.S., Hirano, M., Kim, E.Y., Iwata, H.
Organizer
DIOXIN Madrid 2014 / 34th International Symposium on Halogenated Persistent Organic Pollutants
Place of Presentation
Madrid, Spain
Year and Date
2014-09-04
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[Presentation] In vitro and in silico assessment of transactivation potencies of Baikal seal estrogen receptors αand β by persistent organic pollutants and bisphenols2014
Author(s)
Yoshinouchi, Y., Shimizu, S., Suzuki, K., Lee, J.S., Nakata, H., Hirano, M., Kim, E.Y., Agusa, T., Iwata, H.
Organizer
DIOXIN Madrid 2014 / 34th International Symposium on Halogenated Persistent Organic Pollutants
Place of Presentation
Madrid, Spain
Year and Date
2014-09-04
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[Presentation] Effects of polychlorinated biphenyls on the expression of cytochrome P450s in beagle dogs2014
Author(s)
Tamura, S., Yoo, J., Nomiyama, K., Mizukawa, H., Tanabe, S., Agusa, T., Kim, E.Y., Hirano, M., Iwata, H.
Organizer
DIOXIN Madrid 2014 / 34th International Symposium on Halogenated Persistent Organic Pollutants
Place of Presentation
Madrid, Spain
Year and Date
2014-09-04
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[Presentation] Halogenated polyaromatics in soil from an e-waste burning site in Ghana.2014
Author(s)
Tue, N.M., Goto, A., Takahashi, S., Itai, T., Asante, K., Nomiyama, K., Tanabe, S.
Organizer
The 34th International Symposium on Halogenated Persistent Organic Pollutants (DIOXIN 2014)
Place of Presentation
マドリッド、スペイン
Year and Date
2014-08-31 – 2014-09-05
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[Presentation] Chlorinated and brominated persistent organic pollutants in mass stranded striped dolphins (Stenella coeruleoalba) from Minamisatsuma, Japan.2014
Author(s)
Isobe, T., Kume, N., Amano, M., Tajima, Y., Yamada, T., Tanabe, S.
Organizer
The 34th International Symposium on Halogenated Persistent Organic Pollutants (DIOXIN 2014)
Place of Presentation
マドリッド、スペイン
Year and Date
2014-08-31 – 2014-09-05
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[Presentation] Methylated polycyclic aromatic hydrocarbons and their contribution to AhR-mediated activities in street dust from Asian cities.2014
Author(s)
Tuyen, L.H., Tue, N.M., Takahashi, S., Suzuki, G., Viet, P.H., Subramanian, A., Bulbule, A., Tanabe, S.
Organizer
Urban Environmental Pollution 2014
Place of Presentation
トロント、カナダ
Year and Date
2014-06-12 – 2014-06-15
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