2001 Fiscal Year Annual Research Report

環境化学物質の内分泌撹乱作用と遺伝毒性の発現機構

Research Project

Project/Area Number	13027238
Research Institution	Mie University
Principal Investigator	川西正祐三重大学, 医学部, 教授 (10025637)
Co-Investigator(Kenkyū-buntansha)	村田真理子三重大学, 医学部, 講師 (10171141)
Keywords	内分泌撹乱化学物質 / 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 / ダイゼイン
Research Abstract	近年、多くの環境化学物質が内分泌撹乱作用を有することが明らかとなり、重要な社会問題となっている。これらの物質はヒトに精子減少のような生殖毒性などの多彩な影響をもたらすことが懸念されている。ある種の内分泌撹乱物質はエストロゲン受容体を介したホルモン作用に加え、遺伝子損傷を介して生殖毒性および発がんをもたらすことが推定される。事実、エストロゲンは発がん性を有し、乳がんや子宮がんを起こすことが知られている。本研究では、エストロゲンによる毒性機構を解明し、他の環境化学物質研究にも応用し、以下の知見を得ている。 (1)エストロゲンの乳がん誘発機構:我々はエストラジオール(E_2)そのものには遺伝子損傷性はないが、その代謝物であるカテコールエストロゲンが極めて低濃度で遺伝子を損傷しうることを見い出した。すなわち、エストロゲンの発がんにおいては、E_2代謝物がイニシエーションに関与し、E_2自身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すると考えられる(Int.J.Cancer,92,333-337,2001)。(2)植物エストロゲンによる発がん機構:大豆に含まれるバイオフラボノイドであるダイゼインは細胞増殖活性を有し、ダイゼイン・エストロゲンレセプター複合体と遺伝子上のエストロゲン反応領域との相互作用も認められた。しかし、DNA損傷性は認められなかった。これに対して、その代謝物の1つと考えられる7,3',4'-trihydroxyiosoflavoneは細胞増殖活性は弱いものの、DNA損傷性が認められた。したがって、エストロゲンと同様の機構で発がん性を示す可能性が示唆された。(3)トリニトロトルエン(TNT)の生殖毒性発現機構:TNTを投与したラットでは精子数減少が認められたが、血漿テストステロンの有意な変動がなかったのに対し、精巣および精巣上体から抽出したDNAの8-oxodGの生成量の上昇を認めた。単離DNAを用いた実験でTNTの代謝物がDNAを損傷することを見い出しており、TNTは生体内で生成された代謝物による遺伝子損傷を介して生殖毒性および発がん性をもたらすことが示唆された(Free Radic.Res.,in press)。

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 UNA 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

環境化学物質の内分泌撹乱作用と遺伝毒性の発現機構

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 UNA 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)