Copper oxide nanoparticles impair zygotic genome activation in mouse embryos by disrupting H3K27ac-mediated chromatin remodeling

Given the widespread application of copper oxide nanoparticles (CuONPs), their biosafety has attracted significant attention. However their effects on the developmental capacity of mammalian preimplantation embryos and the underlying mechanisms remain unclear. In this study, we first showed that CuONPs exposure inhibits preimplantation embryo development. The embryotoxicity induced by CuONPs exposure exhibits concentration- and time-dependent effects. Subsequently, through controlled variable experiments with CuONPs-treated embryos, we found that CuONPs primarily affect embryos at the 2-cell stage and a decreased in the level of histone H3 lysine 27 acetylation (H3K27ac) compared to the control group. Further multi-omics sequencing analysis showed that CuONPs lead to reduced enrichment of H3K27ac on zygotic genome activation (ZGA) genes and a marked decrease in chromatin accessibility. At the end, we demonstrated that CuONPs could bind to histone H3 and then occupy the H3K27ac modification sites. In conclusion, our findings indicate that CuONPs exposure interferes with the establishment of H3K27ac on the embryonic genome, resulting in ZGA failure and developmental arrest at the 2-cell stage.