State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, China.
University of Chinese Academy of Sciences, Beijing, 100049, China.
Arch Toxicol. 2019 Sep;93(9):2661-2671. doi: 10.1007/s00204-019-02525-3. Epub 2019 Jul 22.
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 μM 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 μM 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.
双酚类似物包括双酚 A 及其衍生物，是普遍存在的环境污染物，已被证实对动物和人类的神经发育有不良影响。大多数毒理学研究集中在雌激素受体介导的途径上，并没有全面阐明观察到的毒性。O-GlcNAcase（OGA）是大脑中含量最高的酶，在从分子到动物行为的多个层面上对神经元功能起着关键的调控作用。在这项工作中，我们旨在通过鉴定双酚类似物的细胞靶标及其产生的影响，来研究其神经毒性的潜在分子机制。我们开发的电化学生物传感器研究了七种双酚类似物在分子水平上对 OGA 活性的抑制作用。我们发现它们的效力因取代基的不同而不同，其中四溴双酚 A（TBBPA）的效力最强。七种双酚类似物（0-100μM 暴露）显著抑制 PC12 细胞中的 OGA 活性和蛋白 O-GlcNAcylation 水平。双酚类似物对 OGA 的抑制进一步诱导细胞内钙、ROS、炎症反应，抑制增殖，干扰细胞周期，诱导细胞凋亡。特别是，10μM 四溴双酚 A（TBBPA）暴露会损害人神经干细胞（hNSCs）中神经突的生长和发育。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 作为双酚类似物的新细胞靶标，将阐明双酚类似物神经毒性的分子机制。
