Abstract：
The widespread application of nanoparticles (NPs) in various fields has raised health concerns, especially in reproductive health. Our research has shown zinc oxide nanoparticles (ZnONPs) exhibit the most significant toxicity to pre-implantation embryos in mice compared to other common NPs. In patients undergoing assisted reproduction technology (ART), a significant negative correlation was observed between Zn concentration and clinical outcomes. Therefore, this study explores the impact of ZnONPs exposure on pre-implantation embryonic development and its underlying mechanisms. We revealed that both in vivo and in vitro exposure to ZnONPs impairs pre-implantation embryonic development. Moreover, ZnONPs were found to reduce the pluripotency of mouse embryonic stem cells (mESCs), as evidenced by teratoma and diploid chimera assays. Employing multi-omics approaches, including RNA-Seq, CUT&Tag, and ATAC-seq, the embryotoxicity mechanisms of ZnONPs were elucidated. The findings indicate that ZnONPs elevate H3K9me3 levels, leading to increased heterochromatin and consequent inhibition of gene expression related to development and pluripotency. Notably, Chaetocin, a H3K9me3 inhibitor, sucessfully reversed the embryotoxicity effects induced by ZnONPs. Additionally, the direct interaction between ZnONPs and H3K9me3 was verified through pull-down and immunoprecipitation assays. Collectively, these findings offer new insights into the epigenetic mechanisms of ZnONPs toxicity, enhancing our understanding of their impact on human reproductive health.
摘要：
纳米粒子(NPs)在各个领域的广泛应用引发了人们对健康的关注,尤其是在生殖健康方面。我们的研究表明，与其他常见NP相比，氧化锌纳米颗粒（ZnONPs）对小鼠植入前胚胎表现出最显著的毒性。在接受辅助生殖技术（ART）的患者中，锌浓度与临床结局之间存在显著负相关.因此,本研究探讨了ZnONPs暴露对植入前胚胎发育的影响及其潜在机制。我们发现，体内和体外暴露于ZnONPs都会损害植入前的胚胎发育。此外，发现ZnONPs降低小鼠胚胎干细胞（mESCs）的多能性，畸胎瘤和二倍体嵌合体试验证明了这一点。采用多组学方法，包括RNA-Seq,CUT&Tag,和ATAC-seq，阐明了ZnONPs的胚胎毒性机制。研究结果表明，ZnONPs升高H3K9me3水平，导致异染色质增加，从而抑制与发育和多能性相关的基因表达。值得注意的是,Chaetocin,H3K9me3抑制剂，成功逆转了ZnONPs诱导的胚胎毒性效应。此外,ZnONPs和H3K9me3之间的直接相互作用通过下拉法和免疫沉淀法得到验证。总的来说，这些发现为ZnONPs毒性的表观遗传机制提供了新的见解，提高我们对它们对人类生殖健康影响的认识。
