Model of neural development by differentiating human induced pluripotent stem cells into neural progenitor cells to study the neurodevelopmental toxicity of lead

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.

Keywords: Embryoid bodies; Human induced pluripotent stem cells; Lead; Neural progenitor cells; Whole exome sequencing.