Multiple nuclear receptor-regulated endocrine disrupting effects: A case study for bisphenol-induced crosstalk between RARα and ERα signaling pathways.

Given the intricate regulation of endocrine homeostasis, the crosstalk among multiple nuclear receptors (NRs) induced by emerging chemicals has garnered increasing attention. Of particular, the interaction between estrogen receptor alpha (ERα) and retinoic acid receptor alpha (RARα) is now a new focus of research. Herein, six representative analogs of bisphenol A (i.e., BPAF, BPB, BPE, BPF, BPS, and BPZ) were screened for their estrogenic and retinoid-like activities by using the combination of in vitro and in silico assays. Two bisphenols with relatively high ERα and RARα binding affinities (i.e., BPB and BPAF) were selected to study the crosstalk between these two NR-regulated signaling in human breast carcinoma (MCF-7) cells. Both agonism and antagonism of RARα inhibited bisphenol-activated ER-dependent cell proliferation and the downstream gene transcription. Differently, bisphenol-mediated RARα signaling was inhibited by ERα agonism, but enhanced by ERα antagonism. The present study, for the first time, uncovered the inhibition effect of bisphenols on RARα signaling via ERα agonism, and highlighted the antagonistic crosstalk between ERα and RARα signaling. The findings provide a novel perspective to understand the complicated endocrine disrupting effects of emerging chemicals with binding affinities for multiple NRs, and emphasize the importance of studying the crosstalk between diverse NR-regulated signaling that is concerned.