The Role of Peroxisome Proliferator–Activated Receptor Gamma ([Formula: see text]) in Mono(2-ethylhexyl) Phthalate (MEHP)-Mediated Cytotrophoblast Differentiation

BACKGROUND: 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 [Formula: see text] ([Formula: see text]). [Formula: see text] belongs to the nuclear receptor superfamily that regulates, in a ligand-dependent manner, the transcription of target genes. Studies of [Formula: see text]-deficient mice have demonstrated its essential role in lipid metabolism and placental development. In the human placenta, [Formula: see text] is expressed in the villous cytotrophoblast (VCT) and is activated during its differentiation into syncytiotrophoblast. OBJECTIVES: The goal of this study was to investigate the action of mono(2-ethylhexyl) phthalate (MEHP) on [Formula: see text] activity during in vitro differentiation of VCTs. METHODS: We combined immunofluorescence, [Formula: see text] activity/hCG assays, western blotting, and lipidomics analyses to characterize the impacts of physiologically relevant concentrations of MEHP (0.1, 1, and [Formula: see text]) on cultured VCTs isolated from human term placentas. RESULTS: Doses of [Formula: see text] and [Formula: see text] MEHP showed significantly lower [Formula: see text] activity and less VCT differentiation in comparison with controls, whereas, surprisingly, a [Formula: see text] 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. CONCLUSIONS: This study suggests that MEHP has a U-shaped dose–response effect on trophoblast differentiation that is mediated by the [Formula: see text] pathway and acts as an endocrine disruptor in the human placenta. https://doi.org/10.1289/EHP3730