UMR-S1139, Faculté de Pharmacie de Paris, Institut national de la santé et de la recherché médicale (Inserm, National Institute of Health & Medical Research), Paris, France.
Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
Environ Health Perspect. 2019 Feb;127(2):27003. doi: 10.1289/EHP3730.
Phthalates are environmental contaminants commonly used as plasticizers in polyvinyl chloride (PVC) products. Recently, exposure to phthalates has been associated with preterm birth, low birth weight, and pregnancy loss. There is limited information about the possible mechanisms linking maternal phthalate exposure and placental development, but one such mechanism may be mediated by peroxisome proliferator–activated receptor γ (PPARγ). PPARγ belongs to the nuclear receptor superfamily that regulates, in a ligand-dependent manner, the transcription of target genes. Studies of PPARγ-deficient mice have demonstrated its essential role in lipid metabolism and placental development. In the human placenta, PPARγ is expressed in the villous cytotrophoblast (VCT) and is activated during its differentiation into syncytiotrophoblast.
The goal of this study was to investigate the action of mono(2-ethylhexyl) phthalate (MEHP) on PPARγ activity during differentiation of VCTs.
We combined immunofluorescence, PPARγ activity/hCG assays, western blotting, and lipidomics analyses to characterize the impacts of physiologically relevant concentrations of MEHP (0.1, 1, and 10 μM) on cultured VCTs isolated from human term placentas.
Doses of 0.1 and 1 μM MEHP showed significantly lower PPARγ activity and less VCT differentiation in comparison with controls, whereas, surprisingly, a 10 μM dose had the opposite effect. MEHP exposure inhibited hCG production and significantly altered lipid composition. In addition, MEHP had significant effects on the mitogen-activated protein kinase (MAPK) pathway.
This study suggests that MEHP has a U-shaped dose–response effect on trophoblast differentiation that is mediated by the PPARγ pathway and acts as an endocrine disruptor in the human placenta. https://doi.org/10.1289/EHP3730.
邻苯二甲酸酯是环境污染物，常用于聚氯乙烯 (PVC) 制品的增塑剂。最近，邻苯二甲酸酯的暴露与早产、低出生体重和妊娠丢失有关。关于将母体邻苯二甲酸酯暴露与胎盘发育联系起来的可能机制的信息有限，但其中一种机制可能是通过过氧化物酶体增殖物激活受体 γ (PPARγ) 介导的。PPARγ 属于核受体超家族，以配体依赖的方式调节靶基因的转录。PPARγ 缺陷小鼠的研究表明，它在脂质代谢和胎盘发育中起着至关重要的作用。在人胎盘组织中，PPARγ 在绒毛细胞滋养层 (VCT) 中表达，并在其分化为合体滋养层时被激活。
本研究旨在研究单（2-乙基己基）邻苯二甲酸酯 (MEHP) 在 VCT 分化过程中对 PPARγ 活性的作用。
我们结合免疫荧光、PPARγ 活性/hCG 测定、western blot 和脂质组学分析，研究了生理相关浓度的 MEHP（0.1、1 和 10 μM）对从人足月胎盘分离的培养 VCT 的影响。
与对照组相比，0.1 和 1 μM MEHP 剂量显示出显著降低的 PPARγ 活性和更少的 VCT 分化，而令人惊讶的是，10 μM 剂量则产生相反的效果。MEHP 暴露抑制 hCG 产生并显著改变脂质组成。此外，MEHP 对丝裂原活化蛋白激酶 (MAPK) 途径有显著影响。
本研究表明，MEHP 对滋养层分化具有 U 型剂量反应效应，这种效应是通过 PPARγ 途径介导的，并作为人胎盘的内分泌干扰物发挥作用。https://doi.org/10.1289/EHP3730.
