title: Estrogen-related receptor γ is an in vivo receptor of bisphenol A.
abstract: Bisphenol A (BPA) is an endocrine disruptor that displays estrogenic activity. Several reports suggest that BPA may have estrogen receptor-independent effects. In zebrafish, 50 μM BPA exposure induces otic vesicle abnormalities, including otolith aggregation. The purpose of this study was to test if BPA action was mediated in vivo during zebrafish development by the orphan nuclear estrogen related receptor (ERR) γ. Combining pharmacological and functional approaches, we demonstrate that the zebrafish ERRγ mediates BPA-induced malformations in otoliths. Using different bisphenol derivatives, we show that different compounds can induce a similar otolith phenotype than BPA and that the binding affinity of these derivatives to the zebrafish ERRγ correlates with their ability to induce otolith malformations. Morpholino knockdown of ERRγ function suppresses the BPA effect on otoliths whereas overexpression of ERRγ led to a BPA-like otolith phenotype. Moreover, a subphenotypical dose of BPA (1 μM) combined with ERRγ overexpression led to a full-dose (50 μM) BPA otolith phenotype. We therefore conclude that ERRγ mediates the otic vesicle phenotype generated by BPA. Our results suggest that the range of pathways perturbed by this compound and its potential harmful effect are larger than expected.-Tohmé, M., Prud'homme, S. M., Boulahtouf, A., Samarut, E., Brunet, F., Bernard, L., Bourguet, W., Gibert, Y., Balaguer, P., Laudet, V. Estrogen-related receptor γ is an in vivo receptor of bisphenol A.
authors.affiliation: Institut de Génomique Fonctionnelle de Lyon, Ecole Normale Supérieure de Lyon, Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR) 5242, Université Lyon 1, Université de Lyon, Lyon, France;
authors.forename: Marie
authors.initials: M
authors.lastname: Tohmé
authors.affiliation: Institut de Génomique Fonctionnelle de Lyon, Ecole Normale Supérieure de Lyon, Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR) 5242, Université Lyon 1, Université de Lyon, Lyon, France;
authors.forename: Sophie M
authors.initials: SM
authors.lastname: Prud'homme
authors.affiliation: Institut de Recherche en Cancérologie de Montpellier, Institut National de la Santé et de la Recherche Médicale (INSERM) U896, Centre Régional de la Lutte Contre le Cancer Val d'Aurelle Paul Lamarque, Montpellier, France;
authors.forename: Abdel
authors.initials: A
authors.lastname: Boulahtouf
authors.affiliation: Institut de Génomique Fonctionnelle de Lyon, Ecole Normale Supérieure de Lyon, Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR) 5242, Université Lyon 1, Université de Lyon, Lyon, France;
authors.forename: Eric
authors.initials: E
authors.lastname: Samarut
authors.affiliation: Institut de Génomique Fonctionnelle de Lyon, Ecole Normale Supérieure de Lyon, Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR) 5242, Université Lyon 1, Université de Lyon, Lyon, France;
authors.forename: Frédéric
authors.initials: F
authors.lastname: Brunet
authors.affiliation: Institut de Génomique Fonctionnelle de Lyon, Ecole Normale Supérieure de Lyon, Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR) 5242, Université Lyon 1, Université de Lyon, Lyon, France;
authors.forename: Laure
authors.initials: L
authors.lastname: Bernard
authors.affiliation: INSERM U1054, Centre de Biochimie Structurale, Montpellier, CNRS UMR5048, Universités Montpellier 1 and 2, Montpellier, France; and.
authors.forename: William
authors.initials: W
authors.lastname: Bourguet
authors.affiliation: Metabolic Genetic Diseases Laboratory, Metabolic Research Unit, Deakin School of Medicine, Waurn Ponds, Victoria, Australia.
authors.forename: Yann
authors.initials: Y
authors.lastname: Gibert
authors.affiliation: Institut de Recherche en Cancérologie de Montpellier, Institut National de la Santé et de la Recherche Médicale (INSERM) U896, Centre Régional de la Lutte Contre le Cancer Val d'Aurelle Paul Lamarque, Montpellier, France;
authors.forename: Patrick
authors.initials: P
authors.lastname: Balaguer
authors.affiliation: Institut de Génomique Fonctionnelle de Lyon, Ecole Normale Supérieure de Lyon, Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR) 5242, Université Lyon 1, Université de Lyon, Lyon, France; vincent.laudet@ens-lyon.fr.
authors.forename: Vincent
authors.initials: V
authors.lastname: Laudet
mesh_terms: D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D010037:Otolithic Membrane / Q000187:drug effects / Q000378:metabolism; D010636:Phenols / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects*; D011960:Receptors, Estrogen / Q000378:metabolism*; D015027:Zebrafish / Q000378:metabolism*; D000098826:Bisphenol A Compounds
chemical_list: D001559:Benzhydryl Compounds; D010636:Phenols; D011960:Receptors, Estrogen; C006780:bisphenol A; D000098826:Bisphenol A Compounds
keywords: endocrine disrupters; otolith; zebrafish