Studies on quantitative evaluation of inherited germline mutations

• Project/Area Number: 25281027
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Risk sciences of radiation and chemicals
• Research Institution: National Institute of Health Sciences
• Principal Investigator: Masumura Kenichi 国立医薬品食品衛生研究所, 変異遺伝部, 室長 (40291116)
• Co-Investigator(Renkei-kenkyūsha): NOHMI Takehiko 国立医薬品食品衛生研究所, 安全性生物試験研究センター, 客員研究員 (30150890) ; HONMA Masamitsu 国立医薬品食品衛生研究所, 変異遺伝部, 部長 (30250179) ; TOYODA Naomi (HOKAIWADO Naomi) 国立医薬品食品衛生研究所, 変異遺伝部, 非常勤職員 (70381853)
• Project Period (FY): 2013-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥18,460,000 (Direct Cost: ¥14,200,000、Indirect Cost: ¥4,260,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2015: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2014: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2013: ¥7,800,000 (Direct Cost: ¥6,000,000、Indirect Cost: ¥1,800,000)
• Keywords: 遺伝毒性 / ゲノム / 次世代影響 / 遺伝子突然変異 / 環境変異原 / 次世代シークエンサー / 生殖細胞突然変異 / トランスジェニックマウス遺伝子突然変異試験

Outline of Final Research Achievements

De novo germline mutations and their health effects in next generation are important in genetic toxicology. Inherited germline mutations in mice induced by N-ethyl-N-nitrosourea (ENU) were analyzed by whole-exome sequencing. Male gpt delta mice were treated with ENU　and mated with untreated females. ENU-treated and control families were used for whole-exome sequencing. Single nucleotide variants (SNVs) and de novo mutations in the offspring were detected. Frequencies of inherited mutations increased with dosage. The result suggests that direct sequencing analysis may be a useful tool to investigate inherited germline mutations induced by environmental mutagens.

Research Products

• [Journal Article] Transgenic rat models for mutagenesis and carcinogenesis (2017)
  • Author(s): Nohmi T, Masumura K, Toyoda-Hokaiwado N.
  • Journal Title: Genes and Environment Volume: 39 Issue: 1 Pages: 11-11
  • DOI: 10.1186/s41021-016-0072-6
  • Peer Reviewed / Open Access
• [Journal Article] Dose-dependent de novo germline mutations detected by whole-exome sequencing in progeny of ENU-treated male gpt delta mice. (2016)
  • Author(s): Masumura K,Toyoda-Hokaiwado N, Ukai A, Gondo Y, Honma M, Nohmi T
  • Journal Title: Mutation Research Volume: 810 Pages: 30-39
  • DOI: 10.1016/j.mrgentox.2016.09.009
  • Peer Reviewed / Open Access
• [Journal Article] Evaluation of the sensitivity and specificity of in vivo erythrocyte micronucleus and transgenic rodent gene mutation tests to detect rodent carcinogens (2016)
  • Author(s): Morita T , Hamada S, Masumura K, Wakata A, Maniwa J, Takasawa H, Yasunaga K, Hashizume, T, Honma M.
  • Journal Title: Mutation Research Volume: 802 Pages: 1-29
  • DOI: 10.1016/j.mrgentox.2016.03.008
  • Peer Reviewed / Open Access
• [Journal Article] Estimation of the frequency of inherited germline mutations by whole exome sequencing in ethyl nitrosourea-treated and untreated gpt delta mice. (2016)
  • Author(s): Masumura K, Toyoda-Hokaiwado N, Ukai A, Gondo Y, Honma M, Nohmi T
  • Journal Title: Genes and Environment Volume: 38 Issue: 1 Pages: 10-10
  • DOI: 10.1186/s41021-016-0035-y
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Genomic integration of lambda EG10 transgene in gpt delta transgenic rodents (2015)
  • Author(s): Masumura K, Sakamoto Y, Kumita W, Honma M, Nishikawa A, Nohmi T.
  • Journal Title: Genes and Environment Volume: 37 Issue: 1 Pages: 24-24
  • DOI: 10.1186/s41021-015-0024-6
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Alterations in the mutagenicity and mutation spectrum induced by benzo[a]pyrene instilled in the lungs of gpt delta mice of various ages (2015)
  • Author(s): Aoki Y, Akiko A, Sugawara Y, Hiyoshi-Arai K, Goto S, Masumura K, Nohmi T.
