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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 and Yasuyuki Shimohigashi
Environmental Health Perspectives
Vol. 116, No. 1 (Jan., 2008), pp. 32-38
Stable URL: http://www.jstor.org/stable/4641298
Page Count: 7
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Since scans are not currently available to screen readers, please contact JSTOR User Support for access. We'll provide a PDF copy for your screen reader.
Direct Evidence Revealing Structural Elements Essential for the High Binding Ability of Bisphenol A to Human Estrogen-Related Receptor-γ
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Abstract

BACKGROUND: Various lines of evidence have shown that bisphenol A [BPA; $HO-C_{6}H_{4};-C(CH_{3})_{2}- C_{6}H&_{4}-OH$] acts as an endocrine disruptor when present in very low doses. We have recently demonstrated that BPA binds strongly to human estrogen-related $receptor-\gamma$ ($ERR-\gamma$) in a binding assay using $[^{3}H]4-hydroxytamoxifen$ ($[^{3}H]4-OHT$). We also demonstrated that BPA inhibits the deactivation activity of 4-OHT. OBJECTICES: In the present study, we intended to obtain direct evidence that BPA interacts with $ERR-\gamma$ as a strong binder, and also to clarify the structural requirements of BPA for its binding to $ERR-\gamma$. METHODS: We examined $[^{3}H]BPA$ in the saturation binding assay using the ligand binding domain of $ERR-\gamma$ and analyzed the result using Scatchard plot analysis. A number of BPA derivatives were tested in the competitive binding assay using $[^{3}H]BPA$ as a tracer and in the luciferase reporter gene assay. RESULTS: $[^{3}H]BPA$ 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 $ERR-\gamma$, 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 $ERR-\gamma$ 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 $ERR-\gamma$.

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