title: Activation of Peroxisome Proliferator-Activated Receptor Gamma and Disruption of Progesterone Synthesis of 2-Ethylhexyl Diphenyl Phosphate in Human Placental Choriocarcinoma Cells: Comparison with Triphenyl Phosphate.
abstract: 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.
authors.affiliation: MOE Laboratory for Earth Surface Processes, College of Urban and Environmental Sciences, Peking University , Beijing 100871, China.
authors.forename: Wenxin
authors.initials: W
authors.lastname: Hu
authors.affiliation: MOE Laboratory for Earth Surface Processes, College of Urban and Environmental Sciences, Peking University , Beijing 100871, China.
authors.forename: Fumei
authors.initials: F
authors.lastname: Gao
authors.affiliation: MOE Laboratory for Earth Surface Processes, College of Urban and Environmental Sciences, Peking University , Beijing 100871, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Laboratory of Hygienic Chemistry and Molecular Toxicology, Gifu Pharmaceutical University , 1-25-4 Daigaku-nishi, Gifu, Gifu 501-1196, Japan.|Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science 3500-3, Minamitamagaki, Suzuka, Mie 513-8670, Japan.
authors.forename: Youhei
authors.initials: Y
authors.lastname: Hiromori
authors.affiliation: Laboratory of Hygienic Chemistry and Molecular Toxicology, Gifu Pharmaceutical University , 1-25-4 Daigaku-nishi, Gifu, Gifu 501-1196, Japan.
authors.forename: Shuhei
authors.initials: S
authors.lastname: Arakawa
authors.affiliation: Laboratory of Hygienic Chemistry and Molecular Toxicology, Gifu Pharmaceutical University , 1-25-4 Daigaku-nishi, Gifu, Gifu 501-1196, Japan.
authors.forename: Hisamitsu
authors.initials: H
authors.lastname: Nagase
authors.affiliation: Laboratory of Hygienic Chemistry and Molecular Toxicology, Gifu Pharmaceutical University , 1-25-4 Daigaku-nishi, Gifu, Gifu 501-1196, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Nakanishi
authors.affiliation: MOE Laboratory for Earth Surface Processes, College of Urban and Environmental Sciences, Peking University , Beijing 100871, China.
authors.forename: Jianying
authors.initials: J
authors.lastname: Hu
mesh_terms: D002822:Choriocarcinoma / Q000378:metabolism*; D005260:Female; D006801:Humans; D062105:Molecular Docking Simulation; D010755:Organophosphates / Q000378:metabolism*; D047495:PPAR gamma / Q000378:metabolism*; D011247:Pregnancy; D011374:Progesterone / Q000096:biosynthesis*; D014594:Uterine Neoplasms / Q000378:metabolism*
chemical_list: D010755:Organophosphates; D047495:PPAR gamma; C018535:2-ethylhexyldiphenylphosphate; D011374:Progesterone; C005445:triphenyl phosphate