2-Ethylhexyl
diphenyl phosphate (EHDPP), an
organophosphate flame retardant (OPFR), is frequently detected in human blood. In this study, the sensitive dual-
luciferase reporter gene assay and molecular docking were used to investigate the activation of EHDPP to human
peroxisome proliferator-activated receptor gamma (PPARG). Results show that EHDPP exhibited stronger PPARG activation (EC20: 2.04 μM) than
triphenyl phosphate (TPhP) (EC20: 2.78 μM). EHDPP upregulated the gene expression of 3β-hydroxysteroid
dehydrogenase type 1 (3β-HSD1) in human placental
choriocarcinoma cells in a dose-dependent manner, and the lowest observable effective concentration was 10 μM, lower than that of TPhP (20 μM). EHDPP significantly altered
progesterone secretion at a lower concentration (10 μM) than that of TPhP (20 μM), and both EHDPP and TPhP significantly promoted
human chorionic gonadotropin (hCG) production at 20 μM. Furthermore, inactivation of PPARG by either a pharmacological inhibitor (
GW9662) or
small interfering RNA (
siRNA) abolished the change in
progesterone secretion and gene expression in the cells exposed to EHDPP, suggesting that the PPARG signaling pathway plays a role in the upregulation of
progesterone by the two OPFRs. This is the first report to show that OPFRs can alter the biosynthesis of
progesterone in the placenta, which could affect female reproduction and fetal development.