title: Differentiation of human placental BeWo cells by the environmental contaminant benzo(a)pyrene.
abstract: Polycyclic aromatic hydrocarbons (PAHs) such as benzo(a)pyrene (BaP) are widely-distributed environmental contaminants known to exert toxic effects in various tissues, including placenta. PAHs have notably been shown to inhibit proliferation of trophoblastic cells. The present study was designed to determine whether PAHs can concomitantly affect differentiated functions of trophoblastic cells. BaP was found to induce expression and secretion of β-human chorionic gonadotropin (β-hCG) in human trophoblastic BeWo cells. The PAH also increased mRNA expressions of other trophoblastic differentiation markers, including those of the steroid metabolism enzymes CYP19A1 and HSD11B2 and of the fusogenic protein syncytin-2; in parallel, it triggered syncytialisation of BeWo cells. BaP-mediated β-hCG and syncytin-2 up-regulation was prevented by co-treatment by the aryl hydrocarbon receptor (AhR) antagonist CH-223191 or by knocking-down AhR expression through siRNA transfection. However, the potent AhR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) failed to induce expression of β-hCG and syncytin-2, indicating that activation of the AhR pathway, known to be implicated in most, if not all, effects of PAHs, was required, but not sufficient. Interestingly, the p53 signaling pathway was activated by BaP, but not by TCDD, in BeWo cells and co-treatment by the p53 inhibitor pifithrin-α or siRNAs-mediated silencing of p53 prevented up-regulation of β-hCG and syncytin-2 induced by BaP. Taken together, these data demonstrate that BaP induces differentiation of placental trophoblastic BeWo cells in an AhR- and p53-dependent manner.
authors.affiliation: Institut de Recherches en Santé, Environnement et Travail (IRSET), UMR INSERM U1085, Faculté de Pharmacie, 2 Avenue du Pr Léon Bernard, 35043 Rennes, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Le Vee
authors.affiliation: Institut de Recherches en Santé, Environnement et Travail (IRSET), UMR INSERM U1085, Faculté de Pharmacie, 2 Avenue du Pr Léon Bernard, 35043 Rennes, France.
authors.forename: Elise
authors.initials: E
authors.lastname: Kolasa
authors.affiliation: Institut de Recherches en Santé, Environnement et Travail (IRSET), UMR INSERM U1085, Faculté de Pharmacie, 2 Avenue du Pr Léon Bernard, 35043 Rennes, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Jouan
authors.affiliation: Pôle Biologie, Centre Hospitalier Universitaire, 2 rue Henri Le Guilloux, 35033 Rennes, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Collet
authors.affiliation: Institut de Recherches en Santé, Environnement et Travail (IRSET), UMR INSERM U1085, Faculté de Pharmacie, 2 Avenue du Pr Léon Bernard, 35043 Rennes, France; Pôle Biologie, Centre Hospitalier Universitaire, 2 rue Henri Le Guilloux, 35033 Rennes, France. Electronic address: olivier.fardel@univ-rennes1.fr.
authors.forename: Olivier
authors.initials: O
authors.lastname: Fardel
mesh_terms: D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000235:genetics / Q000378:metabolism; D001141:Aromatase / Q000235:genetics / Q000378:metabolism; D001564:Benzo(a)pyrene / Q000633:toxicity*; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D004785:Environmental Pollutants / Q000633:toxicity*; D005260:Female; D016158:Genes, p53 / Q000235:genetics; D006801:Humans; D010920:Placenta / Q000166:cytology / Q000187:drug effects*; D011247:Pregnancy; D060888:Real-Time Polymerase Chain Reaction; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D004785:Environmental Pollutants; D001564:Benzo(a)pyrene; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; C468387:HSD11B2 protein, human; D001141:Aromatase; C561410:CYP19A1 protein, human
keywords: Aryl hydrocarbon receptor; Benzo(a)pyrene; Placenta; Polycyclic aromatic hydrocarbon; Syncytialisation; β-hCG