Bisphenol AF Is a Full Agonist for the Estrogen Receptor ERα but a Highly Specific Antagonist for ERβ

Abstract

BackgroundBisphenol AF has been acknowledged to be useful for the production of CF3-containing polymers with improved chemical, thermal, and mechanical properties. Because of the lack of adequate toxicity data, bisphenol AF has been nominated for comprehensive toxicological characterization.ObjectivesWe aimed to determine the relative preference of bisphenol AF for the human nuclear estrogenic receptors ERα and ERβ and the bisphenol A–specific estrogen-related receptor ERRγ, and to clarify structural characteristics of receptors that influence bisphenol AF binding.MethodsWe examined receptor-binding activities of bisphenol AF relative to [3H]17β-estradiol (for ERα and ERβ) and [3H]bisphenol A (for ERRγ). Functional luciferase reporter gene assays were performed to assess receptor activation in HeLa cells.ResultsWe found that bisphenol AF strongly and selectively binds to ERs over ERRγ. Furthermore, bisphenol AF receptor-binding activity was three times stronger for ERβ [IC50 (median inhibitory concentration) = 18.9 nM] than for ERα. When examined using a reporter gene assay, bisphenol AF was a full agonist for ERα. In contrast, it was almost completely inactive in stimulating the basal constitutive activity of ERβ. Surprisingly, bisphenol AF acted as a distinct and strong antagonist against the activity of the endogenous ERβ agonist 17β-estradiol.ConclusionOur results suggest that bisphenol AF could function as an endocrine-disrupting chemical by acting as an agonist or antagonist to perturb physiological processes mediated through ERα and/or ERβ.

Bisphenol AF as an Inducer of Estrogen Receptor β (ERβ): Evidence for Anti-estrogenic Effects at Higher Concentrations in Human Breast Cancer Cells

“…Although bisphenols including BPAF have been shown to function as activators of ERα under E2-depleted/low conditions, such as in HeLa cells (human cervical adenocarcinoma; negative for aromatase, an enzyme responsible for E2 production), 3,24) this phenomenon was not observed in other cell lines including HepG2 (human hepatocellular carcinoma; positive for aromatase) and Ishikawa (human endometrial adenocarcinoma; positive for aromatase). 4,25) We utilized MCF-7 cells, which produce E2 at pmol levels (i.e., 0.26 pM/10 6 cells), 26) and in the presence of exogenously added 1 nM E2, as expected, the stimulation of ERα by bisphenols was not detected in MCF-7 cells (Fig.…”

“…2) Bisphenols (BPA, BPB, BPS, and BPAF) have been shown to exert positive effects on estrogen receptor (ER)α-mediated transcriptional activation in in vitro studies (i.e., nanomolar concentrations) [3][4][5][6][7] ; however, it currently remains unclear whether these bisphenols affect the expression of ERα/β, and if this is coupled with the "modulation" of estrogen signaling. Therefore, more detailed toxicological data need to be acquired in order to establish the toxicological basis of bisphenols in vitro.…”

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

“…Most measured concentrations in the environment are below levels associated with adverse effects on aquatic organisms. However, it has been reported that BPA could cause various ''low-dose effects'', such as decreasing daily sperm production and fertility in male mice (Gupta 2000;Matsushima et al, 2010). And some occasionally environmental levels of BPA exceed the lowest effect concentrations in aquatic organisms and thus could potentially cause some adverse effects on aquatic ecosystems (Crain et al, 2007).…”

“…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).…”

“…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.…”