Exposure to zinc oxide nanoparticles inhibits preimplantation embryonic development by disrupting zygotic genome activation

The potential adverse effects of zinc oxide nanoparticles (ZnONPs) on human reproductive health may arise from their increasing industrial and commercial applications. However, their effects on preimplantation embryonic development and the related molecular mechanisms are still not well understood. Here, we demonstrate that ZnONPs exposure exhibit toxicity to a critical developmental period in mice. We observed that sustained exposure to ZnONPs in vitro resulted in embryonic development arrest at the 2-cell stage. To identify the susceptible stage, we controlled experiments to treat embryos with ZnONPs in the different processes of early embryonic development and determined that ZnONPs mainly to affect 2-cell stage embryos. According to the RNA-seq and EU (5-ethynyl uridine) analysis, the transcriptional activity of minor ZGA genes increased in the late 2-cell embryos following ZnONPs exposure. Subsequently, we employed multi-omics assays, including CUT&Tag and ATAC-seq. We found that ZnONPs exposure led to increased enrichment of H3K27ac (Histone H3 acetylated lysine 27) in late 2-cell embryos and enhanced chromatin accessibility, which led to abnormal upregulation of minor zygotic genome activation (ZGA) genes. In addition, the direct occupancy of ZnONPs at H3K27ac modification sites was verified through pulldown and immunoprecipitation. In conclusion, our findings demonstrate that ZnONPs exposure disrupting minor ZGA by interfering with H3K27ac erasure on the embryonic genome and ultimately impairing the developmental potential of embryos.