Developmental Brain Disorders due to Physical Agents

发育中的胚胎暴露于辐照和高温等物理物质中可引起各种发育异常，胚胎的中枢神经系统和轴向骨骼最容易受到其致畸作用的影响。在本研究中，我们考察了人类胚胎的神经发育过程，并在小鼠身上进行了一系列实验，得到了以下结果：在人类胚胎中，除了未来的颈椎区域被广泛认为是神经管（NT）关闭的起始部位外，神经管关闭也开始于中脑-斜脑边界和神经沟的吻端。第一个闭合的尾侧延伸开始于颈椎水平向下延伸到神经沟的尾端那里形成了后神经。人类神经管闭合的这一新发现可以解释各种类型神经管缺陷（NTD）的发病机制。妊娠期（GD） 13 ~ 14时，42℃和43℃的热应激可显著抑制胚胎脑神经前体细胞的增殖和迁移，增加凋亡神经元的死亡。热应激抑制GD14-16神经元向原始面神经节的迁移，延缓神经节的形成。GD7-9的热应激导致胚胎中Hox基因表达的阶段性变化，并产生相应的同源性椎体转化。孕鼠从GD0至GD9每天给予叶酸（3 mg/kg），并在GD8时加热，可显著降低胎儿NTD的患病率。以上结果表明，在器官发生的关键时期，胚胎暴露在高温下会干扰基因表达，导致多种发育异常，妊娠早期补充FA可以抑制热致畸胎症。

Exposure of developing embryos to such physical agents as irradiation and hyperthermia can cause various developmental abnormalities, and the central nervous system and axial skeleton of the embryo are most susceptible to their teratogenic effects. In the present study, we examined the neurulation process in human embryos and carried out a series of experiments using mice, and obtained the following results.1. In human embryos, in addition to the future cervical region that is widely accepted as an initiation site of neural tube (NT) closure, NT closure initiates also at the mesencephalic-rhombencephalic boundary and at the rostral end of the neural groove. The caudal extension of the first closure initiating at the cervical level was found to proceed down to the caudal end of the neural groove where the posterior neuropre is formed. This new finding of the human NT closure can explain the pathogenesis of various types of neural tube defects (NTD).2. When pregnant mice were heat-stressed at 42 or 43 C at gestational day (GD) 13-14, the proliferation and migration of neural precursor cells were significantly suppressed and apoptotic neuronal death increased in the embryonic brain.3. Heat stress at GD14-16 inhibited the migration of neurons to the primordial facial ganglia and retarded the ganglion formation in mouse embryos.4. Heat stress at GD7-9 caused stage-specific shifts of Hox gene expression in the embryos and produced corresponding homeotic vertebral transformations.5. When pregnant mice were given folic acid (FA) (3 mg/kg) daily from GD0 through GD9 and heated at GD8, the prevalence of NTD in the fetuses was significantly reduced.The above results showed that exposure of embryos to hyperthermia at the critical period of organogenesis can interfere with gene expression, resulting in a variety of developmental abnormalities, and that FA supplementation early in pregnancy can suppress heat-induced teratogenesis.