Zearalenone and its metabolites provoke contrasting modulatory responses on estrogen and androgen receptors: Insights into the molecular basis of endocrine disruption in live cells.

Zearalenone (ZEA) is a non-steroidal mycotoxin enrouted mainly through the consumption of contaminated dietary products. Some traditional studies with ZEA have implied influence on several cellular and endocrine processes. However, detailed advanced insights into the molecular basis of ZEA-induced toxicity under defined live-cell conditions remain unexplored. This study uses molecular docking and cell-based approaches to investigate the interactions between ZEA, its metabolites (⍺-ZOL, β-ZOL), steroid receptors ERα/β, and androgen receptor (AR). The studies were performed with HEK293T and HepG2-derived stable cell lines exposed to 1 μM of ZEA, ⍺-ZOL, β-ZOL, and cognate steroids, 17β-estradiol, and 5⍺-DHT (10 nM). Fluorescent protein-tagged cytoplasmic-shifted ER⍺/β and AR chimeras enabled visualization of receptor-xenobiotic interactions under live-cell conditions. Key parameters examined included i) receptor subcellular localization, ii) ligand-receptor interactions, iii) transcriptional function, and iv) receptor-chromatin interactions. Competitive reporter-gene assays were also performed with ⍺-ZOL and β-ZOL (0.1-1.0 μM) in the presence of 5⍺-DHT (EC50; 10 M). ZEA metabolites promoted i) ER⍺/β and AR nuclear translocation, ii) ERα/β transactivation, iii) repression of DHT-induced AR transactivation, and iv) contrasting receptor-chromatin interactions. This study suggests that endocrine disruptions are driven by a complex interplay of agonistic and/or antagonistic effects of ZEA and its metabolites on receptor function, contributing to potential health risks.