Receptor-binding affinities of bisphenol A and its next-generation analogs for human nuclear receptors

An endocrine-disrupting chemical Bisphenol A (BPA) binds specifically to a nuclear receptor (NR) named ERR gamma. Although the importance of receptor-binding evaluation for human NRs is often stressed, the binding characteristics of so-called next-generation (NextGen) bisphenol compounds are still poorly understood. The ultimate objective of this investigation was to evaluate BPA and its NextGen analogs for their abilities to bind to 21 human NRs, the greatest members of NRs for which tritium-labeled specific ligands were available. After establishing the detailed assay conditions for each NR, the receptor binding affinities of total 11 bisphenols were evaluated in competitive binding assays. The results clearly revealed that BPA and the NextGen bisphenols of BPAF, BPAP, BPB, BPC, BPE, and BPZ were highly potent against one or more of NRs such as CAR, ER alpha, ER beta, ERR gamma, and GR, with IC50 values of 3.3-73 nM. These bisphenols were suggested strongly to be disruptive to these NRs. BPM and BPP also appeared to be disruptive, but less potently. BPF exhibited only weak effects and only against estrogen-related NRs. Surprisingly, most doubtful bisphenol BPS was supposed not to be disruptive. The NRs to which BPA and NextGen bisphenols did not bind were RAR alpha, RAR beta, RAR gamma, and VDR. PPAR gamma, ROR alpha, ROR beta, ROR gamma, RXR alpha, RXR beta, and RXR gamma, exhibited very weak interaction with these bisphenols. The ten remaining NRs, namely, ERR gamma, ER beta, ER alpha, CAR, GR, PXR, PR, AR, LXR beta, and LXR alpha, showed distinctly strong binding to some bisphenols in this order, being likely to have consequential endocrine-disruption effects.