| Project/Area Number |
19K17339
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 52050:Embryonic medicine and pediatrics-related
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| Research Institution | Ohu University |
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Principal Investigator |
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| Project Period (FY) |
2019-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2020: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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| Keywords | 過剰肋骨 / 催奇形性 / 骨格異常 / 先天異常 / ホメオボックス / 系統差 |
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| Outline of Research at the Start |
過剰肋骨は催奇形性試験で胎仔に観察される骨格所見であるが、その成因は不明であり、リスク評価上の課題となっている。申請者はこれまで薬剤誘発性モデルラットを構築し、ホメオボックス遺伝子が成因である可能性を突き止めた。本研究は自然発生性に過剰肋骨を生じるラット系統の解析等を行い、その成因を明らかにすることで、先天異常の機序解明と毒性試験やリスク評価への貢献を目指すものである。
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| Outline of Final Research Achievements |
Oral administration of 5-Fluorocytosine (5FC) to pregnant rats on GD9 and 13 was shown to induce thoracolumbar supernumerary ribs and abnormal digits, respectively, with the changes in the expression of Homeobox(Hox) genes in fetuses. Because the abnormalities of digits were severe and the expression of cyclin genes were changed, we conducted in vitro evaluations. Cytotoxicity and the changes of expressions of cyclin genes shown with 5FU, the positive target, were not observed. Therefore, the onset of skeletal abnormalities with 5FC were not directly caused by apoptosis induced toxicity.
Next, we conducted to elucidate by sequence analysis rat strains (Wistar / SD). Although no significant differences were observed in most sites of Hox genes, a significant difference was shown in a certain region, which overlaps with a miRNA that negatively regulate the expression of multiple Hox genes and control posteriorization of axial skeleton with regulating the expression of multiple Hox genes.
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| Academic Significance and Societal Importance of the Research Achievements |
医薬品や農薬、食品添加物などは有害性に関する各種毒性試験がなされ、その一つに生殖発生毒性試験がある。そこで生殖や形態などが観察されるが、骨格異常のひとつである過剰肋骨はその成因は不明であり安全性評価の課題となっていた。
本研究はこれまでのモデル動物を用いた研究に加え、培養細胞を用いた評価および過剰肋骨の自然発生が多い系統と少ない系統の比較検討を行い、その毒性学的意義を多角的に考察した。
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