2020 Fiscal Year Final Research Report

Establishment of Novel Bioassays for in vivo Genotoxicity Prediction and Mechanism Characterization

Research Project

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Project/Area Number	16H06306
Research Category	Grant-in-Aid for Scientific Research (S)
Allocation Type	Single-year Grants
Research Field	Risk sciences of radiation and chemicals
Research Institution	Kyoto University
Principal Investigator	Takeda Shunichi 京都大学, 医学研究科, 教授 (60188191)
Co-Investigator(Kenkyū-buntansha)	廣田耕志東京都立大学, 理学研究科, 教授 (00342840) 笹沼博之京都大学, 医学研究科, 准教授 (00531691) 安井学国立医薬品食品衛生研究所, 変異遺伝部, 室長 (50435707) Brown John 京都大学, 医学研究科, 講師 (90583188) 津田雅貴京都大学, 医学研究科, 特定助教 (00734104)
Project Period (FY)	2016-05-31 – 2021-03-31
Keywords	トキシコロジー / 人体有害物質 / 遺伝毒物学 / 発がん物質 / 変異原 / TK6細胞 / ケモインフォマティクス
Outline of Final Research Achievements	We have achieved the following results. First, we created DNA repair enzyme-deficient TK6 strains and have successfully increased by over several times the sensitivity of the thymidine kinase (TK) mutation test stipulated in the Chemical Substances Control Law more than fivefold. We have been creating TK6 mutant strains for rapidly classifying mutagenic chemicals according to their mutagenic mechanisms. We have shown the list of TK6 mutant strains on the TK6 Consortium website and deposited the Riken Biobank. In terms of elucidating new mechanisms for genotoxicity and mutagenicity, we have obtained the following results. We discovered a pathway to repair sex hormone-induced DNA damage and demonstrated that sex hormones are highly genotoxic to epithelial cells in the mammary gland and prostate in the absence of this newly identified pathway. We also discovered a novel DNA damage repair pathway that suppresses formalin-induced mutagenicity.
Free Research Field	有害化学物質を合理的に規制する方法の開発
Academic Significance and Societal Importance of the Research Achievements	学術的意義は、性ホルモン及び環境ホルモンの発癌性に関する学術的意義と、新規DNA損傷修復経路を発見である（Saha LK. et al., 2020）。社会的意義は、in silico毒性予測への貢献と、変異原性の作用機序を正確に解明するシステムを構築したことにある。