Molecular mechanism of Bisphenol A on androgen receptor antagonism

Abstract

Bisphenol A (BPA), one of the highest production volume chemicals, is a typical endocrine-disrupting chemical (EDC) that exhibits antiandrogenic activity. However, how BPA antagonizes androgen effects remains ambiguous. In this study, the in silico and in vitro assays were carried out to explore the molecular mechanism(s) of BPA on androgen receptor (AR) antagonism. In reporter gene assay, BPA caused a significant antagonistic effect on 5α-dihydrotestosterone (DHT)-induced AR transcriptional activity at concentrations of 10^-9 M-10^-5 M. The results of molecular docking and molecular dynamics simulations indicated the availability of BPA binding to the ligand binding domain of AR. BPA treatment prevented the inhibition of receptor degradation caused by DHT binding to AR. BPA exposure also abolished DHT-dependent dissociation of AR from its co-chaperone, 90-kDa heat shock protein (Hsp90), and resulted in the blockage of DHT-induced AR nuclear translocation. This is the first report to show that BPA inhibited the DHT-induced stabilization of AR and the DHT-induced dissociation of AR-Hsp90 complex. This study provided new evidence for further understanding the precise mechanisms of antagonism of BPA on AR.

Keywords: Androgen receptor; Antagonism; Antiandrogen; Bisphenol A; Endocrine-disrupting chemicals.