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

Air pollution, especially from ultrafine particles (PM_0.1, ≤0.1 μm), is increasingly recognized for its detrimental effects on health. The influence of PM_0.1 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 PM_0.1-induced neurodevelopmental toxicity. By employing <i>N</i>6-methyladenosine (m⁶A) methylated RNA immunoprecipitation sequencing and bioinformatics, we identified <i>Zic1</i> as a key target of PM_0.1-induced developmental disturbances. Our mechanistic findings indicate that PM_0.1 enhances m⁶A methylation of <i>Zic1</i> by upregulating <i>Mettl3</i>, 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_0.1 from combustion sources competitively bind to METTL3, potentially exacerbating neurodevelopmental toxicity. This study not only underscores the severe impact of PM_0.1 on neurodevelopment but also reveals the pivotal role of m⁶A modification in mediating these effects, providing valuable insights and potential therapeutic targets for mitigating PM_0.1-related health risks.