Fujian Provincial Key Laboratory of Environmental Factors and Cancer, School of Public Health, Fujian Medical University, Fuzhou, 350122, China; Department of Preventive Medicine, School of Public Health, Fujian Medical University, Fuzhou, 350122, China.
Fujian Provincial Key Laboratory of Environmental Factors and Cancer, School of Public Health, Fujian Medical University, Fuzhou, 350122, China; The Key Laboratory of Environment and Health, School of Public Health, Fujian Medical University, Fuzhou, 350122, China.
Environ Pollut. 2022 Mar 15;297:118749. doi: 10.1016/j.envpol.2021.118749. Epub 2021 Dec 27.
Cobalt is an environmental toxicant that is known to damage human health. However, the molecular mechanisms underlying cobalt-induced neurotoxicity have not been elucidated in detail. In the present research, we used human neuroglioma H4 cells as an in vitro model. Cells were exposed to CoCl (0, 100, 200, 400 μM) for 24 h. We performed mA sequencing techniques and constructed FTO-knockdown/FTO-overexpressing cells to investigate the role of FTO-mediated mA modification in regulating apoptosis following CoCl induced oxidative stress. Our study has shown CoCl exposure led to the decrease of demethylase FTO as well as elevated oxidative stress. However, NAC treatment could partly reverse the reduction of FTO expression as well as the degree of ROS via eliminating oxidative stress. Meanwhile, MeRIP-seq and RNA-seq further revealed the potential function mA modification in regulating apoptosis. More importantly, KEGG pathway and Gene ontology (GO) analyses further elucidated that the differentially mA-modified genes were aggregated in apoptosis-related pathways. Mechanistic analysis indicated that knockdown of FTO facilitated CoCl-induced apoptosis via caspase activation and G1/S cell cycle arrest. Nevertheless, overexpression of FTO partly attenuated the increased apoptosis following CoCl exposure. More notably, we observed that FTO regulated apoptosis in an mA-dependent manner. Therefore, our findings reveal that CoCl induced ROS affected the mA modification of apoptosis-related genes by decreasing the expression of FTO, thereby resulting in the activation of apoptosis. These findings provide important insights into CoCl-induced apoptosis and mA modification and propose a novel strategy for studying environmental toxicant-related neurodegeneration.
钴是一种环境毒物，已知会损害人类健康。然而，钴诱导神经毒性的分子机制尚未详细阐明。在本研究中，我们使用人神经胶质瘤 H4 细胞作为体外模型。细胞暴露于 CoCl（0、100、200、400 μM）24 小时。我们进行了 mA 测序技术，并构建了 FTO 敲低/FTO 过表达细胞，以研究 FTO 介导的 mA 修饰在调节 CoCl 诱导的氧化应激后细胞凋亡中的作用。我们的研究表明，CoCl 暴露导致去甲基酶 FTO 的减少以及氧化应激的增加。然而，NAC 处理可以部分逆转 FTO 表达的减少以及 ROS 的程度，通过消除氧化应激。同时，MeRIP-seq 和 RNA-seq 进一步揭示了 mA 修饰在调节细胞凋亡中的潜在功能。更重要的是，KEGG 通路和基因本体论（GO）分析进一步阐明了差异 mA 修饰的基因聚集在细胞凋亡相关途径中。机制分析表明，FTO 的敲低通过半胱氨酸天冬氨酸蛋白酶激活和 G1/S 细胞周期阻滞促进 CoCl 诱导的细胞凋亡。然而，FTO 的过表达部分减轻了 CoCl 暴露后增加的细胞凋亡。更值得注意的是，我们观察到 FTO 通过 mA 依赖性方式调节细胞凋亡。因此，我们的研究结果表明，CoCl 诱导的 ROS 通过降低 FTO 的表达来影响细胞凋亡相关基因的 mA 修饰，从而导致细胞凋亡的激活。这些发现为 CoCl 诱导的细胞凋亡和 mA 修饰提供了重要的见解，并提出了研究环境毒物相关神经退行性变的新策略。
