2010 Fiscal Year Annual Research Report
化学物質による細胞内受容体―異物代謝酵素シグナル伝達系撹乱の感受性支配因子の解明
Project/Area Number |
21221004
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Research Institution | Ehime University |
Principal Investigator |
岩田 久人 愛媛大学, 沿岸環境科学研究センター, 教授 (10271652)
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Co-Investigator(Kenkyū-buntansha) |
能勢 眞人 愛媛大学, プロテオ医学研究センター, 教授 (70030913)
石橋 弘志 愛媛大学, 沿岸環境科学研究センター, グローバルCOE准教授 (90403857)
鈴木 賢一 愛媛大学, 沿岸環境科学研究センター, グローバルCOE助教 (90363043)
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Keywords | シトクロムP450 (cytochrome P450) / aryl hydrocarbon receptor (AHR) / constitutive androstane receptor (CAR) / pregnane X receptor (PXR) / peroxisome proliferator-activated receptor (PPAR) / 感受性 / 化学物質 / persistent organic pollutants (POPs) |
Research Abstract |
本年度得られた成果は、以下の(1)-(5)のように要約できる。 (1)CYP遺伝子プロモーター/エンハンサー領域の解析:魚類および両生類のCYP1ファミリーに属する遺伝子のプロモーター/エンハンサー領域の塩基配列を解析し、アリルハイドロカーボン受容体(AHR)が結合する特定配列が各遺伝子上流域に存在することがわかった。この配列の位置・数には種・遺伝子特異性が認められた。 (2)CYP遺伝子のクローニング:カワウの肝臓cDNAライブラリーから、4種類のCYP2分子種(CYP2AC1・CYP2AF1・CYP2C45・CYP2J25)を同定した。さらにカワウ肝臓の各CYP2 mRNA発現量と化学物質蓄積濃度との関係を解析し、CYP2C45・CYP2J25の発現は有機フッ素化合物暴露により抑制されることを示唆した。 (3)細胞内受容体と相互作用する化学物質の網羅的解析:水棲哺乳類のAHRおよびペルオキシソーム増殖剤応答性受容体(PPAR)を発現させたレポーター遺伝子アッセイ系を構築し、ダイオキシン類や有機フッ素系化合物による標的遺伝子転写活性化能について測定した。さらにこれら化学物質の立体構造と各物質の相対効力の関係を解析し、構造-活性相関を見出した。 (4)CYPによる化学物質代謝能の解明と代謝経路・産物の網羅的解析:水棲哺乳類CYP1分子種を対象に、酵母によるCYPタンパク質発現系を構築した。本発現系を利用して、アルコキシレゾルフィンやエストロジェンを基質とした各CYP1分子種の代謝パラメーターを代謝産物毎に測定した。 (5)細胞内受容体およびCYP以外の感受性規定因子の探索:マウス各系統の脾細胞をTCDD処理し、CYP1A1遺伝子発現量の用量依存性の系統差を調査した。その結果、AHRの遺伝子型は鈍感型であるにもかかわらず、CYP1A1発現誘導能が高いマウス系統が存在することを確認した。また、これらマウス系統のCYP1A1遺伝子の上流域には差が認められなかったことから、感受性差はAHRやCYP以外の要因が関与していると推察された。
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Author(s)
Kim, E.Y., Suda, T., Tanabe, S., Batoev, V.B., Petrov, E.A., Iwata, H.
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Author(s)
Agusa, T., Takagi, K., Miller, T.W., Kubota, R., Anan, Y., Iwata, H., Tanabe, S.
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[Journal Article] 8-Hydroxy-2'-deoxyguanosine and arsenic compounds in urine and serum of a 4-year-old child suffering from acute promyelocytic leukemia during treatment with arsenic trioxide.2011
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Fujihara, J., Hasegawa, M., Kanai, R., Agusa, T., Iwata, H., Tanabe, S., Yasuda, T., Yamaguchi, S., Takeshita, H.
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Journal Title
Forensic Toxicology
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Watanabe, M.X., Kunisue, T., Tao, L., Kannan, K., Subramanian, An., Tanabe, S., Iwata, H.
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Environmental Toxicology and Chemistry
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[Journal Article] Hepatic CYP1A introduction by chlorinated dioxins and related compounds in the endangered black-footed albatross from the North Pacific.2010
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Kubota, A., Watanabe, M., Kunisue, T., Kim, E.Y., Tanabe, S., Iwata, H.
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Journal Title
Environmental Science & Technology
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[Journal Article] Effects of in ovo exposure to 2,3,7,8-tetrachlorodibenzo-p-doxin on hepatic AHR/ARNT CYP1A signaling pathways in common cormorants (Phalacrocoraxcarbo).2010
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Iwata, H., Nagahama, N., Kim, E.Y., Watanabe, M.X., Sudo, A.
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Journal Title
Comparative Biochemistry and Physiology, Part C
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[Journal Article] Exposure, metabolism, and health effects of arsenic in residents from arsenic-contaminated groundwater areas of Vietnam and Cambodia : A review.2010
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Agusa, T., Kunoto, T., Kubota, R., Inoue, S., Fujihara, J., Minh, T.B., Ha, N.N., Tu, N.P.C., Trang, P.T.K., Chamnan, C., Takeshita, H., Iwata, H., Tuyen, B.C., Viet, P.H., Tana, T.S., Tanabe, S.
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Reviews on Environmental Health
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[Journal Article] A microarray data analysis method to evaluate the impact of contaminants on wild animals.2010
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Tanaka, Y., Komori, H., Mori, S., Soga, Y., Tsubaki, T., Terada, M., Miyazaki, T., Fujino, T., Nakamura, S., Kanno, H., Sawasaki, T., Endo, Y., Nose, M.
