Development of risk assessment method on brain development focusing on aberrant regulation of DNA methylation
| Project/Area Number |
18H02341
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Review Section |
Basic Section 42020:Veterinary medical science-related
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| Research Institution | Tokyo University of Agriculture and Technology |
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Principal Investigator |
Shibutani Makoto 東京農工大学, (連合)農学研究科(研究院), 卓越教授 (20311392)
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| Co-Investigator(Kenkyū-buntansha) |
佐藤 薫 国立医薬品食品衛生研究所, 薬理部, 室長 (10311391)
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000)
Fiscal Year 2020: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2019: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
Fiscal Year 2018: ¥7,540,000 (Direct Cost: ¥5,800,000、Indirect Cost: ¥1,740,000)
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| Keywords | In vivo発達神経毒性試験法 / 化学物質リスク / 海馬神経新生 / DNAメチル化異常 / 簡易スクリーニング法 |
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| Outline of Final Research Achievements |
To acquire in vivo biomarkers for irreversible developmental neurotoxicity, next-generation sequencing analysis of genes showing promoter hypermethylation and transcript-level downregulation was performed in the hippocampal dentate gyrus of rats irreversibly disrupting neurogenesis after developmental exposure to three different irreversible developmental neurotoxicants. A total of eight genes were obtained by means of the validation analysis in terms of methylation and gene expression of the obtained candidate genes, and neurogranin, which irreversibly reduced immunoreactive cell number, was identified.
In addition, we clarified the toxicity targets and mechanisms of disruptive neurogenesis caused by developmental exposure and repeated postpubertal treatment of developmental neurotoxicants critically important in humans using rats.
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| Academic Significance and Societal Importance of the Research Achievements |
現在までに確立してきた既知の神経新生指標を用いた神経新生障害評価系に加え、メチル化に端を発する不可逆的な発達神経毒性を検出可能なバイオマーカーを獲得したことにより、病理発生を基盤とする評価法の体系化に資する情報が得られた。更に、一般毒性試験の枠組みでの検出性の証明により、発達神経毒性の簡便な不可逆影響スクリーニングが可能となり、新たなスクリーニング試験ガイドラインの策定のみならず、今後の化学物質管理の高度化に資する。
また、ヒト重要脳発達障害物質について、発達神経毒性ガイドラインに準拠した曝露により、不可逆性を含む発達神経毒性が明らかとなり、リスク評価資料としての活用が期待される。
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Report
(4 results)
Research Products
(13 results)
