School of Food Science and Engineering, Hefei University of Technology, Hefei, Anhui Province 230009, PR China.
Toxicol Sci. 2018 Apr 1;162(2):688-701. doi: 10.1093/toxsci/kfx294.
Lead (Pb) prevails among the environmental hazards against human health. Although increasing evidence highlights the epigenetic roles underlying the Pb-induced neurotoxicity, the exact mechanisms concerning histone acetylation and its causative agents are still at its infancy. In the present study, the roles of histone deacetylases 1 and 2 (HDAC1/2), as well as acetylation of Lys9 on histone H3 (Ac-H3K9), in Pb-induced neurotoxicity were investigated. Pb was administered to PC12 cells at 10 μM for 24 h. And Sprague Dawley rats were chronically exposed to Pb through drinking water containing 250 ppm Pb for 2 months. Owing to Pb exposure, it indicated that HDAC2 was up-regulated accompanied by Ac-H3K9 down-regulation. Meanwhile, chromatin immunoprecipitation assay revealed that the changes in HDAC2 were attributed to histone H3 Lys27 trimethylation occupancy on its promoter. Blockade of HDAC2 with either Trichostatin A or HDAC2-knocking down construct (shHDAC2) resulted in amelioration of neurite outgrowth deficits via increasing Ac-H3K9 levels. It implied that HDAC2 plays essential regulatory roles in Pb-induced neurotoxicity. And, coimmunoprecipitation trials revealed that HDAC2 colocalized with HDAC1, forming a so-called HDAC1/2 complex. Subsequently, it was shown that HDAC1/2 repression could markedly prevent neurite outgrowth impairment and rescue the spatial memory deficits caused by Pb exposure, unequivocally implicating this complex in the studied toxicological process. Furthermore, Notch2 maybe the functional target of the HDAC1/2 and Ac-H3K9 alterations. Our study provided insight into the precise roles of HDAC1/2 in Pb-induced neurotoxicity, and thereby provided a promising molecular target for medical intervention of neurological disorders with environmental etiology.
铅（Pb）是对人类健康构成环境危害的主要因素之一。尽管越来越多的证据强调了 Pb 诱导神经毒性的表观遗传作用，但有关组蛋白乙酰化及其引发剂的确切机制仍处于起步阶段。在本研究中，研究了组蛋白去乙酰化酶 1 和 2（HDAC1/2）以及组蛋白 H3 赖氨酸 9 上的乙酰化（Ac-H3K9）在 Pb 诱导的神经毒性中的作用。将 Pb 以 10 μM 的浓度施用于 PC12 细胞 24 小时。并用含有 250 ppm Pb 的饮用水对 Sprague Dawley 大鼠进行慢性 Pb 暴露，持续 2 个月。由于 Pb 暴露，结果表明 HDAC2 上调，同时 Ac-H3K9 下调。同时，染色质免疫沉淀试验表明，HDAC2 的变化归因于其启动子上组蛋白 H3 赖氨酸 27 三甲基化占据。用 Trichostatin A 或 HDAC2 敲低构建体（shHDAC2）阻断 HDAC2，可通过增加 Ac-H3K9 水平改善神经突生长缺陷。这表明 HDAC2 在 Pb 诱导的神经毒性中起重要的调节作用。并且，共免疫沉淀试验表明 HDAC2 与 HDAC1 共定位，形成所谓的 HDAC1/2 复合物。随后表明，HDAC1/2 抑制可显著防止神经突生长损伤，并挽救 Pb 暴露引起的空间记忆缺陷，明确表明该复合物参与了该毒性研究过程。此外，Notch2 可能是 HDAC1/2 和 Ac-H3K9 改变的功能靶标。我们的研究深入了解了 HDAC1/2 在 Pb 诱导的神经毒性中的精确作用，为具有环境病因的神经紊乱的医学干预提供了有前途的分子靶标。
