New insights into mechanism of bisphenol analogue neurotoxicity: implications of inhibition of O-GlcNAcase activity in PC12 cells
New insights into mechanism of bisphenol analogue neurotoxicity: implications of inhibition of O-GlcNAcase activity in PC12 cells
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DOI：
10.1007/s00204-019-02525-3
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发表时间：
2019-09-01
影响因子：
6.1
通讯作者：
Faiola, Francesco
中科院分区：
文献类型：
--
作者：
Gu, Yu-Xin;Liang, Xiao-Xing;Faiola, Francesco
包括双酚A及其衍生物在内的双酚类似物是普遍存在的环境污染物，并且与对动物和人类的不利神经发育影响有关。大多数毒理学研究集中在雌激素受体介导的途径，没有全面阐明观察到的毒性。O-GlcNAcase（OGA）是脑内表达水平最高的酶，在从分子到动物行为的多个层次上对神经元的功能起着重要的调控作用。在这项工作中，我们打算调查的双酚类似物的神经毒性的分子机制，确定其细胞靶点和由此产生的影响。利用自行研制的电化学生物传感器，在分子水平上研究了7种双酚类似物对OGA活性的抑制作用。结果表明，取代基不同，它们的活性也不同，其中四溴双酚A（TBBPA）的活性最强。七种双酚类似物（0-100 μ M暴露）显著抑制PC 12细胞中OGA活性并上调蛋白质O-GlcNAc化水平。双酚类似物抑制OGA进一步诱导细胞内钙、ROS、炎症、增殖抑制、细胞周期干扰、诱导凋亡。特别是10 μ M四溴双酚A（TBBPA）暴露可损害人神经干细胞（hNSCs）突起的生长和发育。OGA/双酚类似物复合物的分子对接揭示了疏水性主导的抑制效力。OGA作为双酚类似物的一个新的细胞靶点，将有助于阐明双酚类似物神经毒性的分子机制。
Bisphenol analogues including bisphenol A and its derivatives are ubiquitous environmental contaminants and have been linked to adverse neurodevelopment effects on animals and humans. Most toxicological research focused on estrogen receptor mediated pathways and did not comprehensively clarify the observed toxicity. O-GlcNAcase (OGA), the highest level in brain, plays a critical role in controlling neuronal functions at multi-levels from molecule to animal behaviors. In this work, we intend to investigate the underlying molecular mechanisms for the neurotoxicity of bisphenol analogues by identifying their cellular targets and the resultant effects. The inhibitory actions of seven bisphenol analogues on the OGA activity at molecular level were investigated by our developed electrochemical biosensor. We found that their potency varied with substituent groups, in which tetrabromo bisphenol A (TBBPA) was the strongest. The seven bisphenol analogues (0-100 mu M exposure) significantly inhibited OGA activity and up-regulated protein O-GlcNAcylation level in PC12 cells. Inhibition of OGA by bisphenol analogues further induced intracellular calcium, ROS, inflammation, repressed proliferation, interfered with cell cycle, induced apoptosis. And especially, 10 mu M tetrabromo bisphenol A (TBBPA) exposure could impair the growth and development of neurite in human neural stem cells (hNSCs). Molecular docking for OGA/bisphenol analogue complexes revealed the hydrophobicity-dominated inhibition potency. OGA, as a new cellular target of bisphenol analogues, would illuminate the molecular mechanism of bisphenol analogues neurotoxicity.