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Studies on the Role of Oxidative Stress in Mutagenesis by Using Nrf2-deficient Mice

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Title Studies on the Role of Oxidative Stress in Mutagenesis by UsingNrf2-deficient Mice( 内容と審査の要旨(Summary) ) Author(s) 土屋, 卓磨 Report No.(Doctoral Degree) 博士(獣医学) 甲第509号 Issue Date 2018-09-21 Type 博士論文 Version ETD URL http://hdl.handle.net/20.500.12099/77270 ※この資料の著作権は、各資料の著者・学協会・出版社等に帰属します。

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  Ặྡ㸦ᮏ㸦ᅜ㸧⡠㸧   ᅵ ᒇ ༟ ☻㸦ᮾி㒔㸧 ୺ ᣦ ᑟ ᩍ ဨ Ặ ྡ    ᒱ㜧኱Ꮫ ᩍᤵ ᰡ ஭ ᚫ ☻ Ꮫ ఩ ࡢ ✀ 㢮   ༤ኈ㸦⋇་Ꮫ㸧 Ꮫ ఩ グ ␒ ྕ   ⋇་༤⏥➨㸳㸮㸷ྕ Ꮫ ఩ ᤵ ୚ ᖺ ᭶ ᪥   ᖹᡂ㸱㸮ᖺ㸷᭶㸰㸯᪥ Ꮫ ఩ ᤵ ୚ ࡢ せ ௳   Ꮫ఩つ๎➨㸲᮲➨㸯㡯ヱᙜ  ◊ ✲ ⛉ ཬ ࡧ ᑓ ᨷ    㐃ྜ⋇་Ꮫ◊✲⛉             ⋇་Ꮫᑓᨷ ◊✲ᣦᑟࢆཷࡅࡓ኱Ꮫ   ᒱ㜧኱Ꮫ Ꮫ ఩ ㄽ ᩥ 㢟 ┠  6WXGLHVRQWKH5ROHRI2[LGDWLYH6WUHVVLQ 