Abstract：
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.
摘要：
丙戊酸(VPA),广泛用作抗癫痫药，在妊娠早期或晚期暴露时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的各种疾病。然而,在神经发育的早期阶段的毒性尚未得到解决。因此,我们研究了VPA在人多能干细胞分化成前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以剂量依赖性方式诱导了不同的发育毒性作用。例如,在前引导神经祖细胞诱导过程中，VPA诱导的细胞死亡更深刻，在后引导神经诱导过程中观察到细胞增殖抑制和分化增强。此外，在后诱导步骤中急性暴露于VPA也会延迟神经类器官培养中随后的神经管样形态发生过程。这些结果表明，在非常早期的胚胎发育过程中，VPA暴露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。
