Investigation on the interaction of pyrethroid pesticides to estrogen receptor alpha through computational and experimental methods

Pyrethroid insecticides are a group of widely used bio-mimetic synthetic pesticides. However, recent studies reported that they could have an accumulation effect in human which may cause series of health problems. Estrogen receptors (ER) are a class of nuclear receptors that are vital in proper physiological behavior of estrogens. To investigate the reproductive toxicity of pyrethroids, homology modeling, molecular docking, molecular dynamic simulations (MDs) were conducted to explore the interaction between pyrethroids and ERα from atomic scale. The human ERα (2YJA) was selected as a template protein for homology modeling. Then eight typical pyrethroids and positive control estradiol were docked to the modeled protein. The highest scoring bifenthrin and the lowest scoring permethrin were chosen for in-depth analysis. MDs showed that the complex formed by permethrin with ERα had a lower RMSD value and binding free energies compared to bifenthrin. Based on these results from microscopic dimension, exposure experiments were implemented to validate the primary conclusions. VTG concentrations in male zebrafish's blood were significantly higher under permethrin exposure than bifenthrin, suggesting a stronger estrogenic activity and binding propensity. In this regard, the structural characteristics of molecules were analyzed, expecting to provide theoretical references for subsequent drug design and rational drug application.