0XWDJHQHVLV E\8VLQJ1UIGHILFLHQW0LFH 㸦1UI Ḟᦆ࣐࢘ࢫࢆ⏝࠸ࡓኚ␗ཎᛶ࡟࠾ࡅࡿ㓟໬ࢫࢺ ࣞࢫࡢᙺ๭࡟㛵ࡍࡿ◊✲㸧 ᑂ ᰝ ጤ ဨ    ୺ᰝ  ᮾி㎰ᕤ኱Ꮫ  ᩍ ᤵ  ῰ ㇂   ῟             ๪ᰝ  ᖏᗈ␆⏘኱Ꮫ  ᩍ ᤵ  ྂ ᯘ ୚ᚿᏳ             ๪ᰝ  ᒾ ᡭ ኱ Ꮫ  ᩍ ᤵ  బ ⸨   ὒ             ๪ᰝ  ᮾி㎰ᕤ኱Ꮫ  ෸ᩍᤵ  ྜྷ ⏣ ᩄ ๎             ๪ᰝ  ᒱ 㜧 ኱ Ꮫ  ᩍ ᤵ  ᰡ ஭ ᚫ ☻   Ꮫ఩ㄽᩥࡢෆᐜࡢせ᪨  ⚾㐩ࡣᖖ࡟⎔ቃ୰࡟࠾࠸࡚✀ࠎࡢⓎࡀࢇ≀㉁ࡢ⬣ጾ࡟ࡉࡽࡉࢀ࡚࠸ࡿࠋᵝࠎ࡞⎔ቃ୰໬ Ꮫ≀㉁ࡢ୰࡛ࡶ㸪㣗ရࢆ௓ࡋ࡚ࣄࢺࡀᦤྲྀࡍࡿྍ⬟ᛶࡢ࠶ࡿ≀㉁ࡢⓎࡀࢇࣜࢫࢡホ౯ࡣ㸪 බ⾗⾨⏕ୖ᭱ࡶ㔜せ࡞ㄢ㢟ࡢ୍ࡘ࡛࠶ࡿࠋࡲࡓ㸪ࡑࢀࡽ࡟ࡼࡾㄏⓎࡉࢀࡿ㓟໬ࢫࢺࣞࢫࡣ㸪 ໬ᏛⓎࡀࢇࡢ㐣⛬࡟࠾࠸࡚㔜せ࡞ᙺ๭ࢆᢸ࠺ࡇ࡜ࡀ▱ࡽࢀ࡚࠸ࡿࠋ㌿෗ᅉᏊࡢ୍ࡘ࡛࠶ࡿ NRF2 ࡣᢠ㓟໬㓝⣲⩌ࡢⓎ⌧ㄪ⠇ࢆ௓ࡋ࡚⏕యෆ࡛㓟໬ࢫࢺࣞࢫ㜵ᚚ࡟㔜せ࡞ᙺ๭ࢆᯝࡓ ࡋ࡚࠾ࡾ㸪ࡑࡢḞᦆື≀ࡣ㓟໬ࢫࢺࣞࢫ࡟ᑐࡋ࡚㧗ឤཷᛶࢆ♧ࡍࡇ࡜ࡀ▱ࡽࢀ࡚࠸ࡿࠋࡲ ࡓ㸪⭈⮚ࡣ᤼ἥࡸ෌྾཰㐣⛬࡛ᵝࠎ࡞≀㉁ࡢ᭚㟢㸪ࡉࡽ࡟᪲┒࡞㓟໬㑏ඖ཯ᛂࡢሙ࡛࠶ࡿ ࡓࡵ㸪㓟໬ࢫࢺࣞࢫࡢᙳ㡪ࢆ᭱ࡶᙉࡃཷࡅࡿ⮚ჾࡢ୍ࡘ࡛࠶ࡿࠋࡑࡢࡓࡵ㸪⭈Ⓨࡀࢇ㐣⛬ ࡟ࡣ㓟໬ࢫࢺࣞࢫࡀᙉࡃ㛵୚ࡋ࡚࠸ࡿ࡜⪃࠼ࡽࢀ࡚࠸ࡿࠋࢽࢺࣟࣇࣛࣥࢺ࢖ࣥ㸦NFT㸧࠾ ࡼࡧ⮯⣲㓟࣒࢝ࣜ࢘㸦KBrO3㸧ࡣࡑࢀࡒࢀṧ␃㎰⸆࠶ࡿ࠸ࡣ㣗ရῧຍ≀࡜ࡋ࡚ࣄࢺࡀᦤྲྀ ࡍࡿྍ⬟ᛶࡢ㧗࠸໬Ꮫ≀㉁࡛࠶ࡿࡀ㸪࠸ࡎࢀࡶࣛࢵࢺ࡟࠾࠸࡚⭈Ⓨࡀࢇᛶࡀሗ࿌ࡉࢀ࡚࠸ ࡿࠋࡲࡓ㸪୧⪅ࡣࡑࢀࡒࢀࢽࢺࣟᇶࡢ㑏ඖ཯ᛂ࠾ࡼࡧࣈ࣑ࣟࣥࣛࢪ࢝ࣝࡢ⏕ᡂࢆ௓ࡋ࡚㓟 ໬ࢫࢺࣞࢫࢆㄏⓎࡍࡿࡓࡵ㸪ࡑࡢⓎࡀࢇᛶ࡬ࡢ㓟໬ࢫࢺࣞࢫࡢ㛵୚ࡀ␲ࢃࢀ࡚࠸ࡿࠋ୍᪉㸪 