Abstract：
Lead (Pb) exposure causes immeasurable damage to multiple human systems, particularly the central nervous system (CNS). In this study, human induced pluripotent stem cells (hiPSCs) were differentiated into neural progenitor cells (NPCs) to investigate the neurotoxic effects of Pb. The hiPSCs were treated with 0, 0.5, 1.0, 2.5, 5.0 and 10.0 μmol/L Pb for 7 days, whereas embryoid bodies (EBs) and NPCs were treated with 0, 0.1, 0.5, and 1.0 μmol/L Pb for 7 days. Pb exposure disrupted the cell cycle and caused apoptosis in hiPSCs, EBs, and NPCs. Besides, Pb inhibited the differentiation of NPCs and EBs. Whole exome sequencing revealed 2509, 2413, and 1984 single nucleotide variants (SNVs) caused by Pb in hiPSCs, EBs, and NPCs, respectively. The common mutation sites in the exon region were mostly nonsynonymous mutations. We identified 18, 19, and 18 common deleterious mutations in hiPSCs, EBs, and NPCs, respectively. Additionally, Online Mendelian Inheritance in Man database analysis revealed 30, 20, and 13 genes related to CNS disorders in hiPSCs, EBs, and NPCs, respectively. Our findings suggest that this in vitro model may supplement animal models and be applied to the study of neurodevelopmental toxicity in the future.
摘要：
铅（Pb）暴露会对多个人类系统造成不可估量的损害，特别是中枢神经系统（CNS）。在这项研究中,人诱导多能干细胞（hiPSCs）分化为神经祖细胞（NPCs），以研究铅的神经毒性作用。用0、0.5、1.0、2.5、5.0和10.0μmol/LPb处理hiPSCs7天,而胚状体（EBs）和NPCs用0、0.1、0.5和1.0μmol/LPb处理7天。铅暴露破坏细胞周期并导致hiPSCs凋亡，EB,和NPC。此外,Pb抑制NPCs和EBs的分化。全外显子组测序揭示了在hiPSCs中由Pb引起的2509、2413和1984单核苷酸变体（SNV），EB,NPC,分别。外显子区域的常见突变位点大多是非同义突变。我们在hiPSC中鉴定了18、19和18个常见的有害突变，EB,NPC,分别。此外,在线孟德尔遗传人数据库分析揭示了30，20和13个基因与中枢神经系统疾病相关的hiPSCs，EB,NPC,分别。我们的发现表明，该体外模型可能会补充动物模型，并在将来应用于神经发育毒性的研究。
