Direct Evidence Revealing Structural Elements Essential for the High Binding Ability of Bisphenol A to Human Estrogen-Related Receptor-γ

Abstract

BackgroundVarious 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.ObjectivesIn 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.MethodsWe 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.ConclusionThese results indicate that the phenol derivatives are potent candidates for the endocrine disruptor that binds to ERR-γ.

Curing and thermal properties of copolymer epoxy resins prepared by copolymerized bisphenol-A and epichlorohydrin with liquefied Dendrocalamus latiflorus

“…However, use of bisphenol-A is often undesirable because it can mimic the body's own hormones and may lead to negative health effects. 9,10 Therefore, determining how to reduce the amount of bisphenol-A while maintaining the performance of the resin is a significant problem that attracts much interest. One possible solution to this problem that has been investigated by some researchers involves blending liquefied wood with epoxy resin.…”

Structural and mechanistic insights into bisphenols action provide guidelines for risk assessment and discovery of bisphenol A substitutes

“…Although the two estrogen receptors (ERs), ERα and ERβ, are considered as the main targets of BPA (13,14), several other cellular targets have been proposed for this compound. We and others have previously demonstrated that BPA or its halogenated derivatives also activate the pregnane X receptor (15,16), the estrogen-related receptor γ (ERRγ) (17), or the peroxisome proliferator activated receptor γ (18,19), and inhibit the androgen receptor (AR) (20) or the thyroid hormone receptor (21,22). BPA has also been reported to interact with the G proteincoupled ER (23), so that the net effect of BPA could be caused by synergistic actions through different pathways.…”

Evaluation of the in vitro estrogenicity of emerging bisphenol analogs and their respective estrogenic contributions in municipal sewage sludge in China

“…These characteristics of BPA have been attributed to the effects on steroid hormone receptors such as ER (Matsushima et al, 2010). Okada et al (2008) reported that BPAF bound more strongly to ERa than BPA, and that it could cause adverse reproductive and developmental effects in several different in vivo and in vitro models (Akahori et al, 2008;Bermudez et al, 2010). TBBPA showed a weak estrogenic response in cultured MCF-7 breast cancer cells (Olsen et al, 2003), and inhibited in vitro estradiol sulfonation (Hamers et al, 2004), indicating the potential for both direct and indirect estrogenic activity in vivo.…”

“…Some BPs exhibited estrogenic activity in the human breast cancer cell line MCF-7, but there were notable differences in activity (Kitamura et al, 2005). Recent studies have shown that the estrogenic activity of BPAF was about one order of magnitude stronger than does BPA (Okada et al, 2008;Matsushima et al, 2010). However, information on the toxicological consequences, environmental presence, and environmental fate of these compounds is still limited.…”