Ultrafine Particulate Matter Exacerbates the Risk of Delayed Neural Differentiation: Modulation Role of METTL3-Mediated mA Modification.

Air pollution, especially from ultrafine particles (PM, ≤0.1 μm), is increasingly recognized for its detrimental effects on health. The influence of PM on neurodevelopmental disorders and its underlying mechanisms remain incompletely understood but are of significant concern. Through an investigation using mouse embryonic stem cells (mESCs), our study has uncovered disruptions in cell cycle dynamics, reduced neural precursor formation, and impaired neurogenesis during mESC neural differentiation as a result of PM-induced neurodevelopmental toxicity. By employing 6-methyladenosine (mA) methylated RNA immunoprecipitation sequencing and bioinformatics, we identified as a key target of PM-induced developmental disturbances. Our mechanistic findings indicate that PM enhances mA methylation of by upregulating , leading to decreased mRNA stability and expression of this gene. Furthermore, the efficacy of the METTL3 inhibitor in alleviating nerve differentiation impairments emphasizes the significance of this pathway. In addition, source analysis, molecular docking, and toxicity analyses show that PAHs with higher ring structures in PM from combustion sources competitively bind to METTL3, potentially exacerbating neurodevelopmental toxicity. This study not only underscores the severe impact of PM on neurodevelopment but also reveals the pivotal role of mA modification in mediating these effects, providing valuable insights and potential therapeutic targets for mitigating PM-related health risks.