Liu Chaoyang, Liu Zehua, Fang Yanyan, Liao Zizhuo, Zhang Zhibing, Yuan Xin, Yu Ting, Yang Yunying, Xiong Min, Zhang Xingyu, Zhang Guoxin, Meng Lanxia, Zhang Zhentao
Department of Neurology, Renmin Hospital of Wuhan University, Wuhan 430060, China; Research Center for Environment and Health, Zhongnan University of Economics and Law, Wuhan 430073, China; Department of Environmental Engineering, Zhongnan University of Economics and Law, Wuhan 430073, China.
Research Center for Environment and Health, Zhongnan University of Economics and Law, Wuhan 430073, China; Department of Environmental Engineering, Zhongnan University of Economics and Law, Wuhan 430073, China.
Environ Int. 2023 Jan;171:107696. doi: 10.1016/j.envint.2022.107696. Epub 2022 Dec 14.
Maneb, a widely-used dithiocarbamate fungicide, remains in the environment and exerts adverse health effects. Epidemiological evidence shows that maneb exposure is associated with a higher risk of Parkinson's disease (PD), one of the most common neurodegenerative diseases. However, the molecular mechanisms underlying maneb-induced neurotoxicity remain unclear. Here we investigated the toxic effects and the underlying mechanisms of maneb on the degeneration of dopaminergic cells and α-synuclein in A53T transgenic mice. In SH-SY5Y cells, exposure to maneb reduces cell viability, triggers neuronal apoptosis, induces mitochondrial dysfunction, and generates reactive oxidative species (ROS) in a dose-dependent manner. Furthermore, Western blot analysis found that the mitochondrial apoptosis pathway (Bcl-2, Bax, cytochrome c, activated caspase-3) and the PKA/CREB signaling pathway (PKA, PDE10A, CREB, p-CREB) were changed by maneb both in vitro and in vivo. In addition, the activation of the mitochondrial apoptosis pathway induced by maneb was attenuated by activating PKA. Therefore, these results suggest that the PKA/CREB signaling pathway is involved in maneb-induced apoptosis. This study provides novel insights into maneb-induced neurotoxicity and the underlying mechanisms, which may serve as a guide for further toxicological assessment and standard application of maneb.
代森锰锌是一种广泛使用的二硫代氨基甲酸盐类杀菌剂，会残留在环境中并对健康产生不良影响。流行病学证据表明，接触代森锰锌会增加患帕金森病（PD）的风险，帕金森病是最常见的神经退行性疾病之一。然而，代森锰锌诱导神经毒性的分子机制仍不清楚。在此，我们研究了代森锰锌对A53T转基因小鼠多巴胺能细胞变性和α-突触核蛋白的毒性作用及其潜在机制。在SH-SY5Y细胞中，接触代森锰锌会降低细胞活力，引发神经元凋亡，诱导线粒体功能障碍，并以剂量依赖的方式产生活性氧化物质（ROS）。此外，蛋白质印迹分析发现，线粒体凋亡途径（Bcl-2、Bax、细胞色素c、活化的半胱天冬酶-3）和PKA/CREB信号通路（PKA、PDE10A、CREB、p-CREB）在体外和体内均因代森锰锌而发生改变。此外，激活PKA可减弱代森锰锌诱导的线粒体凋亡途径的激活。因此，这些结果表明PKA/CREB信号通路参与了代森锰锌诱导的凋亡。本研究为代森锰锌诱导的神经毒性及其潜在机制提供了新的见解，这可能为代森锰锌的进一步毒理学评估和标准应用提供指导。
