Takeuchi I K, Takeuchi Y K
J Anat. 1985 May;140 ( Pt 3)(Pt 3):403-12.
Maternal intraperitoneal administration of 1 mg/kg 5-azacytidine to pregnant S1c:ICR mice on gestational Day 7.5 resulted in a high incidence of exencephalic offspring. Histological examination of untreated 7.5 days mouse embryos revealed that the head folds were formed in the anterior halves of the embryos, whereas the primitive streaks still remained in the posterior halves. At 12 hours after 5-azacytidine administration (8.0 days embryos), numerous pyknotic cells were observed in the neurectoderm of the head folds, in the embryonic ectoderm and the migrating mesoderm of the primitive streak region. These pyknotic cells had almost disappeared from the embryonic tissues, and few abnormalities were encountered, in embryos 24 hours after 5-azacytidine administration (8.5 days embryos), except for the slight reduction in thickness of the neurectoderm of the head folds compared with that in untreated 8.5 days embryos. In untreated 9.5 days embryos, the head folds had entirely closed along the anterior neuroaxes, whereas those treated with 5-azacytidine 48 hours earlier displayed head folds that were open in various degrees along the neuroaxes anterior to the fourth ventricle. The primary cause of 5-azacytidine-induced exencephaly is considered to be attributable to a powerful cell-killing action of 5-azacytidine and the subsequent loss of germinal cells in the neurectoderm of the head folds. The precise mechanisms by which this damage results in the failure of neural tube closure in the cephalic region remains unclear.
在妊娠第7.5天，给怀孕的S1c:ICR小鼠腹腔注射1 mg/kg的5-氮杂胞苷，导致无脑儿后代的发生率很高。对未经处理的7.5天龄小鼠胚胎进行组织学检查发现，胚胎前半部分形成了头褶，而后半部分仍保留着原条。在注射5-氮杂胞苷后12小时（8.0天龄胚胎），在头褶的神经外胚层、胚胎外胚层和原条区域迁移的中胚层中观察到大量固缩细胞。在注射5-氮杂胞苷后24小时（8.5天龄胚胎），这些固缩细胞几乎从胚胎组织中消失，除了与未经处理的8.5天龄胚胎相比，头褶神经外胚层厚度略有减小外，未发现其他异常。在未经处理的9.5天龄胚胎中，头褶已沿前神经轴完全闭合，而在48小时前接受5-氮杂胞苷处理的胚胎中，头褶在第四脑室前方的神经轴上呈不同程度的开放状态。5-氮杂胞苷诱导无脑畸形的主要原因被认为是5-氮杂胞苷强大的细胞杀伤作用以及随后头褶神经外胚层中生殖细胞的丢失。这种损伤导致头部区域神经管闭合失败的确切机制尚不清楚。