  • Journal Title: Genes and Environment Volume: 37 Issue: 1 Pages: 7-7
  • DOI: 10.1186/s41021-015-0004-x
  • Peer Reviewed / Open Access
• [Journal Article] Role of p53 in the progression from ochratoxin A-induced DNA damage to gene mutations in the kidneys of mice. (2015)
  • Author(s): Kuroda K, Hibi D, Ishii Y, Yokoo Y, Takasu S, Kijima A, Matsushita K, Masumura K, Kodama Y, Yanai T, Sakai H, Nohmi T, Ogawa K, Umemura T.
  • Journal Title: Toxicol Sci. Volume: 144 Issue: 1 Pages: 65-76
  • DOI: 10.1093/toxsci/kfu267
  • Peer Reviewed
• [Journal Article] In vivo evidence that DNA polymerase kappa is responsible for error-free bypass across DNA cross-links induced by mitomycin C. (2014)
  • Author(s): Takeiri A, Wada NA, Motoyama S, Matsuzaki K, Tateishi H, Matsumoto K, Niimi N, Sassa A, Grúz P, Masumura K, Yamada M, Mishima M, Jishage KI, Nohmi T.
  • Journal Title: DNA Repair Volume: 24 Pages: 113-121
  • DOI: 10.1016/j.dnarep.2014.09.002
  • Peer Reviewed / Open Access
• [Journal Article] Genotoxicity of phenacetin in the kidney and liver of Sprague-Dawley gpt delta transgenic rats in 26-week and 52-week repeated-dose studies. (2014)
  • Author(s): Kawamura Y, Hayashi H, Masumura K, Numazawa S, Nohmi T.
  • Journal Title: Toxicology Volume: 324 Pages: 10-17
  • DOI: 10.1016/j.tox.2014.07.003
  • Peer Reviewed / Open Access
• [Journal Article] Ochratoxin A induces DNA double-strand breaks and large deletion mutations in the carcinogenic target site of gpt delta rats (2014)
  • Author(s): K. Kuroda, D. Hibi, Y. Ishii, S. Takasu, A. Kijima, K. Matsushita, K. Masumura, M. Watanabe, Y. Sugita-Konishi, H. Sakai, T. Yanai, T. Nohmi, K. Ogawa and T. Umemura
  • Journal Title: Mutagenesis Volume: 29 Issue: 1 Pages: 27-36
  • DOI: 10.1093/mutage/get054
  • Peer Reviewed
• [Journal Article] Evaluation of in vivo genotoxicity induced by N-ethyl-N-nitrosourea, benzo[a]pyrene, and 4-nitroquinoline-1-oxide in the Pig-a and gpt assays (2013)
  • Author(s): K. Horibata, A. Ukai, T. Kimoto, T. Suzuki, N. Kamoshita, K. Masumura, T. Nohmi and M. Honma
  • Journal Title: Environ. Mol. Mutagen. Volume: 54 Issue: 9 Pages: 747-754
  • DOI: 10.1002/em.21818
  • Peer Reviewed
• [Journal Article] Evaluation of the genotoxicity of tamoxifen in the liver and kidney of F344 gpt delta transgenic rat in 3-week and 13-week repeated dose studies (2013)
  • Author(s): Y. Kawamura, H. Hayashi, Y. Kurata, K. Hirasuka, K. Masumura and T. Nohmi
  • Journal Title: Toxicol. Volume: 312 Pages: 56-62
  • DOI: 10.1016/j.tox.2013.07.014
  • Peer Reviewed
• [Presentation] 全エキソーム解析を用いたENU 投与雄マウスの次世代個体における生殖細胞系列突然変異頻度の測定 (2016)
  • Author(s): 増村健一，鵜飼明子，豊田尚美，権藤洋一，能美健彦，本間正充
  • Organizer: 日本環境変異原学会第45回大会
