Bisphenol A Represses Dopaminergic Neuron Differentiation from Human Embryonic Stem Cells through Downregulating the Expression of Insulin-like Growth Factor 1
Bisphenol A Represses Dopaminergic Neuron Differentiation from Human Embryonic Stem Cells through Downregulating the Expression of Insulin-like Growth Factor 1
复制标题
双酚 A 通过下调胰岛素样生长因子 1 的表达来抑制人胚胎干细胞的多巴胺能神经元分化
DOI：
10.1007/s12035-016-9898-y
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发表时间：
2017-07-01
影响因子：
5.1
通讯作者：
Liu, Jiayin
中科院分区：
文献类型：
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作者：
Huang, Boxian;Ning, Song;Liu, Jiayin
双酚 A (BPA) 是一种普遍存在的化合物，在胚胎发育过程中可能成为有毒物质。人类胚胎干细胞（hESC）为评估环境化学物质对人类产前发育的影响提供了一个有价值的模型。在我们的研究中，将 1 μM BPA 应用于 hESC 衍生的胚状体 (hEB)，并研究了 BPA 对神经细胞分化的影响。暴露于 BPA 后，胰岛素样生长因子 1 (IGF-1) 以及外胚层、神经元祖细胞和多巴胺能 (DA) 神经元的标记基因的表达水平均受到抑制。 hESC 来源的神经前体细胞 (NPC) 和 DA 神经元的数量减少。此外，DA神经元分泌的酪氨酸羟化酶（TH）和多巴胺的产量也减少。当提供重组 IGF-1 时，BPA 引起的抑制部分或完全缓解。我们进一步的甲基化微阵列分析表明，SRY 相关的 HMG-box 5 (SOX5)（可能是 IGF-1 的增强子）的启动子上有较高的甲基化水平。一致地，接下来的定量聚合酶链反应 (qPCR) 结果证实 SOX5 表达下调。我们的研究表明BPA主要通过下调IGF-1表达来抑制DA神经元分化，这可能归因于IGF-1上游基因启动子甲基化水平的改变。我们的研究结果首先阐述了IGF-1介导的BPA影响神经元分化的机制，这有助于阐明BPA毒性对产前神经发育的独特机制。
Bisphenol A (BPA) is a ubiquitous compound emerging as a possible toxicant during embryonic development. Human embryonic stem cell (hESC) promises a valuable model for evaluating the effects of environmental chemicals on human prenatal development. In our study, 1 μM BPA were applied to hESC-derived embryoid bodies (hEBs) and effects of BPA on neural cell differentiation were investigated. The expression level of insulin-like growth factor 1 (IGF-1) and marker genes for ectoderm, neuron progenitor cells, and dopaminergic (DA) neurons were all repressed upon BPA exposure. The population of hESC-derived neural precursor cells (NPCs) and DA neurons were decreased. Furthermore, yield of DA neuron-secreted tyrosine hydroxylase (TH) and dopamine were also reduced. When recombinant IGF-1 supplied, BPA-caused repressions were partially or completely relieved. Our further methylation microarray analysis indicated that there was a higher methylation level on the promoter of SRY-related HMG-box 5 (SOX5), a possible enhancer ofIGF-1. Consistently, next quantitative polymerase chain reaction (qPCR) results confirmed thatSOX5expression was downregulated. Our investigation suggests that BPA represses DA neuron differentiation mainly through downregulatingIGF-1expression, which may attribute to the altered methylation level on the promoter ofIGF-1upstream genes. Our findings first elaborate the mechanism of IGF-1-mediated BPA effects on neuronal differentiation, which is helpful to illuminate the unique mechanism of BPA toxicity on prenatal neurodevelopment.