Phthalates constitute a family of environmental contaminants widely used as plasticizers in polyvinyl chloride (PVC) materials, which are found in medical devices, food, and indoor air. Mono(2-ethylhexyl) phthalate (MEHP) is the main metabolite of di(2-ethylhexyl) phthalate (DEHP), one of the most widespread plasticizers. Some phthalates are able to cross the placental barrier and have been detected in placental tissues, amniotic fluid, and cord blood. Maternal exposure to these compounds has been associated with preterm births, low birth weight, and pregnancy loss, but the mechanisms linking this exposure to placental development remained poorly understood. One of them may involve peroxisome proliferator-activated receptor gamma (PPARγ), a nuclear receptor that regulates the transcription of target genes in a ligand-dependent manner and plays an essential role in lipid metabolism and placental development. In the human placenta, PPARγ is expressed by the villous cytotrophoblast (VCT) and activated during its differentiation into syncytiotrophoblast, a structure that mediates gaseous and nutritional exchanges as well as endocrine functions at the interface between the maternal and fetal circulations.
To characterize the action of MEHP on PPARγ activity during cytotrophoblast differentiation, the authors cultured VCTs isolated from term human placentas and exposed them to physiologically relevant concentrations of MEHP (0.1, 1, and 10 μM). The approach combined immunofluorescence, assays of PPARγ activity and human chorionic gonadotropin (hCG), western blot, and lipidomic analyses.
The results reveal a U-shaped response. The 0.1 and 1 μM doses significantly reduced PPARγ activity and VCT differentiation compared with controls, whereas the 10 μM dose produced the opposite effect, promoting cell fusion. In all cases, MEHP exposure inhibited hCG production: the increased syncytialization observed at high dose was therefore not accompanied by an improvement in trophoblast function, but by a loss of secretion of this key pregnancy hormone. MEHP also altered the lipid composition of the cells in a dose-dependent manner — global lipidomic analysis having identified 115 differentially expressed lipids at 10 μM versus 50 at 0.1 μM — and disrupted the mitogen-activated protein kinase (MAPK) pathways, with distinct effects on ERK, P38, and JNK.
This work suggests that MEHP acts as an endocrine disruptor in the human trophoblast, exerting a U-shaped dose-response effect on differentiation mediated by the PPARγ pathway and accompanied by alterations in lipid metabolism. The authors nevertheless highlight the limitations of the study — single origin of the placentas (Paris region), small sample size, and lack of demographic data — which restrict its generalizability, and call for further investigations, in particular to confirm the U-shaped dose-response curve.