  • Place of Presentation: つくば国際会議場
  • Year and Date: 2016-11-17
• [Presentation] Estimation of the frequency of inherited germline mujtations by whole-exome sequencing in ethylnitrosourea-treated gpt delta mice (2016)
  • Author(s): Masumura K, Toyoda-Hokaiwado N, Ukai A, Gondo Y, Honma M, Nohmi T
  • Organizer: 47th Annual Meeting of Environmental Mutagenesis and Genomics Society
  • Place of Presentation: Westin Kansas City at Crown center
  • Year and Date: 2016-09-24
  • Int'l Joint Research
• [Presentation] Analysis of inherited germline mutations of ENU-treated mice by whole exome sequencing (2016)
  • Author(s): Masumura K, Toyoda-Hokaiwado N, Ukai A, Gondo Y, Honma M, Nohmi T
  • Organizer: Society of Toxicology 55th Annual meeting
  • Place of Presentation: New Orleans Ernest N. Morial Convention Center, LA, USA
  • Year and Date: 2016-03-13
  • Int'l Joint Research
• [Presentation] マウス肝発がん物質を用いた遺伝毒性および発がん性の定量的分析に関する研究 (2016)
  • Author(s): 増村健一，本間正充
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜
• [Presentation] ゲノム解析による経世代突然変異の検出 (2016)
  • Author(s): 増村健一
  • Organizer: 平成28年度日本環境変異原学会公開シンポジウム
  • Place of Presentation: がん研究振興財団国際交流会館
  • Invited
• [Presentation] アクリルアミドの生殖細胞における変異原性の検討 (2015)
  • Author(s): 増村健一
  • Organizer: 日本環境変異原学会第44回大会
  • Place of Presentation: 九州大学馬出キャンパス
  • Year and Date: 2015-11-27
  • Invited
• [Presentation] DNA polymerase kappaはin vivoにおいて、cisplatinに対する損傷乗越えDNA複製に関与する (2015)
  • Author(s): 本山茂記、竹入章、松尾沙織里、和田直子、寺社下浩一、三島雅之、新見直子、Petr Gruz、増村健一、山田雅巳、能美健彦
  • Organizer: 日本環境変異原学会第44回大会
  • Place of Presentation: 九州大学馬出キャンパス
  • Year and Date: 2015-11-27
• [Presentation] gpt deltaマウスの生殖細胞におけるアクリルアミド誘発突然変異の解析 (2015)
  • Author(s): 萩尾宗一郎、阿部正義、林清吾、辻菜穂、黒田雄介、古川賢、八木孝司、本間正充、増村健一
  • Organizer: 日本環境変異原学会第44回大会
  • Place of Presentation: 九州大学馬出キャンパス
  • Year and Date: 2015-11-27
• [Presentation] マウス全エキソーム解析によるENU誘発生殖細胞変異スペクトルの解析 (2015)
  • Author(s): 増村健一、鵜飼明子、豊田尚美、権藤洋一、能美健彦、本間正充
  • Organizer: 日本環境変異原学会第44回大会
  • Place of Presentation: 九州大学馬出キャンパス
  • Year and Date: 2015-11-27
• [Presentation] In vitroおよびin vivo遺伝毒性試験の組合せによる齧歯類発がん物質の検出力 (2015)
  • Author(s): 森田健、濱田修一、増村健一、本間正充
  • Organizer: 日本環境変異原学会第44回大会
  • Place of Presentation: 九州大学馬出キャンパス
  • Year and Date: 2015-11-27
• [Presentation] 都市大気浮粒子抽出物がgpt deltaマウス肺で示す変異原性と突然変異スペクトル (2015)
  • Author(s): 青木康展、中島大介、松本みちよ、松本理、柳澤利枝、後藤純雄、増村健一、能美健彦
  • Organizer: 日本環境変異原学会第44回大会
  • Place of Presentation: 九州大学馬出キャンパス
  • Year and Date: 2015-11-27
• [Presentation] ICHガイドラインS2（R1）におけるin vivo試験組合せの検討 (2015)
  • Author(s): 山田雅巳、大杉直弘、髙木久宜、和田邦生、松元郷六、大隅友香、真田尚和、百南綾華、堤絵梨、堀妃佐子、赤沼三恵、増村健一、本間正充
  • Organizer: 日本環境変異原学会第44回大会
  • Place of Presentation: 九州大学馬出キャンパス
  • Year and Date: 2015-11-27
