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Developmental Brain Disorders due to Physical Agents

物理因素引起的脑发育障碍

基本信息

批准号：
10044271
负责人：
SHIOTA Kohei
金额：
$ 2.75万
依托单位：
KYOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B).
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

项目摘要

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.

发育中的胚胎暴露于辐射和高温等物理因素可导致各种发育异常，胚胎的中枢神经系统和中轴骨骼最容易受到其致畸作用的影响。在本研究中，我们研究了人类胚胎神经胚形成过程，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，除了被广泛接受为神经管（NT）闭合起始部位的未来颈部区域外，NT闭合也起始于中脑-菱形脑边界和神经沟的吻端。发现在颈部水平开始的第一闭合的尾侧延伸向下进行到形成后神经前体的神经沟的尾端。这一新发现的人类NT关闭可以解释各种类型的神经管缺陷（NTD）的发病机制。孕鼠在孕13-14天（GD）42或43 ℃热应激时，胚胎脑神经前体细胞的增殖和迁移受到明显抑制，神经元凋亡增加. GD 14 -16热应激抑制小鼠胚胎神经元向面神经节的迁移，延缓面神经节的形成. GD 7 -9热应激引起Hox基因在胚胎中表达的阶段特异性变化，并产生相应的同源异型椎骨转化.孕鼠在GD 0 ~ GD 9每天给予叶酸（FA）3 mg/kg，并在GD 8加热，可显著降低胎儿NTD的患病率。上述结果表明，胚胎在器官形成的关键期暴露于高温可干扰基因表达，导致多种发育异常，妊娠早期补充FA可抑制热致畸作用。