| Project/Area Number |
09480128
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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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| Research Field |
環境影響評価(含放射線生物学)
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| Research Institution | University of Occupational and Environmental Health |
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Principal Investigator |
NORIMURA Toshiyuki Univ. Occup. & Environm. Health, Sci. Med, Professor, 医学部, 教授 (20039530)
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| Co-Investigator(Kenkyū-buntansha) |
NOMOTO Satoshi Univ. Occup. & Environm. Health, Sci. Med, Professor, 医学部, 助手 (90258608)
OOTSUYAMA Akira Univ. Occup. & Environm. Health, Sci. Med, Associate Professor, 医学部, 助教授 (10194218)
KATO Fumio Univ. Occup. & Environm. Health, Sci. Med, Research Associate, 医学部, 助手 (20309959)
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| Project Period (FY) |
1997 – 1999
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| Project Status |
Completed (Fiscal Year 1999)
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| Budget Amount *help |
¥7,200,000 (Direct Cost: ¥7,200,000)
Fiscal Year 1999: ¥1,900,000 (Direct Cost: ¥1,900,000)
Fiscal Year 1998: ¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 1997: ¥3,700,000 (Direct Cost: ¥3,700,000)
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| Keywords | p53 gene / apoptosis / malformation / X-rays / dose-rate dependence / tissue repair / p53-deficient mouse / p53ノックアウトマウス / p53 |
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| Research Abstract |
When X-rays were given at high dose rate (450mGy/min), p53(-/-) mice showed a 70% incidence of anomalies and a 7% incidence of deaths, whereas p53(+/+) mice had a 20% incidence of anomalies and a 60% incidence of deaths. This reciprocal relationship of radiosensitivity to anomalies and to deaths supports the notion that fetal tissues have a p53-dependent "guardian" of the tissue that aborts cells bearing radiation-induced teratogenic DNA damage. In fact, frequency of cells dying by apoptosis after X-irradiation with 2 Gy on 9.5 gestation increased markedly for p53(+/+) fetuses but did not increase for p53(-/-) fetuses. Furthermore, the higher susceptibility of irradiated heterozygous p53(+/-) fetuses to malformation is related to a twofold lower rate of p53-dependent apoptosis than wild-type P53(+/+) fetuses. When an equal dose of 2 Gy was given at low dose rate (1.2mGy/min), the anomaly (death) incidence was 11% (5%) for p53(+/+) mice with 10% (9%) control incidence, and 36% (16%) for p53(-/-) mice with 22% (12%) control incidence. DNA repair is so proficient as to nearly completely eliminate a small amount of DNA damage produced by a low dose rate exposure in the embryonic tissues, however it remained teratogenic for p53(-/-) mice unable to carry out apoptosis.
These results suggest that complete elimination of teratogenic damage from irradiated tissues requires the concerted cooperation of two mechanisms ; proficient DNA repair and the p53-dependent apoptotic tissue repair. When concerted DNA repair and apoptosis functions efficiently, there is a threshold dose-rate for radiation-induced malformations.
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