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

在高剂量率(450mGymin)照射下，P53(-/-)小鼠的异常发生率为70%，死亡发生率为7%，而P53(+/+)小鼠的异常发生率为20%，死亡发生率为60%。对异常和死亡的辐射敏感性的这种相互关系支持这样一种观点，即胎儿组织有一个依赖于p53的组织守护人，该组织负责流产承担辐射诱导的致畸DNA损伤的细胞。P53(+/+)胎儿经2Gy射线照射后，细胞凋亡率明显增加，而P53(-/-)胎儿细胞凋亡率无明显增加。此外，辐射后杂合子p53(+/-)胎儿对畸形的易感性更高，这与p53依赖的细胞凋亡率比野生型p53(+/+)胎儿低两倍有关。在低剂量率(1.2mGymin)下等剂量照射时，p53(+/+)小鼠的异常(死亡)发生率为11%(5%)，对照组发生率为10%(9%)，p53(-/-)小鼠异常(死亡)发生率为36%(16%)，对照组发生率为22%(12%)。DNA修复技术非常成熟，几乎可以完全消除低剂量率暴露所造成的胚胎组织中的少量DNA损伤，但对于无法进行细胞凋亡的P53(-/-)小鼠来说，它仍然是致畸的。这些结果表明，完全消除辐射组织的致畸损伤需要两种机制的协同作用：熟练的DNA修复和依赖于P53的凋亡组织修复。当协调的DNA修复和细胞凋亡有效发挥作用时，辐射诱发的畸形存在一个阈值剂量率。

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.