Release of bound steroid from the androgen and estrogen receptors is induced by DDT and its analogs.

The pesticide p,p'-DDT (DDT) and its analogs (p,p'-DDD, o,p'-DDD, and p,p'-DDE) inhibit the binding of dihydrotestosterone (DHT) to the androgen receptor (AR) and estradiol (E2) to the estrogen receptor (ERα) ligand-binding domains (LBDs), as previously reported. In this study, we introduce assays to measure the release of receptor-bound steroids. These compounds induced the release of DHT from the AR LBD and E2 from the ERα LBD. These findings suggest that DDT and its analogs may interact with a surface site on the LBD, thereby allosterically disrupting steroid binding. One potential site is binding function 3 (BF3). To explore this possibility, ligand docking studies were performed. The results revealed a correlation between interaction energy at the BF3 site and compound potency in the steroid release assay. Specific AR residues-Asn833, Phe673, and Pro723-appear to play key roles in ligand interaction with the BF3 site. In ERα, Met315, Val478, Lys481, and Pro365 are likely important for compound binding. Two residue pairs (Asn833 and Pro723 in AR and Val478 and Pro365 in ERα) occupy topologically equivalent positions within the BF3 sites, suggesting a conserved interaction mode across receptors. Based on these results we speculate that DDT and its analogs may act as endocrine-disrupting chemicals by modulating receptor activity through an allosteric mechanism involving the BF3 site.