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;
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;
FASEB J. 2014 Jul;28(7):3124-33. doi: 10.1096/fj.13-240465. Epub 2014 Apr 17.
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.
双酚 A (BPA) 是一种具有雌激素活性的内分泌干扰物。有几项报告表明，BPA 可能具有雌激素受体非依赖性作用。在斑马鱼中，50μM 的 BPA 暴露会引起耳泡异常，包括耳石聚集。本研究的目的是测试在斑马鱼发育过程中，孤核雌激素相关受体 (ERR)γ 是否通过体内途径介导 BPA 的作用。我们结合药理学和功能方法，证明了斑马鱼 ERRγ 介导 BPA 诱导的耳石畸形。使用不同的双酚衍生物，我们表明不同的化合物可以诱导与 BPA 相似的耳石表型，并且这些衍生物与斑马鱼 ERRγ 的结合亲和力与其诱导耳石畸形的能力相关。ERRγ 功能的 morpholino 敲低抑制了 BPA 对耳石的作用，而 ERRγ 的过表达导致了类似于 BPA 的耳石表型。此外，BPA 的亚表型剂量（1μM）与 ERRγ 的过表达相结合导致了全剂量（50μM）BPA 耳石表型。因此，我们得出结论，ERRγ 介导了 BPA 产生的耳泡表型。我们的结果表明，这种化合物及其潜在的有害影响所干扰的途径范围比预期的要大。-Tohmé，M.，Prud'homme，S. M.，Boulahtouf，A.，Samarut，E.，Brunet，F.，Bernard，L.，Bourguet，W.，Gibert，Y.，Balaguer，P.，Laudet，V.。雌激素相关受体 γ 是双酚 A 的体内受体。
