Release of Bound Steroid from the Androgen and Estrogen Receptors Is Induced by DDT and Its Analogs

Authors

• Matthew D. Rosales, The University of Texas Rio Grande Valley
• Tahyra Soto, The University of Texas Rio Grande Valley
• Jacqueline I. Goodship, The University of Texas Rio Grande Valley
• Ahyssa R. Cruz, The University of Texas Rio Grande Valley
• Isaac A. Rodriguez, The University of Texas Rio Grande Valley
• Ventura Cuba Flores, The University of Texas Rio Grande Valley
• Amanda Chavez, The University of Texas Rio Grande Valley
• Monica P. Solis, The University of Texas Rio Grande Valley
• Esmeralda Lopez, The University of Texas Rio Grande Valley
• Frank B. Dean, The University of Texas Rio Grande Valley
• Evangelia Kotsikorou, The University of Texas Rio Grande ValleyFollow

Document Type

Article

Publication Date

11-1-2026

Abstract

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.

Comments

http://creativecommons.org/licenses/by-nc/4.0/

Recommended Citation

Rosales, Matthew D., Tahyra Soto, Jacqueline I. Goodship, Ahyssa R. Cruz, Isaac A. Rodriguez, Ventura Cuba Flores, Amanda Chavez, et al. "Release of Bound Steroid from the Androgen and Estrogen Receptors Is Induced by DDT and Its Analogs." Toxicology and Applied Pharmacology (2026): 118015. https://doi.org/10.1016/j.taap.2026.118015

Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License

Publication Title

Toxicology and Applied Pharmacology

DOI

https://doi.org/10.1016/j.taap.2026.118015