School of Public Health, Dongguan Key Laboratory of Environmental Medicine, Guangdong Medical University, Guangdong, 523-808, China.
School of Public Health, Dongguan Key Laboratory of Environmental Medicine, Guangdong Medical University, Guangdong, 523-808, China.
Environ Pollut. 2022 May 15;301:119039. doi: 10.1016/j.envpol.2022.119039. Epub 2022 Feb 19.
The health risks of triphenyl phosphate (TPhP) have increased since its widespread application. Using placental trophoblast cell line JEG-3, we demonstrated that TPhP could induce endoplasmic reticulum stress (ERS) and cell apoptosis through PPARγ-mediated lipid metabolism. However, the developmental toxicity of TPhP through the placenta is not known. In this study, prenatal TPhP exposure to mice was investigated. Pregnant mice were orally exposed to TPhP (1 and 5 mg/kg) from embryonic day 0 (E0) until delivery. The results showed that TPhP could accumulate in placenta and impair pregnancy outcomes. After exposure, at E18, placental hormone chorionic gonadotrophin and testosterone levels were significantly decreased, but progesterone and estradiol levels were significantly increased, and placental angiogenesis was activated in the low-dose exposure group. While, in the high-dose exposure group, only estradiol levels were significantly increased. Different with the effect on hormone level or angiogenesis, TPhP significantly increased PPARγ and its regulated lipid transport proteins FABP, FATP, and CD36, and induced lipid accumulation in placental trophoblasts of both low- and high-exposure group. RNA-seq analysis of the placenta identified differentially expressed genes that were mainly involved in the ERS and MAPK signaling pathways. Western blot analysis verified that the protein levels related to ERS stress and apoptosis were significantly increased. To further confirm the role of PPARγ in TPhP mediated placental toxicity, pregnant mice were orally exposed to TPhP (1 mg/kg) or TPhP (1 mg/kg) + GW9662 (PPARγ inhibitor, 2 mg/kg) from E0 until delivery. The results showed that GW9662 could ameliorate the effect of TPhP on placental lipid accumulation, ERS and cell apoptosis, suggesting that PPARγ mediated the placental toxicity of TPhP. Overall, our results indicated that prenatal TPhP exposure impaired pregnancy outcomes, at least partly through PPARγ regulated function of trophoblast.
三苯基磷酸酯（TPhP）广泛应用以来，其健康风险不断增加。本研究利用胎盘滋养层细胞系 JEG-3 证实，TPhP 可通过过氧化物酶体增殖物激活受体γ（PPARγ）介导的脂质代谢诱导内质网应激（ERS）和细胞凋亡。然而，TPhP 通过胎盘的发育毒性尚不清楚。本研究采用孕鼠模型，研究了孕期 TPhP 暴露对胎盘的影响。妊娠 0 天（E0）开始，孕鼠经口给予 TPhP（1 和 5mg/kg），直至分娩。结果表明，TPhP 可在胎盘内蓄积，损害妊娠结局。染毒后，E18 时，低剂量组胎盘激素绒毛膜促性腺激素和睾酮水平显著降低，而孕激素和雌二醇水平显著升高，胎盘血管生成被激活；高剂量组仅雌二醇水平显著升高。与激素水平或血管生成不同，TPhP 显著增加了低、高剂量组胎盘滋养层细胞中 PPARγ 及其调控的脂质转运蛋白 FABP、FATP 和 CD36 的表达，诱导脂质蓄积。胎盘 RNA-seq 分析鉴定出差异表达基因，主要涉及 ERS 和 MAPK 信号通路。Western blot 分析验证了与 ERS 应激和细胞凋亡相关的蛋白水平显著升高。为进一步证实 PPARγ 在 TPhP 介导的胎盘毒性中的作用，孕鼠经口给予 TPhP（1mg/kg）或 TPhP（1mg/kg）+GW9662（PPARγ 抑制剂，2mg/kg），从 E0 至分娩。结果表明，GW9662 可改善 TPhP 引起的胎盘脂质蓄积、ERS 和细胞凋亡，提示 PPARγ 介导了 TPhP 对胎盘的毒性作用。综上所述，本研究结果表明，孕期 TPhP 暴露损害妊娠结局，至少部分是通过 PPARγ 调节滋养层功能实现的。
