Prenatal exposure to environmental insults can increase the risk of developing neurodevelopmental disorders. Administration of the antiepileptic drug valproic acid (VPA) during pregnancy is tightly associated with a high risk of neurological disorders in offspring. However, the lack of an ideal human model hinders our comprehensive understanding of the impact of VPA exposure on fetal brain development, especially in early gestation. Herein, we present the first report indicating the effects of VPA on brain development at early stages using engineered cortical organoids from human induced pluripotent stem cells (hiPSCs). Cortical organoids were generated on micropillar arrays in a controlled manner, recapitulating the critical features of human brain development during early gestation. With VPA exposure, cortical organoids exhibited neurodevelopmental dysfunction characterized by increased neuron progenitors, inhibited neuronal differentiation and altered forebrain regionalization. Transcriptome analysis showed new markedly altered genes (e.g., KLHL1, LHX9, and MGARP) and a large number of differential expression genes (DEGs), some of which are related to autism. In particular, comparison of transcriptome data via GSEA and correlation analysis revealed the high similarity between VPA-exposed organoids with the postmortem ASD brain and autism patient-derived organoids, implying the high risk of autism with prenatal VPA exposure, even in early gestation. These new findings facilitate a better understanding of the cellular and molecular mechanisms underlying postnatal brain disorders (such as autism) with prenatal VPA exposure. This established cortical organoid-on-a-chip platform is valuable for probing neurodevelopmental disorders under environmental exposure and can be extended to applications in the study of diseases and drug testing.

产前暴露于环境侮辱会增加患神经发育障碍的风险。怀孕期间服用抗癫痫药物丙戊酸 (VPA) 与后代神经系统疾病的高风险密切相关。然而，缺乏理想的人体模型阻碍了我们全面了解 VPA 暴露对胎儿大脑发育的影响，尤其是在妊娠早期。在此，我们首次使用来自人类诱导多能干细胞 (hiPSC) 的工程化皮质类器官，展示了 VPA 对早期大脑发育的影响的报告。皮质类器官以受控方式在微柱阵列上生成，重现了早期妊娠期间人类大脑发育的关键特征。随着 VPA 的曝光，皮质类器官表现出神经发育功能障碍，其特征是神经元祖细胞增加、神经元分化抑制和前脑区域化改变。转录组分析显示新的显着改变的基因（例如，KLHL1、LHX9 和 MGARP）和大量差异表达基因 (DEG)，其中一些与自闭症有关。特别是，通过 GSEA 和相关分析比较转录组数据显示，暴露于 VPA 的类器官与死后 ASD 大脑和源自自闭症患者的类器官之间具有高度相似性，这意味着产前暴露于 VPA 的自闭症风险很高，即使在妊娠早期也是如此。这些新发现有助于更好地了解产前 VPA 暴露引起的产后脑部疾病（如自闭症）的细胞和分子机制。