άᛶ㓟⣲✀࡟ࡼࡾᙧᡂࡉࢀࡿ᭱ࡶ௦⾲ⓗ࡞㓟໬ⓗ DNA ᦆയࡢ୍ࡘ࡛࠶ࡿ 8-OHdG ࡣ㸪⮫ ᗋ⌧ሙࡸື≀ᐇ㦂࡟࠾࠸࡚㓟໬ࢫࢺࣞࢫ࣐࣮࣮࢝࡜ࡋ࡚ᗈࡃ⏝࠸ࡽࢀ࡚࠸ࡿࡀ㸪㏆ᖺࡑࡢ ಟ᚟࢚࣮ࣛࡀᵝࠎ࡞㑇ఏᏊࡢኚ␗࡟ࡘ࡞ࡀࡿࡇ࡜ࡀሗ࿌ࡉࢀ࡚࠸ࡿࠋᐇ㝿࡟NFT ࡜ KBrO3 ࡣ㸪࠸ࡎࢀࡶ⭈⮚࡟࠾࠸࡚ 8-OHdG ࡢቑຍࢆకࡗ࡚㑇ఏᏊኚ␗㢖ᗘ㸦MFs㸧ࢆቑຍࡉࡏࡿ ࡀ㸪ࡑࢀࡽࡣࡑࢀࡒࢀtransversion ኚ␗࡜Ḟኻኚ␗ࢆ୺య࡜ࡋࡓ㑇ఏᏊኚ␗ࢆㄏᑟࡍࡿ࡜ࡉ ࢀࡿࠋࡑࡇ࡛ᮏ◊✲࡛ࡣ㸪㓟໬ࢫࢺࣞࢫ࡟㧗ឤཷᛶ࡛࠶ࡾ㸪࠿ࡘᑐ㇟⮚ჾ࡟࠾ࡅࡿin vivo ኚ␗ཎᛶࢆ᳨ฟྍ⬟࡞ື≀ࣔࢹ࡛ࣝ࠶ࡿNrf2-/- gpt delta ࣐࢘ࢫࢆ⏝࠸ࡿࡇ࡜࡛㸪NFT ࠾ࡼ 㸦㸰㸧

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 ࡧKBrO3࡟ࡼࡿኚ␗ཎᛶ࡟࠾ࡅࡿ㓟໬ࢫࢺࣞࢫࡢ㛵୚ࡢᵝᘧࢆ᳨ウࡋࡓࠋ ➨㸯❶࡛ࡣ㸪NFT ࡟ࡼࡿ໬Ꮫᵓ㐀౫Ꮡⓗ࡞㑇ఏẘᛶᶵᗎ࡟࠾ࡅࡿ㓟໬ࢫࢺࣞࢫࡢᙺ๭ࢆ ᫂ࡽ࠿࡟ࡍࡿࡓࡵ㸪 NFT ࡜ࡑࡢ㓟໬ࢫࢺࣞࢫཬࡧ㑇ఏẘᛶࡢཎᅉ࡜᥎ ࡉࢀࡿࢽࢺࣟᇶ ࢆ᭷ࡍࡿࢽࢺࣟࣇࣝࣇ࣮ࣛࣝ㸦NFA㸧࡟ࡘ࠸࡚㸪Nrf2+/+࠾ࡼࡧNrf2-/- gpt delta ࣐࢘ࢫࢆ⏝࠸ ࡚Ⓨࡀࢇᶆⓗ࡛࠶ࡿ⭈⮚࡟࠾ࡅࡿ㑇ఏᏊኚ␗ゎᯒࢆᐇ᪋ࡋࡓࠋNRF2 ࡢไᚚࢆཷࡅࡿᢠ㓟 ໬㓝⣲࡛࠶ࡿNQO1 ࡣ㸪ࡑࡢ㑇ఏᏊ࠾ࡼࡧ⺮ⓑ㉁ࡢⓎ⌧ࣞ࣋ࣝࡀ Nrf2+/+࣐࢘ࢫࡼࡾࡶNrf2 -/-࣐࢘ࢫ࡟࠾࠸࡚ⴭࡋࡃᑠࡉࡃ㸪Nrf2-/- gpt delta ࣐࢘ࢫࡀ㓟໬ࢫࢺࣞࢫ࡟ᑐࡋ࡚㧗ឤཷᛶࢆ♧ ࡍࡇ࡜ࡀ☜ㄆࡉࢀࡓࠋࡇࡢࡼ࠺࡞᮲௳ୗ࡛㸪Nrf2-/-࣐࢘ࢫ࡟ᑐࡋ࡚NFT ࢆ 70 mg/kg య㔜ࡢ ⏝㔞࡛⤒ཱྀᢞ୚ࡋࡓ࡜ࡇࢁ㸪⭈⮚࡟࠾࠸࡚8-OHdG