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

当以高剂量率（450mGy/min）给予x射线时，p53（-/-）小鼠显示70%的异常发生率和7%的死亡率，而p53（+/+）小鼠显示20%的异常发生率和60%的死亡率。这种对异常和死亡的辐射敏感性的相互关系支持了这样一种观点，即胎儿组织具有p53依赖的组织“监护人”，该组织可以使携带辐射诱导的致畸性DNA损伤的细胞流产。事实上，在9.5妊娠期2 Gy x射线照射后，p53（+/+）胎儿细胞凋亡的频率明显增加，而p53（-/-）胎儿细胞凋亡的频率没有增加。此外，辐照杂合子p53（+/-）胎儿对畸形的易感性较高，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（1.2mGy/min）给予2 Gy等剂量时，p53（+/+）小鼠异常（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修复非常熟练，几乎完全消除了胚胎组织中低剂量率暴露产生的少量DNA损伤，但对于无法进行细胞凋亡的p53（-/-）小鼠来说，它仍然具有致畸性。这些结果表明，完全消除辐照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p53依赖性的凋亡组织修复。当协调一致的DNA修复和细胞凋亡功能有效时，存在辐射诱导畸形的阈剂量率。

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.