School of Public Health, Guangxi Medical University, Nanning 530021, China.
School of Basic Medical Sciences, Guangxi Medical University, Nanning 530021, China; Key Laboratory of Basic Research on Regional Diseases (Guangxi Medical University) , Education Department of Guangxi Zhuang Autonomous Region, Nanning 530021, China.
Ecotoxicol Environ Saf. 2024 Jun 1;277:116365. doi: 10.1016/j.ecoenv.2024.116365. Epub 2024 Apr 24.
Microglia, the resident immune cells of the central nervous system (CNS), play a dual role in neurotoxicity by releasing the NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome and brain-derived neurotrophic factor (BDNF) in response to environmental stress. Suppression of BDNF is implicated in learning and memory impairment induced by exposure to manganese (Mn) or lead (Pb) individually. Methyl CpG Binding Protein 2 (MeCp2) and its phosphorylation status are related to BDNF suppression. Protein phosphatase2A (PP2A), a member of the serine/threonine phosphatases family, dephosphorylates substrates based on the methylation state of its catalytic C subunit (PP2Ac). However, the specific impairment patterns and molecular mechanisms resulting from co-exposure to Mn and Pb remain unclear. Therefore, the purpose of this study was to explore the effects of Mn and Pb exposure, alone and in combination, on inducing neurotoxicity in the hippocampus of mice and BV2 cells, and to determine whether simultaneous exposure to both metals exacerbate their toxicity. Our findings reveal that co-exposure to Mn and Pb leads to severe learning and memory impairment in mice, which correlates with the accumulation of metals in the hippocampus and synergistic suppression of BDNF. This suppression is accompanied by up-regulation of the epigenetic repressor MeCp2 and its phosphorylation status, as well as demethylation of PP2Ac. Furthermore, inhibition of PP2Ac demethylation using ABL127, an inhibitor for its protein phosphatase methylesterase1 (PME1), or knockdown of MeCp2 via siRNA transfection in vitro effectively increases BDNF expression and mitigates BV2 cell damage induced by Mn and Pb co-exposure. We also observe abnormal activation of microglia characterized by enhanced release of the NLRP3 inflammasome, Casepase-1 and pro-inflammatory cytokines IL-1β, in the hippocampus of mice and BV2 cells. In summary, our experiments demonstrate that simultaneous exposure to Mn and Pb results in more severe hippocampus-dependent learning and memory impairment, which is attributed to epigenetic suppression of BDNF mediated by PP2A regulation.
小胶质细胞是中枢神经系统（CNS）的固有免疫细胞，在环境应激下通过释放 Nlrp3 炎性小体和脑源性神经营养因子（BDNF）发挥双重作用。BDNF 的抑制作用与锰（Mn）或铅（Pb）单独暴露引起的学习和记忆损伤有关。甲基 CpG 结合蛋白 2（MeCp2）及其磷酸化状态与 BDNF 抑制有关。蛋白磷酸酶 2A（PP2A）是丝氨酸/苏氨酸磷酸酶家族的成员，根据其催化 C 亚基（PP2Ac）的甲基化状态使底物去磷酸化。然而，Mn 和 Pb 共同暴露引起的具体损伤模式和分子机制尚不清楚。因此，本研究旨在探讨 Mn 和 Pb 单独和联合暴露对小鼠海马和 BV2 细胞神经毒性的影响，以及两种金属同时暴露是否会加剧其毒性。我们的研究结果表明，Mn 和 Pb 联合暴露会导致小鼠严重的学习和记忆损伤，这与金属在海马中的积累以及 BDNF 的协同抑制有关。这种抑制伴随着表观遗传抑制因子 MeCp2 的上调及其磷酸化状态，以及 PP2Ac 的去甲基化。此外，通过 ABL127 抑制 PP2Ac 的去甲基化（其蛋白磷酸酶甲硫醇酯酶 1（PME1）抑制剂），或通过 siRNA 转染体外敲低 MeCp2，有效增加 BDNF 的表达并减轻 Mn 和 Pb 联合暴露诱导的 BV2 细胞损伤。我们还观察到小胶质细胞的异常激活，表现为 NLRP3 炎性小体、半胱天冬酶-1 和促炎细胞因子 IL-1β的释放增加，这在小鼠海马和 BV2 细胞中均有体现。综上所述，我们的实验表明，Mn 和 Pb 同时暴露会导致更严重的海马依赖性学习和记忆损伤，这归因于 PP2A 调节的 BDNF 的表观遗传抑制。
