Laboratory of Kampo Pharmacology, Yokohama University of Pharmacy, Yokohama 245-0066, Japan.
Liver Cancer Prevention Research Unit, RIKEN Cluster for Pioneering Research, Wako, Saitama 351-0198, Japan.
Int J Mol Sci. 2020 Aug 3;21(15):5564. doi: 10.3390/ijms21155564.
Stress in early life has been linked with the development of late-life neurological disorders. Early developmental age is potentially sensitive to several environmental chemicals such as alcohol, drugs, food contaminants, or air pollutants. The recent advances using three-dimensional neural sphere cultures derived from pluripotent stem cells have provided insights into the etiology of neurological diseases and new therapeutic strategies for assessing chemical safety. In this study, we investigated the neurodevelopmental effects of exposure to thalidomide (TMD); 2,2',4,4'-tetrabromodiphenyl ether; bisphenol A; and 4-hydroxy-2,2',3,4',5,5',6-heptachlorobiphenyl using a human embryonic stem cell (hESC)-derived sphere model. We exposed each chemical to the spheres and conducted a combinational analysis of global gene expression profiling using microarray at the early stage and morphological examination of neural differentiation at the later stage to understand the molecular events underlying the development of hESC-derived spheres. Among the four chemicals, TMD exposure especially influenced the differentiation of spheres into neuronal cells. Transcriptomic analysis and functional annotation identified specific genes that are TMD-induced and associated with ERK and synaptic signaling pathways. Computational network analysis predicted that TMD induced the expression of DNA-binding protein inhibitor ID2, which plays an important role in neuronal development. These findings provide direct evidence that early transcriptomic changes during differentiation of hESCs upon exposure to TMD influence neuronal development in the later stages.
早期生活中的压力与晚年神经紊乱的发展有关。早期发育阶段可能容易受到多种环境化学物质的影响，如酒精、药物、食物污染物或空气污染物。最近利用多能干细胞衍生的三维神经球体培养物取得的进展为神经疾病的病因学提供了新的见解，并为评估化学物质安全性提供了新的治疗策略。在这项研究中，我们使用人胚胎干细胞（hESC）衍生的球体模型，研究了暴露于沙利度胺（TMD）、2,2',4,4'-四溴二苯醚、双酚 A 和 4-羟基-2,2',3,4',5,5',6-七氯联苯对神经发育的影响。我们将每种化学物质暴露于球体中，并在早期阶段使用微阵列进行全局基因表达谱的组合分析，在后期进行神经分化的形态学检查，以了解 hESC 衍生球体发育的分子事件。在这四种化学物质中，TMD 暴露特别影响球体向神经元细胞的分化。转录组分析和功能注释确定了 TMD 诱导的与 ERK 和突触信号通路相关的特定基因。计算网络分析预测 TMD 诱导了 DNA 结合蛋白抑制剂 ID2 的表达，ID2 在神经元发育中起着重要作用。这些发现提供了直接证据，表明 TMD 暴露后 hESC 分化过程中的早期转录组变化会影响后期神经元的发育。
