The biological effects of cerium dioxide nanoparticles (CeO2NPs), a novel material in the biomedical field, have attracted widespread attention. Our previous study confirmed that exposure to CeO2NPs during pregnancy led to abnormal trophoblast invasion during early placental development, thereby impairing placental development. The potential mechanisms may be related to low-quality decidualization triggered by CeO2NPs exposure, such as an imbalance in trophoblast invasion regulators secreted by decidual cells. However, the intermediate link mediating the “dialogue” between decidual cells and trophoblasts during this process remains unclear. As an important connection between cells, exosomes participate in the “dialogue” between endometrial cells and trophoblasts. Exosomes transfer bioactive microRNA into target cells, which can target and regulate the level of mRNA in target cells. Here, we constructed a mice primary uterine stromal cell-induced decidualization model in vitro, and detected the effect of CeO2NPs exposure on the expression of decidual-derived exosomal miRNAs by high-throughput sequencing. Bioinformatics analysis and dual-luciferase reporter assays were performed to identify target genes of the screened key miRNAs in regulating trophoblast invasion. Finally, the role of the screened miRNAs and their target genes in regulating trophoblast (HTR-8/SVneo cells) invasion was confirmed. The results showed that CeO2NPs exposure inhibited trophoblast invasion by promoting miR-99a-5p expression in decidual-derived exosomes, and Ppp2r5a is a potential target gene for miR-99a-5p to inhibit trophoblast invasion. This study revealed the molecular mechanism by which CeO2NPs exposure inhibits trophoblast invasion from the perspective of decidual derived exosomal miRNAs. These results will provide an experimental basis for screening potential therapeutic targets for the negative biological effects of CeO2NPs exposure and new ideas for studying the mechanism of damage to trophoblast cells at the decidual-foetal interface by harmful environmental or occupational factors.

中文翻译：

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蜕膜来源的外泌体 miR-99a-5p 靶向 Ppp2r5a 以抑制响应于 CeO2NPs 暴露的滋养细胞侵袭

纳米二氧化铈（CeO2NPs）作为生物医学领域的一种新型材料，其生物学效应引起了广泛关注。我们之前的研究证实，怀孕期间暴露于 CeO2NPs 会导致胎盘早期发育过程中异常的滋养细胞侵袭，从而损害胎盘发育。潜在的机制可能与 CeO2NPs 暴露引发的低质量蜕膜化有关，例如蜕膜细胞分泌的滋养层入侵调节因子失衡。然而，在此过程中介导蜕膜细胞和滋养细胞之间“对话”的中间环节仍不清楚。外泌体作为细胞间的重要联系，参与子宫内膜细胞与滋养细胞的“对话”。外泌体将具有生物活性的 microRNA 转移到靶细胞中，它可以靶向和调节靶细胞中 mRNA 的水平。在这里，我们在体外构建了小鼠原代子宫基质细胞诱导的蜕膜化模型，并通过高通量测序检测了 CeO2NPs 暴露对蜕膜来源的外泌体 miRNA 表达的影响。进行了生物信息学分析和双荧光素酶报告基因测定，以确定筛选的关键 miRNA 在调节滋养层侵袭中的靶基因。最后，证实了筛选的miRNA及其靶基因在调节滋养层（HTR-8/SVneo细胞）侵袭中的作用。结果表明，CeO2NPs暴露通过促进蜕膜来源外泌体中miR-99a-5p的表达来抑制滋养细胞侵袭，Ppp2r5a是miR-99a-5p抑制滋养细胞侵袭的潜在靶基因。本研究从蜕膜来源的外泌体 miRNA 的角度揭示了 CeO2NPs 暴露抑制滋养细胞侵袭的分子机制。这些结果将为筛选CeO2NPs暴露的负面生物学效应的潜在治疗靶点提供实验基础，为研究有害环境或职业因素对蜕膜-胎儿界面滋养层细胞的损伤机制提供新思路。