• [Presentation] トランスジェニック動物遺伝子突然変異試験におけるin vivo変異原性と発がん性の相関に関する研究 (2015)
  • Author(s): 増村健一，森田健，本間正充
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場
  • Year and Date: 2015-10-08
• [Presentation] Detection of rodent carcinogens and non-carcinogens by in vivo erythrocyte micronucleus and transgenic rodent mutation tests (2015)
  • Author(s): Morita T, Hamada S, Masumura K, Honnma M
  • Organizer: 44th Annual Meeting of European Environmental Mutagenesis and Genomics Society
  • Place of Presentation: Clarion Congress Hotel, Prague, Czech Republic
  • Year and Date: 2015-08-23
  • Int'l Joint Research
• [Presentation] gpt deltaマウスを用いたアクリルアミドの生殖細胞遺伝子突然変異の解析 (2015)
  • Author(s): 萩尾宗一郎，小川いづみ，阿部正義，林清吾，辻菜穂，黒田雄介，古川賢，八木孝司，本間正充，増村健一
  • Organizer: 第42回日本毒性学会学術年会
  • Place of Presentation: 石川県立音楽堂
  • Year and Date: 2015-06-29
• [Presentation] Sensitivity of inactivated DNA polymerase kappa knock-in mice to mitomycin C (2015)
  • Author(s): Takeiri A, Naoko AW, Motoyama S, Matsuzaki K, Tateishi H, Matsumoto K, Niimi N, Sassa A, Grúz P, Masumura K, Yamada M, Mishima M, Jishage K, Nohmi T
  • Organizer: The 7th International Congress of Asian Society of Toxicology
  • Place of Presentation: International Convention Center Jeju Island, South Korea
  • Year and Date: 2015-06-23
  • Int'l Joint Research
• [Presentation] Point mutations and deletions induced by aging in liver of gpt delta transgenic rats (2014)
  • Author(s): Masumura K, Toyoda-Hokaiwado N, Ishii Y, Umemura T, Honma M, Nishikawa A, Nohmi T
  • Organizer: 4th Asian Conference on Environmental Mutagens
  • Place of Presentation: CSIR-Indian Institute of Chemical Biology, Kolkata, India
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] マウス全エクソンシークエンス解析による経世代突然変異の測定 (2014)
  • Author(s): 増村健一，豊田尚美，権藤洋一，能美健彦，本間正充
  • Organizer: 日本環境変異原学会第43回大会
  • Place of Presentation: 一橋講堂
  • Year and Date: 2014-12-04 – 2014-12-05
• [Presentation] gpt deltaマウスを用いたアクリルアミドの生殖細胞に対する遺伝毒性評価 (2014)
  • Author(s): 萩尾宗一郎，小川いづみ，阿部正義，林清吾，辻菜穂，黒田雄介，古川賢，八木孝司，本間正充，増村健一
  • Organizer: 日本環境変異原学会第43回大会
  • Place of Presentation: 一橋講堂
  • Year and Date: 2014-12-04 – 2014-12-05
• [Presentation] DMHを用いたF344系統gpt deltaラット突然変異試験と小核試験(末梢血，骨髄，肝臓，大腸)の統合法の検討 (2014)
  • Author(s): 堀妃佐子，田中康浩，堤絵梨，百南綾香，増村健一，山田雅巳，藤居亙，北川義徳
  • Organizer: 日本環境変異原学会第43回大会
  • Place of Presentation: 一橋講堂
  • Year and Date: 2014-12-04 – 2014-12-05
• [Presentation] ベンゾ[a]ピレンを気管内投与したgpt deltaマウス肺中に誘導された突然変異の加齢に伴う変化 (2014)
  • Author(s): 青木康展，橋本顕子，菅原良樹，荒井孝子，後藤佐多良、増村健一，能美健彦
  • Organizer: 日本環境変異原学会第43回大会
  • Place of Presentation: 一橋講堂
  • Year and Date: 2014-12-04 – 2014-12-05
• [Presentation] Mitomycin CによるDNA損傷に対するDNA polymerase kappaの役割 -γH2AXを指標にした免疫組織学的解析 (2014)
  • Author(s): 本山茂記，竹入章，松尾沙織里，和田直子，寺社下浩一，三島雅之，新見直子，Petr Grúz，増村健一，山田雅巳，能美健彦
