Maternal exposure to nano-titanium dioxide impedes fetal development via endothelial-to-mesenchymal transition in the placental labyrinth in mice

Abstract

Background: 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.

Results: 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.

Conclusion: 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.

Keywords: Blood vessel; Developmental toxicity; Endothelial-to-mesenchymal transition; Placenta; Titanium dioxide nanoparticle.