Peroxisome Proliferator-Activated Receptor γ Is a Target for Halogenated Analogs of Bisphenol A

Abstract

Background: The occurrence of halogenated analogs of the xenoestrogen bisphenol A (BPA) has been recently demonstrated both in environmental and human samples. These analogs include brominated [e.g., tetrabromobisphenol A (TBBPA)] and chlorinated [e.g., tetrachlorobisphenol A (TCBPA)] bisphenols, which are both flame retardants. Because of their structural homology with BPA, such chemicals are candidate endocrine disruptors. However, their possible target(s) within the nuclear hormone receptor superfamily has remained unknown.Objectives: We investigated whether BPA and its halogenated analogs could be ligands of estrogen receptors (ERs) and peroxisome proliferator–activated receptors (PPARs) and act as endocrine-disrupting chemicals.Methods: We studied the activity of compounds using reporter cell lines expressing ERs and PPARs. We measured the binding affinities to PPARγ by competitive binding assays with [3H]-rosiglitazone and investigated the impact of TBBPA and TCBPA on adipocyte differentiation using NIH3T3-L1 cells. Finally, we determined the binding mode of halogenated BPAs to PPARγ by X-ray crystallography.Results: We observed that TBBPA and TCBPA are human, zebrafish, and Xenopus PPARγ ligands and determined the mechanism by which these chemicals bind to and activate PPARγ. We also found evidence that activation of ERα, ERβ, and PPARγ depends on the degree of halogenation in BPA analogs. We observed that the bulkier brominated BPA analogs, the greater their capability to activate PPARγ and the weaker their estrogenic potential.Conclusions: Our results strongly suggest that polyhalogenated bisphenols could function as obesogens by acting as agonists to disrupt physiological functions regulated by human or animal PPARγ.

High-Content Analysis Provides Mechanistic Insights into the Testicular Toxicity of Bisphenol A and Selected Analogues in Mouse Spermatogonial Cells

“…In addition, for BPAF and TBBPA, introducing a halogen into the bisphenol structure could contribute to their higher toxicities. This is because the degree of halogenation in BPA analogues could alter activation of ERs and peroxisome proliferator-activated receptors (PPARs) (Riu et al, 2011). By substituting different chemical groups and degree of halogenation, BPA and its analogues could exert differential toxicities via various receptor binding sites and binding affinities.…”

Bisphenol A Inhibits Voltage-Activated Ca2+ Channels in Vitro: Mechanisms and Structural Requirements

“…It is very well documented that BPA and various related compounds bind to hormone receptors and influence multiple endocrine pathways Okada et al, 2008;Swedenborg et al, 2009;Riu et al, 2011;Soriano et al, 2012). Beyond this, recent studies provide evidence that BPA can directly interact with biologically active proteins such as enzymes and ion channels (Hiroi et al, 2006;Asano et al, 2010;Hashimoto et al, 2012;O'Reilly et al, 2012;Pandey and Deshpande, 2012).…”

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.…”