Direct Evidence Revealing Structural Elements Essential for the High Binding Ability of Bisphenol A to Human Estrogen-Related Receptor-γ
Top Cited Papers
- 1 January 2008
- journal article
- Published by Environmental Health Perspectives in Environmental Health Perspectives
- Vol. 116 (1), 32-38
- https://doi.org/10.1289/ehp.10587
Abstract
Various lines of evidence have shown that bisphenol A [BPA; HO-C6H4-C(CH3)2-C6H4-OH] acts as an endocrine disruptor when present in very low doses. We have recently demonstrated that BPA binds strongly to human estrogen-related receptor-γ (ERR-γ ) in a binding assay using [3H]4-hydroxytamoxifen ([3H]4-OHT). We also demonstrated that BPA inhibits the deactivation activity of 4-OHT. In the present study, we intended to obtain direct evidence that BPA interacts with ERR-γ as a strong binder, and also to clarify the structural requirements of BPA for its binding to ERR-γ. We examined [3H]BPA in the saturation binding assay using the ligand binding domain of ERR-γ and analyzed the result using Scatchard plot analysis. A number of BPA derivatives were tested in the competitive binding assay using [3H]BPA as a tracer and in the luciferase reporter gene assay. [3H]BPA showed a KD of 5.50 nM at a Bmax of 14.4 nmol/mg. When we examined BPA derivatives to evaluate the structural essentials required for the binding of BPA to ERR-γ , we found that only one of the two phenol-hydroxyl groups was essential for the full binding. The maximal activity was attained when one of the methyl groups was removed. All of the potent BPA derivatives retained a high constitutive basal activity of ERR-γ in the luciferase reporter gene assay and exhibited a distinct inhibitory activity against 4-OHT. These results indicate that the phenol derivatives are potent candidates for the endocrine disruptor that binds to ERR-γ.Keywords
This publication has 24 references indexed in Scilit:
- Structural Evidence for Endocrine Disruptor Bisphenol A Binding to Human Nuclear Receptor ERRThe Journal of Biochemistry, 2007
- X-ray Crystal Structures of the Estrogen-related Receptor-γ Ligand Binding Domain in Three Functional States Reveal the Molecular Basis of Small Molecule RegulationJournal of Biological Chemistry, 2006
- Endocrine disruptor bisphenol A strongly binds to human estrogen-related receptor γ (ERRγ) with high constitutive activityToxicology Letters, 2006
- Large effects from small exposures. II. The importance of positive controls in low-dose research on bisphenol AEnvironmental Research, 2006
- Structural Basis for the Deactivation of the Estrogen-related Receptor γ by Diethylstilbestrol or 4-Hydroxytamoxifen and Determinants of SelectivityPublished by Elsevier BV ,2004
- Reproductive Malformation of the Male Offspring Following Maternal Exposure to Estrogenic ChemicalsProceedings of the Society for Experimental Biology and Medicine, 2000
- Binding Characteristics of Dialkyl Phthalates for the Estrogen ReceptorBiochemical and Biophysical Research Communications, 1999
- A Physiologically Based Approach To the Study of Bisphenol a and Other Estrogenic Chemicals On the Size of Reproductive Organs, Daily Sperm Production, and BehaviorToxicology and Industrial Health, 1998
- Relative binding affinity-serum modified access (RBA-SMA) assay predicts the relative in vivo bioactivity of the xenoestrogens bisphenol A and octylphenol.Environmental Health Perspectives, 1997
- Estrogenicity of resin-based composites and sealants used in dentistry.Environmental Health Perspectives, 1996