Department of Environmental Health, College of Public Health, Zhengzhou University, Zhengzhou, Henan province, China; Environment and Health Innovation Team, College of Public Health, Zhengzhou University, Zhengzhou, Henan province 450001, China.
Department of Environmental Health, College of Public Health, Zhengzhou University, Zhengzhou, Henan province, China.
Int J Biol Macromol. 2022 Sep 30;217:219-228. doi: 10.1016/j.ijbiomac.2022.07.060. Epub 2022 Jul 13.
To investigate the mechanism of Silent information regulator 1 (SIRT1) regulation of DNA methylation and thus the expression of synaptic plasticity-related genes induced by lead (Pb) exposure, the early-life Sprague-Dawley rats and PC12 cells were used to establish Pb exposure models and treated with SIRT1 agonists (resveratrol and SRT1720). In vivo results demonstrated that Pb exposure increased the expression of DNMTs, MeCP2, PP1 and cleaved caspase3, decreased the expression of SIRT1, BDNF and RELIN and altered DNA methylation levels of synaptic plasticity genes. Moreover, we observed marked pathological damage in the hippocampal CA1 region of the 0.2 % Pb-exposure group. After treatment with resveratrol, the effects of Pb exposure on the expression of the above molecules and pathological features were significantly ameliorated in the hippocampus of rats. In vitro results showed that after the treatment with SRT1720, the expression of SIRT1 was activated and thus reversed the effect on DNMTs, MeCP2, apoptosis and synaptic plasticity-related genes and their DNA methylation levels induced by Pb exposure. In conclusion, we validated the important protective role of SIRT1 in neurotoxicity induced by Pb exposure through in vivo and in vitro experiments, providing potential therapeutic targets for the treatment and prevention of brain damage.
为了研究沉默信息调节因子 1（SIRT1）调节 DNA 甲基化的机制，从而探讨铅（Pb）暴露诱导的突触可塑性相关基因表达的机制，本研究使用早期生活的 Sprague-Dawley 大鼠和 PC12 细胞建立了 Pb 暴露模型，并使用 SIRT1 激动剂（白藜芦醇和 SRT1720）进行处理。体内结果表明，Pb 暴露增加了 DNMTs、MeCP2、PP1 和 cleaved caspase3 的表达，降低了 SIRT1、BDNF 和 RELIN 的表达，并改变了突触可塑性基因的 DNA 甲基化水平。此外，我们观察到 0.2% Pb 暴露组大鼠海马 CA1 区有明显的病理损伤。用白藜芦醇处理后，Pb 暴露对上述分子表达和大鼠海马病理特征的影响明显减轻。体外结果表明，SRT1720 处理后，SIRT1 的表达被激活，从而逆转了 Pb 暴露对 DNMTs、MeCP2、凋亡和突触可塑性相关基因及其 DNA 甲基化水平的影响。总之，本研究通过体内和体外实验验证了 SIRT1 在 Pb 暴露诱导的神经毒性中的重要保护作用，为治疗和预防脑损伤提供了潜在的治疗靶点。
