Kim Jeongah, Park Si-Hyung, Sun Woong
Department of Anatomy, College of Medicine, Korea University, Seoul, Korea.
Int J Stem Cells. 2025 Feb 28;18(1):49-58. doi: 10.15283/ijsc24066. Epub 2024 Jul 8.
Valproic acid (VPA), widely used as an antiepileptic drug, exhibits developmental neurotoxicity when exposure occurs during early or late pregnancy, resulting in various conditions ranging from neural tube defects to autism spectrum disorders. However, toxicity during the very early stages of neural development has not been addressed. Therefore, we investigated the effects of VPA in a model where human pluripotent stem cells differentiate into anterior or posterior neural tissues. Exposure to VPA during the induction of neural stem cells induced different developmental toxic effects in a dose-dependent manner. For instance, VPA induced cell death more profoundly during anteriorly guided neural progenitor induction, while inhibition of cell proliferation and enhanced differentiation were observed during posteriorly guided neural induction. Furthermore, acute exposure to VPA during the posterior induction step also retarded the subsequent neurulation-like tube morphogenesis process in neural organoid culture. These results suggest that VPA exposure during very early embryonic development might exhibit cytotoxicity and subsequently disrupt neural differentiation and morphogenesis processes.
丙戊酸（VPA）作为一种广泛使用的抗癫痫药物，在妊娠早期或晚期接触时会表现出发育神经毒性，导致从神经管缺陷到自闭症谱系障碍等各种病症。然而，神经发育早期阶段的毒性尚未得到研究。因此，我们在一个人类多能干细胞分化为前脑或后脑神经组织的模型中研究了VPA的作用。在神经干细胞诱导过程中接触VPA会以剂量依赖的方式诱导不同的发育毒性作用。例如，在前脑导向的神经祖细胞诱导过程中，VPA更显著地诱导细胞死亡，而在后脑导向的神经诱导过程中则观察到细胞增殖受到抑制和分化增强。此外，在后脑诱导步骤中急性接触VPA也会阻碍神经类器官培养中随后的神经胚样神经管形态发生过程。这些结果表明，在胚胎发育极早期接触VPA可能会表现出细胞毒性，并随后破坏神经分化和形态发生过程。
