Direct evidence revealing structural elements essential for the high binding ability of bisphenol a to human estrogen-related receptor-γ

Hiroyuki Okada, Takatoshi Tokunaga, Xiaohui Liu, Sayaka Takayanagi, Ayami Matsushima, Yasuyuki Shimohigashi

Research output: Contribution to journalArticle

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Abstract

Background: 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. Objectives: 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. Methods: 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. Results: [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. Conclusion: These results indicate that the phenol derivatives are potent candidates for the endocrine disruptor that binds to ERR-γ.

Original languageEnglish
Pages (from-to)32-38
Number of pages7
JournalEnvironmental Health Perspectives
Volume116
Issue number1
DOIs
Publication statusPublished - Jan 1 2008

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Estrogen Receptors
Endocrine Disruptors
Phenol
Luciferases
Reporter Genes
Competitive Binding
Hydroxyl Radical
Ligands
4,17 beta-dihydroxy-4-androstene-3-one

All Science Journal Classification (ASJC) codes

  • Public Health, Environmental and Occupational Health
  • Health, Toxicology and Mutagenesis

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Direct evidence revealing structural elements essential for the high binding ability of bisphenol a to human estrogen-related receptor-γ. / Okada, Hiroyuki; Tokunaga, Takatoshi; Liu, Xiaohui; Takayanagi, Sayaka; Matsushima, Ayami; Shimohigashi, Yasuyuki.

In: Environmental Health Perspectives, Vol. 116, No. 1, 01.01.2008, p. 32-38.

Research output: Contribution to journalArticle

Okada, Hiroyuki ; Tokunaga, Takatoshi ; Liu, Xiaohui ; Takayanagi, Sayaka ; Matsushima, Ayami ; Shimohigashi, Yasuyuki. / Direct evidence revealing structural elements essential for the high binding ability of bisphenol a to human estrogen-related receptor-γ. In: Environmental Health Perspectives. 2008 ; Vol. 116, No. 1. pp. 32-38.
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