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Journal Title
The Tohoku Journal of Experimental Medicine.
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Volume: 60
Pages: 430-437
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[Journal Article] Contamination of pharmaceutical and personal care products in sewage treatment plants and surface waters in South Korea and their removal during activated sludge treatment.2010
Author(s)
Kim, J.W., Ishibashi, H., Hirano, M., Jang, H.S., Kim, J.G., Takao, Y., Ichikawa, N., Shinohara, R., Arizono, K.
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Journal Title
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[Journal Article] Decolorization and estrogenic activity of colored livestock watewater by electrolysis system.2010
Author(s)
Kai, H., Ishibashi, Y., Mori, T., Ishibashi, H., Kawaguchi, T., Ohwaki, H., Arizono, K., Takemasa, T.
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[Presentation] Association of arsenic exposure and genetic polymorphisms with arsenic metabolism in a Vietnamese population.2011
Author(s)
Agusa, T., Kunito, T., Fujiwara, J., Takeshita, T.B., Min, P.K., Viet, P.H., Tanabe, S., Iwata, H.
Organizer
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Place of Presentation
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Year and Date
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[Presentation] 2,3,7,8-tetrachlorodibenzo-p-dioxin responsive transcripts in avian embryonic liver, identified by large-scale differential display system with vertebrate-common degenerate oligonucleotide primers.2011
Author(s)
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Organizer
Society of Toxicology 50^<th> anniversary annual meeting
Place of Presentation
Washington, D.C., USA.
Year and Date
20110306-20110310
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[Presentation] Functional analyses of the mysid ecdysteroid receptor : molecular cloning, DNA binding ability and ligand-induced transactivation.2010
Author(s)
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Organizer
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Year and Date
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[Presentation] Cytochrome P450 CYP2 genes in the common cormorant : evolutionary relationships with diapsid CYP2 clan sequences and chemical effects on their expression.2010
Author(s)
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Organizer
10^<th> International symposium on cytochrome P450 biodiversity and biotechnology
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Year and Date
20101003-20101007
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[Presentation] Effects of endogenous and xenobiotic ligands on DNA binding and transactivation of the mysid ecdysteroid receptor.2010
Author(s)
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Organizer
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Place of Presentation
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Year and Date
20100922-20100923
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[Presentation] Common and different gene loci susceptible to sialoadenitis and dacryoadenitis in a sjogren's syndrome mouse model.2010
Author(s)
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Place of Presentation
Kobe, Japan
Year and Date
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[Presentation] A novel mouse model for primary focal segmental glomerulosclerosis developing associated with insertional mutagenesis by transgene.2010
Author(s)
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Place of Presentation
Kobe, Japan
Year and Date
20100823-20100827
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[Presentation] Allelic polymorphism of murine osteopontin implicates functional differences in antigen presentation by dendritic cells.2010
Author(s)
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Organizer
14th International Congress of Immunology
Place of Presentation
Kobe, Japan
Year and Date
20100823-20100827
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[Presentation] Accumulation of trace elements in harp seals (Phoca groenlandica) from Pangnirtung in Baffin Island, Canada.2010
Author(s)
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Organizer
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Place of Presentation
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Year and Date
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[Presentation] Methylation of inorganic arsenic and genetic polymorphisms in arsenic (+III oxidation state) methyltransferase in a Vietnamese population.2010
Author(s)
Agusa, T., Fujihara, J., Takeshita, H., Tanabe, S., Iwata, H., Kunito, T., Minh, T.B., Trang, P.T.K., Viet, P.H.
Organizer
The 3^<rd> International Congress on Arsenic in the Environment
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Year and Date
20100517-20100521
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[Book] Development of an in vitro reporter gene assay for screening the ecdysone receptor agonists in mysid crustacean, Interdisciplinary Studies on Environmental Chemistry Vol.4, Environmental Specimen Bank : Exploring Possibility of Setting-up ESBs in Developing Countries2010
Author(s)
Hirano, M., Ishibashi, H., Kim, E.Y., Arizono, K., Iwata, H.
Total Pages
7
Publisher
TERRAPUB
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[Book] Toxic effects of 2,3,7,8-tetrachlorodibenzo p-dioxin (TCDD) on peripheral nervous system of developing red seabream (Pagrus major) embryos, Interdisciplinary Studies on Environmental Chemistry Vol.4, Environmental Specimen Bank : Exploring Possibility of Setting-up ESBs in Developing Countries2010
Author(s)
Iida, M., Kim, E.Y., Murakami, Y., Shima, Y., Iwata, H.
Total Pages
6
Publisher
TERRAPUB
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[Book] Interindividual variation in arsenic metabolism in a Vietnamese population : association with 17 single nucleotide polymorphisms in AS3MT, Interdisciplinary Studies on Environmental Chemistry vol.3, Bioloical Responses to Contaminants : from Molecular to Community Level2010
Author(s)
Agusa, T., Iwata, H., Fujihara, J., Kunito, T., Takeshita, H., Minh, T.B., Trang, P.T.K., Viet, P.H., Tanabe, S.
Total Pages
7
Publisher
TERRAPUB
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[Book] Methylation of inorganic arsenic and genetic polymorphisms in arsenic (+III oxidation state)methyltransferase in a Vietnamese population, Arsenic in Geosphere and Human Diseases2010
Author(s)
Agusa, T., Fujihara, J., Takeshita, H., Tanabe, S., Iwata, H., Kunito, T., Minh, T.B., Trang, P.T.K., Viet, P.H.
Total Pages
3
Publisher
CRC Press
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