Highly potent binding and inverse agonist activity of bisphenol A derivatives for retinoid-related orphan nuclear receptor RORγ

The plastic chemical bisphenol A (BPA) has recently been suspected to be a base structure of endocrine disrupting chemicals, which achieve their adverse effects by interfering with human nuclear receptors. For instance, BPA, bisphenol AF, and tetrabromo- or tetrachloro-BPA (X4-BPA) have been characterized as binders for ERRγ, ER, and PPARγ, respectively. This ongoing string of findings has led to apprehension that some other BPA derivatives might also perturb important human nuclear receptors. The retinoid-related orphan receptor RORγ has been strongly suspected to be a target of highly hydrophobic chemical substances because of its extreme affinity for lipophilic sterols. In the present study, we tested a series of BPA derivatives for their ability to bind to RORγ, and identified two distinctly potent derivatives having isopropyl or sec-butyl groups at positions adjacent to the BPA-4-hydroxyl group. In particular, di-sec-butyl-BPA has emerged as a considerably potent ligand (IC50 = 146 nM). In the reporter gene assay, these compounds suppressed the basal constitutive transcriptional activity originally induced by wild-type RORγ. The present results strongly suggested that RORγ, and perhaps also RORα and RORβ, binds highly hydrophobic and sterically hindered chemical substances, inducing some unspecified physiological and biochemical disruptions.

► We identified two potent RORγ binders, di-isopropyl-BPA and di-sec-butyl-BPA.
► Di-sec-butyl-BPA has emerged as a considerably potent binder (IC50 = 146 nM).
► They suppressed the basal constitutive transcriptional activity induced by RORγ.