ࡢቑຍࢆకࡗࡓ MFs ࡢቑຍࡀࡳࡽࢀࡓ ࡀ㸪ࡇࡢ᫬ࢢ࢔ࢽࣥሷᇶࡢ transversion ኚ␗ࢆ୺య࡜ࡋ࡚࠸ࡓࠋ୍᪉㸪NFA ࡣ 8-OHdG ࢆ ቑຍࡉࡏࡓࡀMFs ࡣቑຍࡉࡏ࡞࠿ࡗࡓࠋࡇࢀࡽࡢࡇ࡜࠿ࡽ㸪NFT ࡟ࡼࡿ㑇ఏẘᛶ࡟㓟໬ࢫ ࢺࣞࢫࡣ㛵୚ࡍࡿࡀNFA ࡣ㓟໬ࢫࢺࣞࢫࢆㄏⓎࡍࡿࡶࡢࡢ㑇ఏẘᛶ࡟⤖ࡧࡘ࠿࡞࠸ࡇ࡜㸪 ࡉࡽ࡟ࢽࢺࣟᇶ࡟ࡼࡿ㑇ఏẘᛶࡢⓎ⏕࡟ഃ㙐࡜ࡢ┦஫཯ᛂࡀᙳ㡪ࡋ࡚࠸ࡿࡇ࡜ࡀ♧၀ࡉࢀ ࡓࠋࡇࢀࡽࡢ⤖ᯝࡣ௒ᚋ㛤Ⓨࡉࢀࡿ᪂つࢽࢺࣟࣇࣛࣥ㢮ࡢࣜࢫࢡホ౯࡟ࡶ᭷⏝࡜⪃࠼ࡽࢀ ࡓࠋ ➨㸰❶࡛ࡣ㸪KBrO3࠾ࡼࡧNFT ࡟ࡼࡾㄏⓎࡉࢀࡿ㓟໬ࢫࢺࣞࢫ࡜ࡑࢀ࡟⥆ࡃ㑇ఏᏊኚ␗ ࡢ㛵㐃ࢆ᫂ࡽ࠿࡟ࡍࡿࡓࡵ㸪KBrO3࠾ࡼࡧNFT ࡟ࡘ࠸࡚ྠᵝࡢ᪉ἲ࡛㑇ఏᏊኚ␗ゎᯒ࠾ࡼ ࡧ8-OHdG  ᐃࢆᐇ᪋ࡋࡓࠋNqo1 ࡢⓎ⌧ࣞ࣋ࣝゎᯒ࡟࠾࠸࡚㸪Nrf2+/+࣐࢘ࢫ࡛ࡣ୧⪅ࡢᢞ ୚࡟ࡼࡾࡑࡢⓎ⌧ࡀ㢧ⴭ࡟ቑຍࡋࡓࡢ࡟ᑐࡋ㸪Nrf2-/-࣐࢘ࢫ࡛ࡣኚ໬ࡀࡳࡽࢀࡎ㸪ᢞ୚ࡢ᭷ ↓࡟࠿࠿ࢃࡽࡎNrf2+/+࣐࢘ࢫࡼࡾࡶప್ࢆ♧ࡋࡓࠋࡇࡢࡇ࡜࠿ࡽNrf2-/- gpt delta ࣐࢘ࢫࡣ ➨㸯❶࡜ྠᵝ࡟㓟໬ࢫࢺࣞࢫ࡟ᙉࡃ᭚㟢ࡉࢀ࡚࠸ࡿࡇ࡜ࡀ☜ㄆࡉࢀࡓࠋࡇࡢ࡜ࡁ㸪1,500 ppm ࡢ⏝㔞࡛ KBrO3 ࢆ㣧Ỉᢞ୚ࡍࡿ࡜㸪8-OHdG ࡢቑຍࢆకࡗ࡚Ḟኻኚ␗ࢆ୺య࡜ࡋ࡚ MFs ࡀ㢧ⴭ࡟ቑຍࡋ㸪ࡑࡢቑຍࡢ⛬ᗘࡣ Nrf2-/-࡟࠾࠸࡚Nrf2+/+ࡼࡾࡶ኱ࡁࡃ㸪ྠ᫬࡟Nrf2 -/-࣐࢘ࢫ࡛ࡣḞኻࢧ࢖ࢬࡢቑຍࡶࡳࡽࢀࡓࠋ୍᪉㸪2,500 ppm ࡢ⏝㔞࡛ NFT ࢆΰ㣵ᢞ୚ࡍࡿ ࡜㸪8-OHdG ࡢቑຍࢆకࢃࡎ࡟ࢢ࢔ࢽࣥሷᇶࡢ transversion ኚ␗ࢆ୺య࡜ࡋ࡚ MFs ࡢቑຍࡀ ࡳࡽࢀ㸪ࡇࡢ᫬ࡶࡑࡢቑຍࡢ⛬ᗘࡣ Nrf2-/-࡟࠾࠸࡚ Nrf2+/+ࡼࡾࡶ኱ࡁ࠿ࡗࡓࠋࡇࢀࡽࡢࡇ ࡜࠿ࡽ㸪KBrO3ࡢᙉ࠸㓟໬ຊ࡟㉳ᅉࡍࡿ8-OHdG