Biological defense mechanisms against teratogenic damage and the role of p53 gene

致畸损伤的生物防御机制及p53基因的作用

• 批准号: 09480128
• 负责人: NORIMURA Toshiyuki
• 金额: $ 4.61万
• 依托单位: University of Occupational and Environmental Health
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09480128/
• 关键词: 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

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.

在高剂量率（450 mGy/min）X射线照射下，p53（-/-）小鼠畸形率为70%，死亡率为7%，而p53（+/+）小鼠畸形率为20%，死亡率为60%。这种对异常和死亡的辐射敏感性的相互关系支持了这样的观点，即胎儿组织具有依赖于p53的组织“监护人”，其使具有辐射诱导的致畸DNA损伤的细胞流产。事实上，在孕9.5天用2戈伊X射线照射后，p53（+/+）胎儿细胞凋亡死亡的频率显著增加，但p53（-/-）胎儿没有增加。此外，受照射的杂合型p53（+/-）胎儿对畸形的更高易感性与p53依赖性细胞凋亡率比野生型P53（+/+）胎儿低两倍有关。当以低剂量率（1.2 m戈伊/min）给予等剂量2戈伊时，p53（+/+）小鼠异常（死亡）发生率为11%（5%），对照组为10%（9%）; p53（-/-）小鼠异常（死亡）发生率为36%（16%），对照组为22%（12%）。低剂量率照射对胚胎组织产生的少量DNA损伤几乎完全消除，但对p53（-/-）小鼠仍有致畸作用，不能进行细胞凋亡。熟练的DNA修复和p53依赖的凋亡组织修复。当协同DNA修复和细胞凋亡有效地发挥作用时，辐射诱导的畸形存在一个阈值剂量率。

项目成果

Ootsuyama, A., Okazaki, R., Norimura, T.: "Effect of extended exposure of low-dose radiation on autoimmune diseases of immunologically depressed MRL/MpJ-gld/gld mice."Proceedings of the 10th international congress of the international radiation protection

Ootsuyama, A.、Okazaki, R.、Norimura, T.：“低剂量辐射长期暴露对免疫抑制 MRL/MpJ-gld/gld 小鼠自身免疫性疾病的影响。”国际放射学会第十届国际大会论文集

法村 俊之: "p53:癌抑制の分子メカニズムと臨床応用(監修:佐谷秀行)" 秀潤社(細胞工学別冊 BioReviewシリーズ), 142 (1998)

Toshiyuki Homura：“P53：癌症抑制的分子机制和临床应用（导师：Hideyuki Saya）” Shujunsha（细胞工程特别版BioReview系列），142（1998）

法村 俊之: "放射線の生体影響とその修飾,p53依存性アポトーシスによる奇形抑制"放射線科学臨時増刊号. 42・6. 169-175 (1999)

Toshiyuki Homura：“放射线的生物学效应及其修饰，以及 p53 依赖性细胞凋亡对畸形的抑制”放射学特刊 42・6（1999）。

法村 俊之: "p53:アポトーシスによる奇形抑制"日本医事新報. 3919. 30-32 (1999)

Toshiyuki Homura：“P53：通过细胞凋亡抑制畸形”日本医学报纸 3919. 30-32 (1999)。

Kato, F., Ootsuyama, A., Norimura, T.: "Dose rate effectiveness in radiation-induced teratogenesis in mice."Proceedings of the 10th international congress of the international radiation protection association. (in press). (2000)

Kato, F.、Ootsuyama, A.、Norimura, T.：“小鼠辐射致畸的剂量率有效性。”国际辐射防护协会第十届国际大会记录。