Binding, activity and risk assessment of bisphenols toward farnesoid X receptor pathway: In vitro and in silico study

Bisphenols have been identified as emerging environmental pollutants of high concern with potential adverse effects through interactions with receptor-mediated pathways. However, their potential mechanism of action and health risks through the farnesoid X receptor (FXR) pathway remain poorly understood. In the present study, we aimed to explore the potential disruption mechanism of bisphenols through the FXR signalling pathway. Receptor binding assays showed that bisphenols bound to FXR directly, with tetrabromobisphenol A (TBBPA; 34-fold), tetrachlorobisphenol A (TCBPA; 8.7-fold), bisphenol AF (BPAF; 2.0-fold), and bisphenol B (BPB; 1.9-fold) showing a significantly stronger binding potency than bisphenol A (BPA). In receptor transcriptional activity assays, bisphenols showed agonistic activity toward FXR, with BPAF, BPB, and bisphenol F (BPF) exhibiting higher activity than BPA, but TBBPA and TCBPA showing significantly weaker activity than BPA. Molecular docking results indicated that the number of hydrogen bonds dictated their binding strength. Intracellular concentrations of bisphenols were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS) in receptor activity assays, and it was found that the intracellular concentrations of TBBPA and TCBPA were 40-fold lower than those of BPA. Using the bioactivity concentrations in the FXR receptor activity assay, the liver concentrations of bisphenols were estimated using physiologically-based pharmacokinetic (PBPK) models through their serum concentrations, and the hazard quotient (HQ) values were calculated. The results suggest a potentially high concern for the risk of activating the FXR pathway for some populations with high exposure. Overall, these results indicate that bisphenols can bind to and activate FXR receptors, and that the activation mechanism is dependent on cellular uptake and binding strength. This study provides important information regarding the exposure risk of bisphenols, which can promote the development of environmentally friendly bisphenols.

Agonist activity; Binding potency; Bisphenols; Farnesoid X receptor; Health risk.