铝（Al）已被分类为一种累积性环境污染物，危及人类健康。越来越多的证据表明铝的毒性作用，但对人脑发育的具体影响仍不清楚。氢氧化铝（Al（OH）3）是最常见的疫苗佐剂，也是铝的主要来源，对环境和早期儿童神经发育构成风险。在本研究中，我们利用人类胚胎干细胞（hESCs）制备的人脑器官样体，探讨了5μg/ml或25μg/ml Al（OH）3对神经发生的神经毒性作用，并进行了为期六天的实验。我们发现，早期暴露于Al（OH）3的器官样体会导致大小减小，基础神经前体细胞（NPC）增殖缺陷，并以时间和剂量依赖方式促进神经元发育。转录组分析揭示了Al（OH）3暴露的大脑器官样体中Hippo-YAP1信号通路的显著改变，揭示了一种新的机制，说明了Al（OH）3对人类皮层发育的神经发生有害影响。我们进一步发现，第90天的Al（OH）3暴露主要降低了外放射状胶质细胞（oRGs）的产生，但促进NPC向星形胶质细胞分化。总之，我们建立了一个易于操作的实验模型，可以更好地理解Al（OH）3暴露对人类大脑发育的影响和机制。版权所有©2023年作者。由Elsevier公司发行。保留所有权利。

Aluminum (Al) has been classified as a cumulative environmental pollutant that endangers human health. There is increasing evidence to suggest the toxic effects of Al, but the specific action on human brain development remains unclear. Al hydroxide (Al(OH)3), the most common vaccine adjuvant, is the major source of Al and poses risks to the environment and early childhood neurodevelopment. In this study, we explored the neurotoxic effect of 5 μg/ml or 25 μg/ml Al(OH)3 for six days on neurogenesis by utilizing human cerebral organoids from human embryonic stem cells (hESCs). We found that early Al(OH)3 exposure in organoids caused a reduction in the size, deficits in basal neural progenitor cell (NPC) proliferation, and premature neuron differentiation in a time and dose-dependent manner. Transcriptomes analysis revealed a markedly altered Hippo-YAP1 signaling pathway in Al(OH)3 exposed cerebral organoid, uncovering a novel mechanism for Al(OH)3-induced detrimental to neurogenesis during human cortical development. We further identified that Al(OH)3 exposure at day 90 mainly decreased the production of outer radial glia-like cells(oRGs) but promoted NPC toward astrocyte differentiation. Taken together, we established a tractable experimental model to facilitate a better understanding of the impact and mechanism of Al(OH)3 exposure on human brain development.Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.