ᙧᡂࡣ┤᥋ⓗ࡟Ḟኻኚ␗ࡢቑຍ࡟㛵୚ࡋ ࡚࠸ࡿࡇ࡜ࡀ♧၀ࡉࢀ㸪୍᪉࡛ NFT ࡟ࡼࡿࢢ࢔ࢽࣥሷᇶࡢ transversion ኚ␗࡟ࡣ 8-OHdG ௨እࡢ㓟໬ࢫࢺࣞࢫᅉᏊࡀ㛵୚ࡋ࡚࠸ࡿྍ⬟ᛶࡀ⪃࠼ࡽࢀࡓࠋ ᮏ◊✲࡛ࡣNrf2-/- gpt delta ࣐࢘ࢫࢆ⏝࠸ࡿࡇ࡜࡛㸪࡜ࡶ࡟㓟໬ࢫࢺࣞࢫࡢ㛵୚ࡋࡓ⭈Ⓨ ࡀࢇᶵᗎࡀ␲ࢃࢀࡿ NFT ࠾ࡼࡧ KBrO3࡟ࡘ࠸࡚㸪㓟໬ࢫࢺࣞࢫࡀࡑࢀࡒࢀ␗࡞ࡿᵝᘧ࡛ ኚ␗ཎᛶ࡟㛵୚ࡍࡿࡇ࡜ࢆ᫂ࡽ࠿࡟ࡋࡓࠋࡇࡢࡼ࠺࡟㸪㓟໬ࢫࢺࣞࢫ࡟㛵ࡍࡿࣜࢫࢡホ౯ ࡟࠾࠸࡚8-OHdG ᙧᡂࡀཬࡰࡍᙳ㡪ࡢ኱ࡁࡉࡣ㸪໬Ꮫ≀㉁ࡈ࡜࡟␗࡞ࡿ࡜⪃࠼ࡽࢀࡿࡇ࡜ ࠿ࡽ㸪㓟໬ࢫࢺࣞࢫࢆྵࡴヲ⣽࡞Ⓨࡀࢇᶵᗎࡢ᳨ウࡀ⎔ቃ୰໬Ꮫ≀㉁࡟ࡼࡿⓎࡀࢇࣜࢫࢡ ホ౯࡟ࡣ㔜せ࡛࠶ࡿ࡜⪃࠼ࡽࢀࡓࠋᮏ◊✲ࡢᡂᯝࡣ໬ᏛⓎࡀࢇ࡟࠾ࡅࡿ㓟໬ࢫࢺࣞࢫ࡟ࡘ ࠸࡚ࡢࡼࡾṇ☜࡞ࣜࢫࢡホ౯࡟㈉⊩ࡍࡿࡶࡢ࡛࠶ࡾ㸪㓟໬ࢫࢺࣞࢫ࡟㛵ࡍࡿ᭦࡞ࡿ◊✲ࢆ 㐍ࡵ࡚࠸ࡁࡓ࠸ࠋ 㣗ရ୰໬Ꮫ≀㉁ࡢⓎࡀࢇࣜࢫࢡホ౯ࡣ㸪බ⾗⾨⏕ୖ᭱ࡶ㔜せ࡞ၥ㢟ࡢ1 ࡘ࡛࠶ࡿࠋ㓟໬ ࢫࢺࣞࢫࡢᙳ㡪ࢆᙉࡃཷࡅࡿ⭈⮚࡛ࡣ㸪Ⓨࡀࢇ㐣⛬࡟࠾ࡅࡿ㓟໬ࢫࢺࣞࢫࡢ㛵୚ࡀከࡃሗ ࿌ࡉࢀ࡚࠸ࡿࠋࣛࢵࢺ࡟࠾ࡅࡿ⭈Ⓨࡀࢇ≀㉁࡛࠶ࡿࢽࢺࣟࣇࣛࣥࢺ࢖ࣥ㸦NFT㸧࠾ࡼࡧ⮯ ⣲㓟࣒࢝ࣜ࢘㸦KBrO3㸧ࡣ㸪࠸ࡎࢀࡶ⭈⮚࡟࠾࠸࡚㓟໬ⓗDNA ᦆയࡢ㸯ࡘ࡛࠶ࡿ 8-OHdG ࡢቑຍࢆకࡗ࡚㑇ఏᏊኚ␗㢖ᗘ㸦MFs㸧ࢆቑຍࡉࡏࡿࡀ㸪ࡑࢀࡽࡣࡑࢀࡒࢀ transversion ኚ

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␗࡜Ḟኻኚ␗ࢆ୺࡟ㄏᑟࡍࡿࠋࡑࡇ࡛ᮏ◊✲࡛ࡣ㸪㓟໬ࢫࢺࣞࢫ࡟㧗ឤཷᛶ࡛ୟࡘin vivo ኚ␗ཎᛶࢆ᳨ฟฟ᮶ࡿNrf2-/- gpt delta ࣐࢘ࢫࢆ⏝࠸࡚ 2 ๣࡟ࡼࡿኚ␗ཎᛶ࡟࠾ࡅࡿ㓟໬ࢫ ࢺࣞࢫࡢ㛵୚ࢆ᳨ウࡋࡓࠋ ➨㸯❶࡛ࡣ㸪NFT ࡜ࡑࡢᇶᮏ㦵᱁࡛࠶ࡿࢽࢺࣟࣇࣝࣛࣝ㸦NFA㸧࡟ࡘ࠸࡚㑇ఏᏊኚ␗ゎ ᯒࢆᐇ᪋ࡋࡓࠋࡑࡢ⤖ᯝ㸪Nrf2-/-࣐࢘ࢫ࡟࠾࠸࡚㸪NFT ࡣ 8-OHdG ࡢቑຍࢆకࡗ࡚ transversion ኚ␗ࢆ୺య࡜ࡋ࡚MFs ࢆቑຍࡉࡏࡓࡀ㸪 NFA ࡣ 8-OHdG ࢆቑຍࡉࡏࡓࡀ MFs ࡣቑຍࡉࡏ ࡞࠿ࡗࡓࠋࡇࢀࡽࡢࡇ࡜࠿ࡽ㸪NFT ࡟ࡼࡿ㑇ఏẘᛶ࡟㓟໬ࢫࢺࣞࢫࡣ㛵୚ࡍࡿࡀ NFA ࡣ ཧຍࢫࢺࣞࢫࢆㄏⓎࡍࡿࡶࡢࡢ㸪㑇ఏẘᛶ࡟⤖ࡧࡘ࠿࡞࠸ࡇ࡜㸪ࡉࡽ࡟ࢽࢺࣟᇶ࡟ࡼࡿ㑇 ఏẘᛶࡢⓎ⏕࡟ഃ㙐࡜ࡢ┦஫཯ᛂࡀᙳ㡪ࡋ࡚࠸ࡿࡇ࡜ࡀ♧၀ࡉࢀࡓࠋ ➨㸰❶࡛ࡣ㸪KBrO3ཬࡧ NFT ࡟ࡼࡾㄏⓎࡉࢀࡿ㓟໬ࢫࢺࣞࢫ࡜ࡑࢀ࡟⥆ࡃ㑇ఏᏊኚ␗ ࡢ㛵㐃ࢆ᳨ウࡋࡓࠋࡇࡢ࡜ࡁ Nrf2-/-࣐࢘ࢫ࡟࠾࠸࡚㸪KBrO3ᢞ୚࡟ࡼࡾ 8-OHdG ࡢቑຍࢆ కࡗ࡚Ḟኻኚ␗ࡀNrf2+/+࣐࢘ࢫࡼࡾࡶቑຍࡋ㸪ྠ᫬࡟Ḟኻࢧ࢖ࢬࡢቑຍࡶࡳࡽࢀࡓࠋࡇࢀ ࡟ᑐࡋNFT ᢞ୚⩌࡛ࡣ㸪8-OHdG ࡢቑຍࢆకࢃࡎ࡟ transversion ኚ␗ࢆ୺య࡜ࡋ࡚ MFs ࡀ ࡼࡾቑຍࡋࡓࠋࡇࢀࡽࡢࡇ࡜࠿ࡽ㸪KBrO3ࡢᙉ࠸㓟໬ຊ࡟㉳ᅉࡍࡿ 8-OHdG ᙧᡂࡣ┤᥋ⓗ ࡟Ḟኻኚ␗ࡢቑຍ࡟㛵୚ࡋ࡚࠸ࡿࡇ࡜ࡀ♧၀ࡉࢀ㸪୍᪉࡛ NFT ࡟ࡼࡿ transversion ኚ␗࡟ ࡣ8-OHdG ௨እࡢ㓟໬ࢫࢺࣞࢫᅉᏊࡀ㛵୚ࡋ࡚࠸ࡿྍ⬟ᛶࡀ⪃࠼ࡽࢀࡓࠋ ᮏ◊✲࡟ࡼࡾ㸪NFT ࠾ࡼࡧ KBrO3࡟ࡼࡿኚ␗ཎᛶ࡟࠾࠸࡚㓟໬ࢫࢺࣞࢫࡀࡑࢀࡒࢀ␗ ࡞ࡿ㛵୚ࡢᵝᘧࢆ♧ࡍࡇ࡜ࡀ᫂ࡽ࠿࡟࡞ࡗࡓࠋᮏ◊✲ࡢᡂᯝࡣ໬ᏛⓎࡀࢇ࡟࠾ࡅࡿ㓟໬ࢫ ࢺࣞࢫ࡟ࡘ࠸࡚ࡢࡼࡾṇ☜࡞ࣜࢫࢡホ౯࡟㈉⊩ࡍࡿࡶࡢ࡛࠶ࡿࠋ   ௨ୖ࡟ࡘ࠸࡚㸪ᑂᰝጤဨ඲ဨ୍⮴࡛ᮏㄽᩥࡀᒱ㜧኱Ꮫ኱Ꮫ㝔㐃ྜ⋇་Ꮫ◊✲⛉ࡢᏛ఩ㄽ ᩥ࡜ࡋ࡚༑ศ౯್ࡀ࠶ࡿ࡜ㄆࡵࡓࠋ  ᇶ♏࡜࡞ࡿᏛ⾡ㄽᩥ 㸯㸧㢟   ┠㸸5ROHRIR[LGDWLYHVWUHVVLQWKHFKHPLFDOVWUXFWXUHUHODWHG JHQRWR[LFLW\RIQLWURIXUDQWRLQLQ1UIGHILFLHQWJSWGHOWDPLFH   ⴭ ⪅ ྡ㸸7VXFKL\D7.LMLPD$,VKLL<7DNDVX6<RNRR<1LVKLNDZD$ <DQDL7DQG8PHPXUD7   Ꮫ⾡㞧ㄅྡ㸸-RXUQDORI7R[LFRORJLF3DWKRORJ\   ᕳ࣭ྕ࣭㡫࣭Ⓨ⾜ᖺ㸸㸦㸧㸸㸪,QSUHVV  㸰㸧㢟   ┠㸸0HFKDQLVPVRIR[LGDWLYHVWUHVVLQGXFHGLQYLYRPXWDJHQLFLW\E\ SRWDVVLXPEURPDWHDQGQLWURIXUDQWRLQ   ⴭ ⪅ ྡ㸸7VXFKL\D7.LMLPD$,VKLL<7DNDVX6<RNRR<1LVKLNDZD$ <DQDL7DQG8PHPXUD7   Ꮫ⾡㞧ㄅྡ㸸-RXUQDORI7R[LFRORJLF3DWKRORJ\   ᕳ࣭ྕ࣭㡫࣭Ⓨ⾜ᖺ㸸㸦㸧㸸㸪,QSUHVV  ᪤Ⓨ⾲Ꮫ⾡ㄽᩥ 㸯㸧㢟   ┠㸸$PHGLXPWHUPJSWGHOWDUDWPRGHODVDQLQYLYRV\VWHPIRUDQDO\VLV RIUHQDOFDUFLQRJHQHVLVDQGWKHXQGHUO\LQJPRGHRIDFWLRQ   ⴭ ⪅ ྡ㸸0DWVXVKLWD.,VKLL<7DNDVX6.XURGD..LMLPD$ 7VXFKL\D7.DZDJXFKL+0L\RVKL11RKPL72JDZD. 1LVKLNDZD$DQG8PHPXUD7   Ꮫ⾡㞧ㄅྡ㸸([SHULPHQWDODQG7R[LFRORJLF3DWKRORJ\

(5)

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