磷酸三苯酯(TPhP),一种常见于人类胎盘和母乳中的化学物质,已经被证明会扰乱内分泌系统。我们先前的研究证实,TPhP可以在胎盘中积累并干扰胎盘脂质代谢和类固醇激素的合成,以及通过PPARγ诱导人胎盘滋养层JEG-3细胞内质网(ER)应激。然而,这种破坏背后的分子机制仍然未知。我们的研究旨在确定PPARγ/CD36途径在TPhP诱导的类固醇激素破坏中的作用。我们发现TPhP增加了脂质积累,总胆固醇,低密度和高密度蛋白质胆固醇,黄体酮,雌二醇,糖皮质激素,醛固酮水平,以及与类固醇激素合成相关的基因,包括3βHSD1、17βHSD1、CYP11A、CYP19和CYP21。通过与PPARγ拮抗剂GW9662共暴露或使用siRNA(siCD36)敲低CD36,这些作用在很大程度上被阻断。此外,ER应激抑制剂4-PBA减弱了TPhP对孕酮和糖皮质激素水平的影响,siCD36降低了TPhP诱导的内质网应激相关蛋白水平,包括BiP,PERK,和CHOP。这些发现表明,ER应激也可能在TPhP破坏类固醇激素合成中起作用。由于我们的研究揭示了PPARγ/CD36途径参与TPhP在JEG-3细胞中对类固醇激素生物合成的干扰,有必要进一步研究对胎盘功能和出生结局的潜在影响.
Triphenyl phosphate (TPhP), a chemical commonly found in human placenta and breast milk, has been shown to disturb the endocrine system. Our previous study confirmed that TPhP could accumulate in the placenta and interference with placental lipid metabolism and steroid hormone synthesis, as well as induce endoplasmic reticulum (ER) stress through PPARγ in human placental trophoblast JEG-3 cells. However, the molecular mechanism underlying this disruption remains unknown. Our study aimed to identify the role of the PPARγ/CD36 pathway in TPhP-induced steroid hormone disruption. We found that TPhP increased lipid accumulation, total cholesterol, low- and high-density protein cholesterol, progesterone, estradiol, glucocorticoid, and aldosterone levels, and genes related to steroid hormones synthesis, including 3βHSD1, 17βHSD1, CYP11A, CYP19, and CYP21. These effects were largely blocked by co-exposure with either a PPARγ antagonist GW9662 or knockdown of CD36 using siRNA (siCD36). Furthermore, an ER stress inhibitor 4-PBA attenuated the effect of TPhP on progesterone and glucocorticoid levels, and siCD36 reduced ER stress-related protein levels induced by TPhP, including BiP, PERK, and CHOP. These findings suggest that ER stress may also play a role in the disruption of steroid hormone synthesis by TPhP. As our study has shed light on the PPARγ/CD36 pathway\'s involvement in the disturbance of steroid hormone biosynthesis by TPhP in the JEG-3 cells, further investigations of the potential impacts on the placental function and following birth outcome are warranted.