2001 Fiscal Year Annual Research Report

エストロゲン活性と遺伝子損傷性による環境化学物質の毒性評価法と地域のリスク評価

Research Project

Project/Area Number	11794019
Research Institution	Mie University
Principal Investigator	川西正祐三重大学, 医学部, 教授 (10025637)
Co-Investigator(Kenkyū-buntansha)	及川伸二三重大学, 医学部, 講師 (10277006) 村田真理子三重大学, 医学部, 講師 (10171141) 中島邦夫三重大学, 医学部, 教授 (40022800) 橋爪清三重県科学技術振興センター, 保健環境研究所衛生研究グループ, 総括研究員平工雄介三重大学, 医学部, 助手 (30324510)
Keywords	環境化学物質 / 生殖毒性 / 発がん / ホルモン作用 / 遺伝子損傷 / エストロゲン / トリニトロトルエン / 農薬
Research Abstract	近年、環境化学物質による地球規模の汚染がヒトに対する精子数の減少および子宮内膜症や乳癌等の増加の原因となる可能性が指摘され社会問題となっている。従来の研究では環境化学物質による内分泌撹乱作用ばかりが生殖毒性作用機序として強調されてきた。しかし、遺伝子損傷により生殖細胞にアポトーシスが生じ、精子数の減少や不妊に至る可能性がある。また、発がんについては、体細胞の遺伝子損傷により遺伝子変異(イニシエーション)がおこり、さらにホルモン撹乱作用による細胞増殖(プロモーション)が発がんに関与すると考えられる。本研究では、以下の知見を得ている。(1)女性ホルモンの乳癌誘発機構として、エストラジオール(E_2)の代謝物による遺伝子損傷が発がんのイニシエーションに、E_2による乳腺細胞増殖作用(エストロゲン活性)がプロモーションに関与し発がんに至ることを示唆した。(2)生殖毒性が報告されている爆薬の原料トリニトロトルエン(TNT)は、ラット精巣細胞のDNAを酸化的に損傷することを認め、遺伝子損傷を介して生殖毒性を起こす可能性を示した。(3)生殖毒性作用と発がん性の両作用を有するベンツピレンの酸化的DNA損傷性を明らかにした。(4)エストロゲン感受性ヒト乳癌細胞MCF-7およびエストロゲンレセプターのレポータージーンアッセイを用い、ピレスロイド系農薬の一部にエストロゲン活性があることを見い出した。両検出系は非常によく相関し、有効なエストロゲン作用検出法であることが確認された。(5)内分泌撹乱作用が疑われている化学物質(65物質群)の約6割を農薬が占めている。河川水などの水環境、農作物中の残留農薬に対するGC/MS及びICP/MSを用いた一斉微量分析法を開発した。本研究により内分泌撹乱物質による生殖毒性および発がん機構に内分泌撹乱作用と遺伝子損傷性が重要であることが明らかとなった。また、分析法の開発は地域のリスク評価に寄与すると考えられる。

Research Products
(26 results)

All Other

All Publications (26 results)

