丙戊酸 (VPA) 广泛用作抗癫痫药物，在怀孕早期或晚期接触时会表现出发育性神经毒性，导致从神经管缺陷到自闭症谱系障碍等各种疾病。然而，神经发育早期阶段的毒性尚未得到解决。因此，我们研究了 VPA 在人类多能干细胞分化为前神经组织或后神经组织的模型中的作用。在神经干细胞诱导过程中暴露于 VPA 会以剂量依赖性方式诱导不同的发育毒性作用。例如，VPA 在前向引导的神经祖细胞诱导过程中更深刻地诱导细胞死亡，而在后向引导的神经诱导过程中观察到细胞增殖的抑制和分化的增强。此外，在后诱导步骤中急性暴露于 VPA 也延迟了神经类器官培养中随后的类似神经管的形态发生过程。这些结果表明，在非常早期的胚胎发育过程中接触 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。

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.