Structural Aspects of Potential Endocrine-Disrupting Activity of Stereoisomers for a Common Pesticide Permethrin against Androgen Receptor

Abstract

Simple SummaryHuman exposure to synthetic or naturally occurring endocrine-disrupting compounds (EDCs) contaminating the environment is associated with disruption in endocrine signaling and homeostatic imbalance of hormones. Pyrethroids constitute an important class of extensively used insecticides reported to have endocrine-disrupting activity. Permethrin is one of the most commonly used pyrethroids and exists in isomeric forms. The aim of this study was to investigate and compare the potential endocrine-disrupting activity of permethrin isomers against the androgen receptor (AR). Structural binding studies showed that all permethrin isomer compounds have the potential to compete with native ligand binding in the AR ligand binding pocket. In conclusion, the results of this study suggest that human exposure to commercially produced isomeric forms of permethrin could potentially interfere with the AR function, which may lead to male reproductive dysfunction. Endocrine-disrupting chemicals (EDCs) are a serious global public health and environmental concern. Pyrethroids are insecticide chemicals that are extensively used for crop protection and household purposes but have been identified as EDCs. On account of their ubiquitous environmental presence, human exposure occurs via food, dermal, or inhalation routes and is associated with health problems, including reproductive dysfunction. Permethrin is the most commonly used pyrethroid, and with two chiral centers in its structure, it has four stereoisomeric forms (two enantiomer pairs), i.e., permethrin (1R,3R)-cis, permethrin (1R,3S)-trans, permethrin (1S,3S)-cis, and permethrin (1S,3R)-trans. The current study was performed for predicting the potential endocrine-disrupting activity of the aforementioned four stereoisomers of permethrin against the androgen receptor (AR). The structural binding characterization and binding energy estimations in the AR binding pocket were done using induced fit docking. The structural binding data indicated that all stereoisomers were placed stably in the AR binding pocket and that the estimated binding energy values were comparable to the AR native ligand, except for permethrin (1S,3S)-cis. Furthermore, the commonality in the amino acid interactions to that of the AR native ligand and the binding energy values suggested the potential AR-disrupting activity of all the stereoisomers; however, stereoselective differences were not observed. Taken together, the results suggest that human exposure to permethrin, either as a racemate mixture or in individual stereoisomer form, could potentially interfere with AR function, which may lead to male reproductive dysfunction.