[Publications] S.Ohnishi: "DNA damage induced by hypochlorite and hypobromite with reference to inflammation-associated carcinogenesis"Cancer Lett.. 178. 37-42 (2002)
[Publications] K.Hirakawa: "Catechol and Hydroquinone Have Different Redox Properties Responsible for Their Differential DNA-damaging Ability"Chem. Res. Toxicol. 15. 76-82 (2002)
[Publications] S.Ohnishi: "Double Base Lesions of DNA by a Metabolite of Carcinogenic Benzo[a]pyrene"Biochem. Biophys. Res. Commun.. 290. 778-782 (2002)
[Publications] S.Kawanishi: "Mechanism of Guanine-specific DNA Damage by Oxidative Stress and Its Role in Carcinogenesis and Aging"Mutation Res.(Reviews in Mutation Research). 488. 65-76 (2001)
[Publications] S.Kawanishi: "Oxidative DNA damage in cultured cells and rat lungs by carcinogenic nickel compounds"Free. Radic. Biol. Med.. 31. 108-116 (2001)
[Publications] T.Hishita: "Caspase-3 Activation by Lysosomal Enzymes in Cytochrome c-independent Apoptosis in a Myelodysplastic Syndrome(MDS)-derived Cell Line P39"Cancer Res.. 61. 2878-2884 (2001)
[Publications] S.Oikawa: "Site-specific DNA Damage at GGG Sequence by UVA Involves Acceleration of Telomere Shortening"Biochemistry. 40. 4763-4768 (2001)
[Publications] K.Midorikawa: "Superoxide dismutases enchance H2O2-induced DNA damage and alter its site specificity"FEBS Lett.. 495. 187-190 (2001)
[Publications] M.Murata: "Acrylonitril Enhances H_2O_2-Mediated DNA Damage via Nitrogen-Centered Radical Formation"Chem. Res. Toxicol.. 14. 1421-1427 (2001)
[Publications] S.Oikawa: "Site Specificity and Mechanism of Oxidative DNA Damage Induced by Carcinogenic Catechol"Carcinogenesis. 22. 1239-1245 (2001)
[Publications] M.Murata: "Mechanism of Oxidative DNA Damage Induced by Carcinogenic 4-Aminobihenyl"Free Radic. Biol Med.. 30. 765-773 (2001)
[Publications] M.Murata: "Requirement of Glutathione and Cysteine in Guanine-specific Oxidation of DNA by Carcinogenic Potassium Bromate"Chem. Res. Toxicol.. 14. 678-685 (2001)
[Publications] K.Sakano: "Hydroxyurea Induces Site-specific DNA Damage via Formation of Hydrogen Peroxide and Nitric Oxide"Jpn. J. Cancer Res.. 92. 1166-1174 (2001)
[Publications] Y.Ohkuma: "Sequence-specific DNA damage induced by carcinogenic danthron and anthraquinone in the presence of Cu(II), cytochrome P450 reductase and NADPH"Free. Radic. Res.. 34. 595-604 (2001)
[Publications] S.Ohnishi: "Oxidative DNA damage induced by an N-hydroxy metabolite of carcinogenic 4-dimethylaminoazobenzene"Jpn. J. Cancer Res.. 92. 23-29 (2001)
[Publications] K.Sakano: "Mechanism of Metal-mediated DNA Damage Induced by Metabolites of Carcinogenic 2-Nitropropane"Mutat. Res.. 479. 101-111 (2001)
[Publications] S.Ohnishi: "Oxidative DNA Damage by an N-Hydroxy Metabolite of the Mutagenic Compound Formed from Norharman and Aniline"Mutat.Res.. 494. 63-72 (2001)
[Publications] K.Midorikawa: "Protective Effect of Phytic Acid on Oxidative Damage with Reference to Cancer Chemoprevention"Biochem. Biophys. Res. Commun. 288. 552-557 (2001)
[Publications] Y.Ohkuma: "Oxidative DNA Damage Induced by a Metabolite of Carcinogenic o-Anisidine : Enhancement of DNA Damage and Alteration in its Sequence-Specificity by Superoxide Dismutase"Arch Biochem. Biophys.. 389. 49-56 (2001)
[Publications] S.Ohnishi: "Oxidative DNA Damage by a Metabolite of Carcinogenic 1-Nitropyrene"Biochem. Biophys. Res. Commun.. 280. 48-52 (2001)
[Publications] Y.Hiraku: "Amplification of Bleomycin-induced DNA Cleavage at Cytosine Residues 3' to GGG Sequences by Pyrrole Triamide"Biochem. Pharmaco. 61. 351-356 (2001)
[Publications] Y.Hiraku: "Catechol Estrogens Induce Oxidative DNA Damage and Estradiol Enhances Cell Proliferation."Int. J. Cancer. 92. 333-337 (2001)
[Publications] 及川伸二: "環境因子による酸化的DNA損傷とがん、老化"Environ. Mut. Res. Commun.. 23. 207-213 (2001)
[Publications] S.Kawanishi: "Oxidants and Anitoxidants in Cutaneous Biology"J.Thiele and P.Elsner. 193 (2001)
[Publications] 川西正祐: "中毒学 -基礎・臨床・社会医学-"朝倉書店(荒木俊一編). 408 (2002)
[Publications] 川西正祐: "別冊医学のあゆみ酸化ストレス-フリーラジカル医学生物学の最前線"医歯薬出版(吉川敏一編). 326 (2001)

2001 Fiscal Year Annual Research Report

エストロゲン活性と遺伝子損傷性による環境化学物質の毒性評価法と地域のリスク評価

Principal Investigator

川西 正祐 三重大学, 医学部, 教授 (10025637)

Research Products

[Publications] S.Ohnishi: "DNA damage induced by hypochlorite and hypobromite with reference to inflammation-associated carcinogenesis"Cancer Lett.. 178. 37-42 (2002)

[Publications] K.Hirakawa: "Catechol and Hydroquinone Have Different Redox Properties Responsible for Their Differential DNA-damaging Ability"Chem. Res. Toxicol. 15. 76-82 (2002)

[Publications] S.Ohnishi: "Double Base Lesions of DNA by a Metabolite of Carcinogenic Benzo[a]pyrene"Biochem. Biophys. Res. Commun.. 290. 778-782 (2002)

[Publications] S.Kawanishi: "Mechanism of Guanine-specific DNA Damage by Oxidative Stress and Its Role in Carcinogenesis and Aging"Mutation Res.(Reviews in Mutation Research). 488. 65-76 (2001)

[Publications] S.Kawanishi: "Oxidative DNA damage in cultured cells and rat lungs by carcinogenic nickel compounds"Free. Radic. Biol. Med.. 31. 108-116 (2001)