  • Organizer: 日本環境変異原学会第43回大会
  • Place of Presentation: 一橋講堂
  • Year and Date: 2014-12-04 – 2014-12-05
• [Presentation] gpt deltaラットの加齢により誘発される点突然変異および欠失変異の解析 (2014)
  • Author(s): 増村健一，豊田尚美，石井雄二，梅村隆志，能美健彦，西川秋佳，本間正充
  • Organizer: 第37回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] gpt deltaマウスを用いた加齢に伴い蓄積する遺伝子突然変異の解析 (2014)
  • Author(s): 増村健一，大杉直弘，豊田尚美，能美健彦，本間正充
  • Organizer: 日本進化学会第16回大会
  • Place of Presentation: 高槻現代劇場
  • Year and Date: 2014-08-21 – 2014-08-24
• [Presentation] トランスジェニック動物を用いた遺伝子突然変異試験の動向 (2014)
  • Author(s): 増村健一
  • Organizer: MMS研究会第64回定例会
  • Place of Presentation: 熱海 森の温泉ホテル
  • Year and Date: 2014-06-20 – 2014-06-21
  • Invited
• [Presentation] gpt deltaマウスを用いたENU誘発突然変異と全エクソンシークエンスによる経世代変異の検出 (2013)
  • Author(s): 増村健一，豊田尚美，権藤洋一，能美健彦，本間正充
  • Organizer: 日本環境変異原学会第42回大会
  • Place of Presentation: 岡山コンベンションセンター（岡山県岡山市）
• [Presentation] Spontaneous point mutations and deletions increased with aging in gpt delta transgenic mice and rats (2013)
  • Author(s): Masumura K, Toyoda-Hokaiwado N, Osugi N, Ishii Y, Umemura T, Takagi H, Nishikawa A, Nohmi T, Honma M
  • Organizer: 11th International Conference on Environmental Mutagens
  • Place of Presentation: Bourbon Cataratas Convention & Spa Resort, Foz do Iguazu, Brazil
• [Presentation] gpt deltaラット肝臓における自然突然変異および加齢に伴う変異蓄積の検討 (2013)
  • Author(s): 増村健一，豊田尚美，石井雄二，梅村隆志，能美健彦，西川秋佳，本間正充
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
• [Presentation] MitomycinCによるDNA二本鎖切断誘発に対するDNA polymerase kappaのin vivoにおける役割 (2013)
  • Author(s): 本山茂記，竹入章，松尾沙織里，和田直子，寺社下浩一，三島雅之，新見直子，Gruz P，増村健一，山田雅巳，能美健彦
  • Organizer: 日本環境変異原学会第42回大会
  • Place of Presentation: 岡山コンベンションセンター（岡山県岡山市）
• [Presentation] 臭素酸カリウムがgpt deltaマウス小腸で誘導する突然変異の閾値と変異スペクトルの用量依存性変化 (2013)
  • Author(s): 青木康展，松本みちよ，松本理，増村健一，續輝久，能美健彦
  • Organizer: 日本環境変異原学会第42回大会
  • Place of Presentation: 岡山コンベンションセンター（岡山県岡山市）
• [Presentation] F344系gpt deltaラットを用いた突然変異試験と小核試験（末梢血，骨髄，肝臓，大腸）の統合法の検討 (2013)
  • Author(s): 堀妃佐子，田中康浩，増村健一，山田雅巳，藤居亙
  • Organizer: 日本環境変異原学会第42回大会
  • Place of Presentation: 岡山コンベンションセンター（岡山県岡山市）
• [Presentation] Aging and accumulation of gene mutations: Identification of spontaneous mutations in the tissues of gpt delta transgenic mice
  • Author(s): Masumura K
  • Organizer: National Cancer Forum 2013
  • Place of Presentation: Centara Grand at Central Plaza Ladprao, Bangkok, Thailand
  • Invited
• [Presentation] 第6回IWGT報告およひ共同研究進捗報告：生殖細胞に影響を及ぼす変異原の同定
  • Author(s): 増村健一
  • Organizer: 日本環境変異原学会MMS研究会第63回定例会
  • Place of Presentation: 就実大学（岡山県岡山市）
• [Book] 衛生試験法・注解2015，1.3 遺伝毒性試験法，1.3.3げっ歯類を用いる試験，(2)トランスジェニック動物遺伝子突然変異試験 (2015)
  • Author(s): 増村健一
  • Total Pages: 1300
  • Publisher: （公社）日本薬学会編，金原出版（株）