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Environ Health Perspect. 2008 Jan;116(1):32-8. doi: 10.1289/ehp.10587.

Direct evidence revealing structural elements essential for the high binding ability of bisphenol A to human estrogen-related receptor-gamma.

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  • 1Laboratory of Structure-Function Biochemistry, Department of Chemistry, The Research-Education Centre of Risk Science, Faculty and Graduate School of Sciences, Kyushu University, Fukuoka, Japan.

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-gamma (ERR-gamma ) 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-gamma as a strong binder, and also to clarify the structural requirements of BPA for its binding to ERR-gamma.

METHODS:

We examined [3H]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 [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-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.

KEYWORDS:

bisphenol A; constitutive activity; endocrine disruptor; estrogen receptor; estrogen-related receptor-γ; inverse agonist; nuclear receptor

PMID:
18197296
[PubMed - indexed for MEDLINE]
PMCID:
PMC2199305
Free PMC Article

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