[Publications] T.Hishita: "Caspase-3 Activation by Lysosomal Enzymes in Cytochrome c-independent Apoptosis in a Myelodysplastic Syndrome(MDS)-derived Cell Line P39"Cancer Res.. 61. 2878-2884 (2001)

[Publications] S.Oikawa: "Site-specific DNA Damage at GGG Sequence by UVA Involves Acceleration of Telomere Shortening"Biochemistry. 40. 4763-4768 (2001)

[Publications] K.Midorikawa: "Superoxide dismutases enchance H2O2-induced DNA damage and alter its site specificity"FEBS Lett.. 495. 187-190 (2001)

[Publications] M.Murata: "Acrylonitril Enhances H_2O_2-Mediated DNA Damage via Nitrogen-Centered Radical Formation"Chem. Res. Toxicol.. 14. 1421-1427 (2001)

[Publications] S.Oikawa: "Site Specificity and Mechanism of Oxidative DNA Damage Induced by Carcinogenic Catechol"Carcinogenesis. 22. 1239-1245 (2001)

[Publications] M.Murata: "Mechanism of Oxidative DNA Damage Induced by Carcinogenic 4-Aminobihenyl"Free Radic. Biol Med.. 30. 765-773 (2001)

[Publications] M.Murata: "Requirement of Glutathione and Cysteine in Guanine-specific Oxidation of DNA by Carcinogenic Potassium Bromate"Chem. Res. Toxicol.. 14. 678-685 (2001)

[Publications] K.Sakano: "Hydroxyurea Induces Site-specific DNA Damage via Formation of Hydrogen Peroxide and Nitric Oxide"Jpn. J. Cancer Res.. 92. 1166-1174 (2001)

[Publications] Y.Ohkuma: "Sequence-specific DNA damage induced by carcinogenic danthron and anthraquinone in the presence of Cu(II), cytochrome P450 reductase and NADPH"Free. Radic. Res.. 34. 595-604 (2001)

[Publications] S.Ohnishi: "Oxidative DNA damage induced by an N-hydroxy metabolite of carcinogenic 4-dimethylaminoazobenzene"Jpn. J. Cancer Res.. 92. 23-29 (2001)

[Publications] K.Sakano: "Mechanism of Metal-mediated DNA Damage Induced by Metabolites of Carcinogenic 2-Nitropropane"Mutat. Res.. 479. 101-111 (2001)

[Publications] S.Ohnishi: "Oxidative DNA Damage by an N-Hydroxy Metabolite of the Mutagenic Compound Formed from Norharman and Aniline"Mutat.Res.. 494. 63-72 (2001)

[Publications] K.Midorikawa: "Protective Effect of Phytic Acid on Oxidative Damage with Reference to Cancer Chemoprevention"Biochem. Biophys. Res. Commun. 288. 552-557 (2001)

[Publications] Y.Ohkuma: "Oxidative DNA Damage Induced by a Metabolite of Carcinogenic o-Anisidine : Enhancement of DNA Damage and Alteration in its Sequence-Specificity by Superoxide Dismutase"Arch Biochem. Biophys.. 389. 49-56 (2001)

[Publications] S.Ohnishi: "Oxidative DNA Damage by a Metabolite of Carcinogenic 1-Nitropyrene"Biochem. Biophys. Res. Commun.. 280. 48-52 (2001)

[Publications] Y.Hiraku: "Amplification of Bleomycin-induced DNA Cleavage at Cytosine Residues 3' to GGG Sequences by Pyrrole Triamide"Biochem. Pharmaco. 61. 351-356 (2001)

[Publications] Y.Hiraku: "Catechol Estrogens Induce Oxidative DNA Damage and Estradiol Enhances Cell Proliferation."Int. J. Cancer. 92. 333-337 (2001)

[Publications] 及川伸二: "環境因子による酸化的DNA損傷とがん、老化"Environ. Mut. Res. Commun.. 23. 207-213 (2001)

[Publications] S.Kawanishi: "Oxidants and Anitoxidants in Cutaneous Biology"J.Thiele and P.Elsner. 193 (2001)

[Publications] 川西正祐: "中毒学 -基礎・臨床・社会医学-"朝倉書店(荒木俊一 編). 408 (2002)

[Publications] 川西正祐: "別冊 医学のあゆみ 酸化ストレス-フリーラジカル医学生物学の最前線"医歯薬出版(吉川敏一 編). 326 (2001)

川西正祐三重大学, 医学部, 教授 (10025637)

[Publications] 川西正祐: "中毒学 -基礎・臨床・社会医学-"朝倉書店(荒木俊一編). 408 (2002)

[Publications] 川西正祐: "別冊医学のあゆみ酸化ストレス-フリーラジカル医学生物学の最前線"医歯薬出版(吉川敏一編). 326 (2001)