Abstract：
Triphenyl phosphate (TPhP) is an organophosphate flame retardant that is widely used in many commercial products. The United States Environmental Protection Agency has listed TPhP as a priority compound that requires health risk assessment. We previously found that TPhP could accumulate in the placentae of mice and impair birth outcomes by activating peroxisome proliferator-activated receptor gamma (PPARγ) in the placental trophoblast. However, the underlying mechanism remains unknown. In this study, we used a mouse intrauterine exposure model and found that TPhP induced preeclampsia (PE)-like symptoms, including new on-set gestational hypertension and proteinuria. Immunofluorescence analysis showed that during placentation, PPARγ was mainly expressed in the labyrinth layer and decidua of the placenta. TPhP significantly decreased placental implantation depth and impeded uterine spiral artery remodeling by activating PPARγ. The results of the in vitro experiments confirmed that TPhP inhibited extravillous trophoblast (EVT) cell migration and invasion by activating PPARγ and inhibiting the PI3K-AKT signaling pathway. Overall, our data demonstrated that TPhP could activate PPARγ in EVT cells, inhibit cell migration and invasion, impede placental implantation and uterine spiral artery remodeling, then induce PE-like symptom and impair birth outcomes. Although the exposure doses used in this study was several orders of magnitude higher than human daily intake, our study highlights the placenta as a potential target organ of TPhP worthy of further research.
摘要：
磷酸三苯酯（TPhP）是一种有机磷酸酯阻燃剂，广泛用于许多商业产品中。美国环境保护局已将TPhP列为需要进行健康风险评估的优先化合物。我们先前发现TPhP可以通过激活胎盘滋养层中的过氧化物酶体增殖物激活受体γ（PPARγ）在小鼠的胎盘中积累并损害出生结局。然而,潜在的机制仍然未知。在这项研究中,我们使用小鼠宫内暴露模型，发现TPhP诱导了子痫前期（PE）样症状，包括新的妊娠高血压和蛋白尿。免疫荧光分析显示，在胎盘形成过程中，PPARγ主要在胎盘的迷宫层和蜕膜中表达。TPhP通过激活PPARγ显著降低胎盘植入深度并阻碍子宫螺旋动脉重塑。体外实验结果证实TPhP通过激活PPARγ和抑制PI3K-AKT信号通路抑制绒毛外滋养层（EVT）细胞迁移和侵袭。总的来说,我们的数据表明，TPhP可以激活EVT细胞中的PPARγ，抑制细胞迁移和侵袭，阻碍胎盘植入和子宫螺旋动脉重塑，然后诱发PE样症状并损害分娩结局。尽管本研究中使用的暴露剂量比人类每日摄入量高几个数量级，我们的研究强调胎盘是TPhP的潜在靶器官，值得进一步研究。
