Ultrafine Particulate Matter Exacerbates the Risk of Delayed Neural Differentiation: Modulation Role of METTL3-Mediated m6A Modification

Air pollution, especially from ultrafine particles (PM0.1, ≤0.1 μm), is increasingly recognized for its detrimental effects on health. The influence of PM0.1 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 PM0.1-induced neurodevelopmental toxicity. By employing N6-methyladenosine (m6A) methylated RNA immunoprecipitation sequencing and bioinformatics, we identified Zic1 as a key target of PM0.1-induced developmental disturbances. Our mechanistic findings indicate that PM0.1 enhances m6A methylation of Zic1 by upregulating Mettl3, 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 PM0.1 from combustion sources competitively bind to METTL3, potentially exacerbating neurodevelopmental toxicity. This study not only underscores the severe impact of PM0.1 on neurodevelopment but also reveals the pivotal role of m6A modification in mediating these effects, providing valuable insights and potential therapeutic targets for mitigating PM0.1-related health risks.