Lead, cadmium, arsenic, and mercury combined exposure disrupted synaptic homeostasis through activating the Snk-SPAR pathway
Lead, cadmium, arsenic, and mercury combined exposure disrupted synaptic homeostasis through activating the Snk-SPAR pathway
复制标题
铅、镉、砷和汞的联合暴露通过激活 Snk-SPAR 通路破坏了突触稳态
DOI：
10.1016/j.ecoenv.2018.07.116
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发表时间：
2018
影响因子：
6.8
通讯作者：
Fan Guangqin
中科院分区：
文献类型：
--
作者：
Zhou Fankun;Xie Jie;Zhang Shuyun;Yin Guangming;Gao Yanyan;Zhang Yuanyuan;Bo D;an;Li Zongguang;Liu Sisi;Feng Chang;Fan Guangqin
铅（Pb）、镉（Cd）、砷（As）和汞（Hg）是环境中检测到的主要有毒物质，它们也同时在一般人群的血液、血清和尿液样本中检测到。铅、镉、砷、汞污染区儿童存在早期神经系统损害和多种交互作用。然而，目前对这四种金属的研究大多局限于任意两种金属之间的相互作用，而对任意三种或四种金属之间的相互作用特性研究甚少。在本研究中，我们首先采用析因设计探讨了这四种元素在神经细胞中的神经毒性相互作用的特点。结果表明，铅、镉、砷、汞联合暴露具有协同神经毒性效应，当铅、镉、砷、汞中的个别金属处于人体环境暴露（美国人群血液中）相关水平且低于无明显不良反应水平（NOAEL）时，其毒性效应比任何两种或三种金属所引起的毒性效应更严重。因此，本研究进一步选择了铅、镉、砷、汞等人类环境暴露相关水平的联合暴露，以研究突触稳态作为学习记忆的细胞和分子基础。我们首次报道，铅+镉+砷+汞共暴露诱导剂量依赖性的减少树突的长度和分支，以及棘密度和成熟的表型在原代海马神经元，和刺激的神经突起生长在神经生长因子分化的PC 12细胞。上述突触稳态破坏与血清诱导激酶（Snk）-棘相关Rap GT3激活蛋白（SPAR）通路有关。我们的研究表明，人类环境铅，镉，砷和汞的共同暴露有可能引起协同神经毒性，即使他们的个别金属低于NOAEL，这加强了需要控制和规范潜在的金属污染源。
Lead (Pb), cadmium (Cd), arsenic (As), and mercury (Hg) are among the leading toxic agents detected in the environment, and they have also been detected simultaneously in blood, serum, and urine samples of the general population. Meanwhile early neurologic effects and multiple interactions of Pb, Cd, As, and Hg had been found in children from environmentally polluted area. However, the current studies of these four metals were mostly limited to the interactions between any two metals, whereas the interaction characteristics between any three and four metals were rarely studied. In our study, we firstly explored the characteristics of the neurotoxic interactions among these four elements in nerve cells with factorial designs. The results showed that Pb+Cd+As+Hg co-exposure had a synergistic neurotoxic effect that was more severe than that induced by any two or three metals, when their individual metals were at human environmental exposure (in the blood of U.S. population) relevant levels and below no observed adverse effect levels (NOAELs). Therefore, Pb+Cd+As+Hg co-exposure at human environmental exposure relevant levels were further selected to examine synaptic homeostasis as the cellular and molecular foundation of learning and memory. We reported for the first time that Pb+Cd+As+Hg co-exposure induced dose-dependent decreases of the dendritic lengths and branching, as well as spine density and mature phenotype in primary hippocampal neurons, and the stimulated neurite outgrowths in NGF-differentiated PC12 cells. And the above synaptic homeostasis disruption was associated with serum induced kinase (Snk)-spine associated Rap GTPase activating protein (SPAR) pathway. Our study suggests that human environmental Pb, Cd, As, and Hg co-exposure has the potential to evoke synergistic neurotoxicity even if their individual metals are below NOAELs, which reinforces the need to control and regulate potential sources of metal contamination.