College of Veterinary Medicine, Western University of Health Sciences, Pomona, CA 91766-1854, USA; Center for Excellence in Regional Atmospheric Environment, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen, 361021, China; Key Lab of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen, 361021, China; College of Resources and Environment, University of Chinese Academy of Sciences, Beijing, 100049, China.
College of Veterinary Medicine, Western University of Health Sciences, Pomona, CA 91766-1854, USA; Graduate College of Biomedical Sciences, Western University of Health Sciences, Pomona, CA 91766-1854, USA.
Environ Int. 2019 Jun;127:324-332. doi: 10.1016/j.envint.2019.01.059. Epub 2019 Apr 3.
Bisphenol-A (BPA) is a lipophilic, organic, synthetic compound that has been used as an additive in polycarbonate plastics manufacturing since 1957. Studies have shown that BPA interferes with the development and functions of the brain, but little is known about the effects of BPA on human glutamatergic neurons (hGNs) at the molecular and cellular levels. We investigated the impact of chronic exposure to BPA to hGNs derived from human embryonic stem cells (hESCs). The results showed that chronic exposure of different concentrations of BPA (0, 0.1, 1.0 and 10 μM) to hGNs for 14 days reduced neurite outgrowth in a concentration-dependent manner. Using presynaptic protein synaptophysin and postsynaptic protein PSD-95 antibodies, immunofluorescence staining and western blotting results indicated that BPA exposure altered the morphology of dendritic spines and increased synaptophysin and PSD-95 expression. Furthermore, BPA exposure at concentrations higher than 1.0 μM resulted in the increase of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) expression and deterioration of dendritic spines. In addition, our results suggested that these BPA mediated neurotoxicity effects were due to an increased production of reactive nitrogen species (RNS) and reactive oxygen species (ROS) via increased nitric oxide synthase (iNOS), neuronal nitric oxide synthase (nNOS), 3-nitrotyrosine expression and Ca influx. These results imply that hESC-based neuronal differentiation is an excellent cellular model to examine BPA-induced neurotoxicity on human neurons at the cellular and molecular level.
双酚 A（BPA）是一种亲脂性、有机、合成化合物，自 1957 年以来一直被用作聚碳酸酯塑料制造的添加剂。研究表明，BPA 会干扰大脑的发育和功能，但人们对 BPA 对人类谷氨酸能神经元（hGNs）在分子和细胞水平上的影响知之甚少。我们研究了慢性暴露于 BPA 对源自人类胚胎干细胞（hESCs）的 hGNs 的影响。结果表明，慢性暴露于不同浓度的 BPA（0、0.1、1.0 和 10µM）14 天会以浓度依赖的方式减少神经突生长。使用突触前蛋白突触小体相关蛋白和突触后蛋白 PSD-95 抗体，免疫荧光染色和 Western blot 结果表明，BPA 暴露改变了树突棘的形态，增加了突触小体相关蛋白和 PSD-95 的表达。此外，BPA 暴露浓度高于 1.0µM 会导致α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（AMPAR）表达增加和树突棘恶化。此外，我们的结果表明，这些 BPA 介导的神经毒性作用是由于通过增加一氧化氮合酶（iNOS）、神经元型一氧化氮合酶（nNOS）、3-硝基酪氨酸表达和 Ca2+内流，导致活性氮物种（RNS）和活性氧物种（ROS）的产生增加所致。这些结果表明，基于 hESC 的神经元分化是一种极好的细胞模型，可以在细胞和分子水平上研究 BPA 对人类神经元的神经毒性作用。
