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

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

  • J Hazard Mater. 2025 Jun 20:495:139005. doi: 10.1016/j.jhazmat.2025.139005.
Jiahui Su 1,  Qian S Liu 2,  Xiaoxi Yang 3,  Hanqing Xu 4,  Mengyao Bing 5,  Huinan Liu 1,  Qunfang Zhou 6,  Guibin Jiang 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China; College of Resources and Environment, University of Chinese Academy of Sciences, Beijing 100049, China.
  • 2 State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China. Electronic address: qianl@rcees.ac.cn.
  • 3 State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China. Electronic address: xxyang@rcees.ac.cn.
  • 4 National and Local Joint Engineering Research Center of Ecological Treatment Technology for Urban Water Pollution, Wenzhou University, Wenzhou 325035, China.
  • 5 College of Resources and Environment, University of Chinese Academy of Sciences, Beijing 100049, China; School of Environment, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.
  • 6 State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China; College of Resources and Environment, University of Chinese Academy of Sciences, Beijing 100049, China; School of Environment, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.
PMID: 40561951 DOI: 10.1016/j.jhazmat.2025.139005
Abstract

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.

Keywords

Antagonistic crosstalk; Bisphenols; Estrogen receptor alpha (ERα); Retinoic acid receptor alpha (RARα); Transcriptional level.

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