p53-dependent apoptosis suppresses radiation-induced teratogenesis

据估计，约有一半的人类受孕没有植入子宫，导致无法识别的自然流产，约5%的人类出生时有可识别的畸形。为了找到畸形和流产机制的线索，我们比较了p53缺失（p53^<-/->）和野生型（p53^<+/+>）小鼠中辐射诱导的畸形和流产的发生率。在妊娠第9.5天接受2戈伊的X射线照射后，p53^<-/->小鼠显示出70%的畸形发生率和7%的死亡发生率，而p53^<+/+>小鼠的畸形发生率为20%，死亡发生率为60%。在妊娠第3.5天照射后获得了类似的结果。对异常和胚胎或胎儿致死性的辐射敏感性的这种相互关系支持胚胎或胎儿组织具有p53依赖的组织“监护人”的概念，其使具有辐射诱导的致畸DNA损伤的细胞流产。事实上，X射线照射后，p53^<+/+>胎儿组织中含有凋亡DNA片段的细胞数量显著增加，而p53^<-/->胎儿组织中没有。

About half of human conceptions are estimated not to be implanted in the uterus, resulting in unrecognizable spontaneous abortions, and about 5% of human births have a recognizable malformation. In order to find clues to the mechanisms of malformation and abortion, we compared the incidences of radiation-induced malformations and abortions in p53 null (p53^<-/->) and wildtype (p53^<+/+>) mice. After X-irradiation with 2 Gy on day 9.5 of gestation, 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. Similar results were obtained after irradiation on day 3.5 of gestation. This reciprocal relationship of radiosensitivity to anomalies and to embryonic or fetal lethality supports the notion that embryonic or fetal tissues have a p53-dependent 'guardian' of the tissue that aborts cells bearing radiation-induced teratogenic DNA damage. In fact, after X-irradiation, the number of cells with apoptotic DNA fragments was greatly increased in tissues of the p53^<+/+> fetuses but not in those of the p53^<-/-> fetuses.