Multi-omics analysis reveals zinc oxide nanoparticles impair mouse pre-implantation embryonic development via H3K9me3-dependent heterochromatin alterations. Mus musculus

The widespread application of zinc oxide nanoparticles (ZnONPs) has raised significant health concerns for humans. However, the effect of ZnONPs exposure on pre-implantation embryonic development and its underlying mechanisms is not well understood. This study reveals that ZnONPs exposure, both in vitro and in vivo, impairs pre-implantation embryonic development. Moreover, ZnONPs reduce the pluripotency of mouse embryonic stem cells (mESCs), as demonstrated by teratoma and diploid chimera assays. We employed multi-omics approaches, including RNA-Seq, CUT&Tag, and ATAC-seq, to elucidate the embryotoxicity mechanisms of ZnONPs. Our findings demonstrate that ZnONPs can elevate the level of H3K9me3, thereby increasing the corresponding heterochromatin, and subsequently inhibit development and pluripotency-related genes in inner cell mass (ICM) and mESCs. Further, we confirmed the direct interaction of ZnONPs with H3K9me3 through pull-down and immunoprecipitation assays. Collectively, our findings offer new insights for understanding the toxicity of ZnONPs on human reproductive health from the epigenetic mechanism perspective.