Developmental Brain Disorders due to Physical Agents

发育中的胚胎暴露在辐射和高温等物理因素下可引起各种发育异常，其中中枢神经系统和胚胎的中轴骨最容易受到致畸作用的影响。在本研究中，我们检测了人类胚胎的神经形成过程，并利用小鼠进行了一系列实验，获得了以下结果。在人类胚胎中，除了被广泛接受的未来颈部区域作为神经管闭合的起始点外，神经管闭合还始于中脑-斜脑交界处和神经沟的吻端。第一个闭合的尾端始于颈椎水平，向下延伸到神经沟的尾端，在那里形成后神经前体。这一人类神经管闭合的新发现可以解释各种神经管缺陷(NTD)的发病机制。妊娠13-14天的42℃或43℃热应激可显著抑制胚胎脑神经前体细胞的增殖和迁移，增加神经细胞的凋亡性死亡。GD14-16热应激抑制小鼠胚胎神经细胞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基因表达的阶段性转移，并产生相应的同源异型脊椎转化。孕鼠从GD0至GD9每天给予叶酸(FA)(3 mg/kg)，在GD8加热，可显著降低胚胎NTD的患病率。上述结果表明，胚胎在器官发生关键期加温可干扰基因表达，导致多种发育异常，妊娠早期补充叶酸可抑制热致畸形。

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.