Species Differences in Response to Binding Interactions of Bisphenol A and its Analogs with the Modeled Estrogen Receptor 1 and In Vitro Reporter Gene Assay in Human and Zebrafish.

Adverse impacts associated with the interactions of numerous endocrine-disruptor chemicals (EDCs) with estrogen receptor 1 play a pivotal role in reproductive dysfunction. The predictive studies on these interactions thus are crucial in the risk assessment of EDCs but rely heavily on the accuracy of specific protein structure in three dimensions. As the three-dimensional (3D) structure of zebrafish estrogen receptor 1 (zEsr1) is not available, the 3D structure of zEsr1 ligand-binding domain (zEsr1-LBD) was generated using MODELLER and its quality was assessed by the PROCHECK, ERRAT, ProSA, and Verify-3D tools. After the generated model was verified as reliable, bisphenol A and its analogs were docked on the zEsr1-LBD and human estrogen receptor 1 ligand-binding domain (hESR1-LBD) using the Discovery Studio and Autodock Vina programs. The molecular dynamics followed by molecular docking were simulated using the Nanoscale Molecular Dynamics program and compared to those of the in vitro reporter gene assays. Some chemicals were bound with an orientation similar to that of 17β-estradiol in both models and in silico binding energies showed moderate or high correlations with in vitro results (0.33 ≤ r  ≤ 0.71). Notably, hydrogen bond occupancy during molecular dynamics simulations exhibited a high correlation with in vitro results (r  ≥ 0.81) in both complexes. These results show that the combined in silico and in vitro approaches is a valuable tool for identifying EDCs in different species, facilitating the assessment of EDC-induced reproductive toxicity. Environ Toxicol Chem 2022;41:2431-2443. © 2022 SETAC.