Extensive production and usage of commercially available products containing TiO2 NPs have led to accumulation in the human body. The deposition of TiO2 NPs has even been detected in the human placenta, which raises concerns regarding fetal health. Previous studies regarding developmental toxicity have frequently focused on TiO2 NPs < 50 nm, whereas the potential adverse effects of large-sized TiO2 NPs received less attention. Placental vasculature is essential for maternal–fetal circulatory exchange and ensuring fetal growth. This study explores the impacts of TiO2 NPs (100 nm in size) on the placenta and fetal development and elucidates the underlying mechanism from the perspective of placental vasculature. Pregnant C57BL/6 mice were exposed to TiO2 NPs by gavage at daily dosages of 10, 50, and 250 mg/kg from gestational day 0.5–16.5. TiO2 NPs penetrated the placenta and accumulated in the fetal mice. The fetuses in the TiO2 NP-exposed groups exhibited a dose-dependent decrease in body weight and length, as well as in placental weight and diameter. In vivo imaging showed an impaired placental barrier, and pathological examinations revealed a disrupted vascular network of the labyrinth upon TiO2 NP exposure. We also found an increase in gene expression related to the transforming growth factor-β (TGF-β) -SNAIL pathway and the upregulation of mesenchymal markers, accompanied by a reduction in endothelial markers. In addition, TiO2 NPs enhanced the gene expression responsible for the endothelial-to-mesenchymal transition (EndMT) in cultured human umbilical vein endothelial cells, whereas SNAIL knockdown attenuated the induction of EndMT phenotypes. Our study revealed that maternal exposure to 100 nm TiO2 NPs disrupts placental vascular development and fetal mice growth through aberrant activation of EndMT in the placental labyrinth. These data provide novel insight into the mechanisms of developmental toxicity posed by NPs.

中文翻译：

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母亲接触纳米二氧化钛会通过小鼠胎盘迷路的内皮到间质转化阻碍胎儿发育

含有 TiO2 NP 的市售产品的大量生产和使用已导致其在人体内蓄积。甚至在人类胎盘中也检测到了二氧化钛纳米粒子的沉积，这引起了对胎儿健康的担忧。先前关于发育毒性的研究经常集中在<50 nm的TiO2纳米颗粒上，而大尺寸TiO2纳米颗粒的潜在不利影响较少受到关注。胎盘脉管系统对于母胎循环交换和确保胎儿生长至关重要。本研究探讨了TiO2 NPs（尺寸为100 nm）对胎盘和胎儿发育的影响，并从胎盘血管系统的角度阐明了其潜在机制。从妊娠第 0.5 天至 16.5 天，怀孕的 C57BL/6 小鼠通过管饲法暴露于 TiO2 NP，每日剂量为 10、50 和 250 mg/kg。TiO2 NPs 穿透胎盘并在胎鼠体内积累。TiO2 NP 暴露组的胎儿体重和身长以及胎盘重量和直径呈剂量依赖性下降。体内成像显示胎盘屏障受损，病理检查显示暴露于 TiO2 NP 后迷路血管网络遭到破坏。我们还发现与转化生长因子-β (TGF-β) -SNAIL 通路相关的基因表达增加，间充质标记物上调，同时内皮标记物减少。此外，TiO2 NPs 增强了培养的人脐静脉内皮细胞中负责内皮间质转化 (EndMT) 的基因表达，而 SNAIL 敲低则减弱了 EndMT 表型的诱导。我们的研究表明，母体暴露于 100 nm TiO2 NPs 会通过胎盘迷路中 EndMT 的异常激活来扰乱胎盘血管发育和胎儿小鼠的生长。这些数据为纳米粒子引起的发育毒性机制提供了新的见解。