Modeling the Interaction of Binary and Ternary Mixtures of Estradiol with Bisphenol A and Bisphenol AF in an In Vitro Estrogen-Mediated Transcriptional Activation Assay (T47D-KBluc)

Abstract

Exposure to xenoestrogens occurs against a backdrop to physiological levels of endogenous estrogens. Endogenous estrogen levels vary from low levels in early childhood to high levels during pregnancy and in young women. However, few studies have addressed how xenoestrogens interact with endogenous estrogens. The current study was designed to characterize the individual dose-response curves of estradiol-17beta (E(2)), bisphenol A (BPA), tetrabromo-bisphenol A (TBBPA), and bisphenol AF (BPAF, 4,4'-hexafluoroisopropylidene diphenol) on estrogen-dependent luciferase expression in T47D-KBluc cells and to determine how binary (8 x 8 factorial) and ternary (4 x 4 x 4 factorial) mixtures of an endogenous estrogen (E(2)) interact with BPA and/or BPAF. Log EC(50) and hillslope values with SEs, respectively, for individual compounds were as follows: E(2), -12.10M +/- 0.06071, 0.7702 +/- 0.1739; BPA, -6.679M +/- 0.08505, 1.194 +/- 0.2137; and BPAF, -7.648M +/- 0.05527, 1.273 +/- 0.1739. TBBPA was not evaluated in mixture studies because of its minimally estrogenic response at 3 x10(-5)M and elicited cytotoxicity at higher concentrations. Both the binary mixtures of E(2) with BPA and BPAF and the ternary mixture of E(2), BPA, and BPAF behaved in an additive manner. For binary mixtures, as E(2) concentration increased, higher concentrations of BPA and BPAF were necessary to induce a significant increase in the estrogenic response. Understanding the behavior of mixture interactions of xenoestrogens, like BPA and BPAF, with endogenous estrogens will allow a better assessment of the potential risk associated with exposure to these chemicals, individually or as mixtures.

Assessing developmental toxicity and estrogenic activity of halogenated bisphenol A on zebrafish (Danio rerio)

“…All of these effects of BPA have been attributed to effects on steroid hormone receptors such as ER (Matsushima et al, 2010). BPA and BPAF have been shown to induce estrogen-dependent response in vitro via binding to ER (Song et al, 2006;Bermudez et al, 2010), whereas studies on the estrogenic activity of TBBPA in vitro are inconsistent. The estrogenic activity of TBBPA was examined by several investigators using various in vitro methods.…”

“…Bisphenol A (BPA) is an important industrial chemical which is widely used in the manufacture of polycarbonated plastic, food can linings, chemical papers, and dentistry sealants (Bermudez et al, 2010;Riu et al, 2011). Tetrabromobisphenol A (TBBPA) and tetrachlorobisphenol A (TCBPA) are halogenated derivatives of BPA (HBPAs), which feature bromine or chorine substituents on the phenolic rings, are used as flame retardants (Hakk and Letcher, 2003;Chu et al, 2005;de Wit et al, 2010).…”

“…BPAF has the ability to bind with ERs, and the binding affinity or estrogenic activity was about one order or magnitude stronger than dose BPA (Kitamura et al, 2005;Okada et al, 2008;Matsushima et al, 2010). The higher estrogenic activity of BPAF than BPA was attributed to that the trifluoromethyl group is much more electronegative than the methyl group, which is related to its estrogenic activity (Kitamura et al, 2005;Matsushima et al, 2010;Bermudez et al, 2010). The estrogenic activity of TCBPA was similar to or higher than that of BPA (Meerts et al, 2001;Kitamura et al, 2005;Vandenberg et al, 2009), however, studies on the estrogenic activity of TBBPA in vitro are often inconsistent (Yamasaki et al, 2003;Bay et al, 2004;Wetherill et al, 2007;Akahori et al, 2008).…”

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.…”

Endocrine Disruption Potentials of Bisphenol A Alternatives - Are Bisphenol A Alternatives Safe from Endocrine Disruption?

“…11,12,13,37) The binding affinity of BPAF was approximately 20 times stronger and 48 times stronger than that of BPA as a ligand for ERα and ERβ, respectively.…”