Aluminum hydroxide exposure induces neurodevelopmental impairment in hESC-derived cerebral organoids

• Published in: Ecotoxicology and environmental safety Vol. 256; p. 114863
• Main Authors: Wang, Liuyongwei, Mei, Linqiang, Zang, Zhenle, Cai, Yun, Jiang, Peiyan, Zhou, Lianyu, Du, Zhulin, Yang, Ling, Gu, Zhanjun, Liu, Tianyao, Fan, Xiaotang
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01.05.2023; Elsevier
• Subjects: Aluminum hydroxide; Aluminum Hydroxide - metabolism; Cerebral organoids; Child, Preschool; Hippo signaling pathway; Human Embryonic Stem Cells; Humans; Neural progenitor cells; Neural Stem Cells; Neurogenesis; Neurotoxicity; Organoids - metabolism; OCT; VZ; DMSO; Cerebral organoids; CNS; PFA; Al; BP; ASD; DEGs; Neurotoxicity; TUNEL; ASIA; RNA-seq; SVZ; Al(OH)3; KEGG; Neural progenitor cells; qPCR; Hippo signaling pathway; PBS; RGCs; MMF; GO; CP; Human embryonic stem cells; hiPSCs; CCK8; NPCs; EdU; Aluminum hydroxide; SEM; ICP-MS; oSVZ; hESCs; oRGs
• ISSN: 0147-6513; 1090-2414
• DOI: 10.1016/j.ecoenv.2023.114863

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. [Display omitted] •hESC-derived organoid is an ideal model to evaluate the toxicity of Al(OH)3.•Al(OH)3 exposure at an early stage inhibited NPC proliferation.•Al(OH)3 exposure at a later stage promoted NPC toward astrocyte differentiation.•Hippo-YAP1 signaling pathway is involved in Al(OH)3-induced impaired neurogenesis.