Spinal nerve defects in mouse embryos prenatally exposed to valproic acid
Spinal nerve defects in mouse embryos prenatally exposed to valproic acid
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DOI：
10.1007/s12565-016-0363-9
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发表时间：
2018-01-01
影响因子：
1.2
通讯作者：
Fukui, Yoshihiro
中科院分区：
文献类型：
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作者：
Bold, Juramt;Sakata-Haga, Hiromi;Fukui, Yoshihiro
为了详细检查小鼠产前暴露于丙戊酸诱导的脊神经缺陷，在妊娠第6、7、8或9天对妊娠ICR小鼠皮下注射单剂量400 mg/kg丙戊酸，并在妊娠第10天观察其胚胎。在丙戊酸暴露的胚胎中，使用抗神经丝抗体的整装免疫染色使我们能够识别脊神经缺陷，例如束的丢失、来自相邻节段的束之间的吻合以及背根神经节的节段性模式中断。在实验组中，妊娠第8天暴露于丙戊酸的胚胎中脊神经缺陷的患病率最高。然后，在妊娠第10天检查丙戊酸给药剂量对脊神经缺损患病率的影响，发现其呈剂量依赖性增加。值得注意的是，妊娠第8天暴露于600 mg/kg丙戊酸的所有胚胎均出现脊神经缺损。在妊娠第6-10天补充叶酸（3 mg/kg/天）可抑制丙戊酸诱导的神经管缺陷的患病率，这是产前暴露于丙戊酸的后代的常见畸形，但不能抑制脊神经缺陷。因此，由于产前丙戊酸暴露引起的脊神经缺陷可能是由不同于神经管缺陷的机制引起的。由于预测脊神经缺损是由体节和/或神经嵴细胞的节段性排列中断（这是背根神经节的起源）和/或体节极性异常引起的，因此这种高发生率脊神经缺损的小鼠模型可用于检查丙戊酸对体节发生和体节相关结构的形态发生的影响。
To examine in detail spinal nerve defects induced by prenatal exposure to valproic acid in mice, pregnant ICR mice were subcutaneously injected with a single dose of 400 mg/kg valproic acid on gestational day 6, 7, 8, or 9, and their embryos were observed on gestational day 10. The whole-mount immunostaining using an anti-neurofilament antibody allowed us to identify spinal nerve defects, such as a loss of bundle, anastomosis among bundles arising from adjacent segment, and a disrupted segmental pattern of the dorsal root ganglia, in valproic acid-exposed embryos. The prevalence of spinal nerve defects was the highest in the embryos exposed to valproic acid on gestational day 8 among the experimental groups. Then, effects of the administration dose of valproic acid on the prevalence of spinal nerve defects were examined on gestational day 10 and found to be dose-dependently increased. It was noteworthy that all embryos exposed to 600 mg/kg of valproic acid on gestational day 8 suffered spinal nerve defects. Folic acid (3 mg/kg/day) supplementation during gestational day 6-10 suppressed the prevalence of valproic acid-induced neural tube defects, which are common malformations in offspring prenatally exposed to valproic acid, but not that of spinal nerve defects. Thus, the spinal nerve defects due to prenatal valproic acid exposure might be induced by mechanisms different from those of neural tube defects. Because spinal nerve defects were predicted to be caused by the disrupted segmental arrangement of the somites and/or that of neural crest cells, which was the origin of the dorsal root ganglia and/or abnormal polarity of the somite, this mouse model with spinal nerve defects at high incidence would be useful to examine the effects of valproic acid on the somitogenesis and morphogenesis of somite-associated structures.