Interaction of Per- and Polyfluoroalkyl Substances with Estrogen Receptors in Rainbow Trout (Oncorhynchus mykiss): An In Silico Investigation

Fresh water sources, including lakes, such as the Great Lakes, are some of the most important ecosystems in the world. Despite the importance of these lakes, there is increasing concern about the presence of per- and polyfluoroalkyl substances (PFAS)─among the most prevalent contaminants of our time─due to the ability of PFAS to bioaccumulate and persist in the environment, as well as to its linkages to detrimental human and animal health effects. In this study, PFAS exposure on rainbow trout (Oncorhynchus mykiss) is examined at the molecular level, focusing on the impact of PFAS binding on the alpha (α) and beta (β) estrogen receptors (ERs) using molecular dynamics simulations, binding free energy calculations, and structural analysis. ERs are involved in fundamental physiological processes, including reproductive system development, muscle regeneration, and immunity. This study shows that PFAS binds to both the estrogen α and estrogen β receptors, albeit via different binding modes, due to a modification of an amino acid in the binding site as a result of a reorientation of residues in the binding pocket. As ER overactivation can occur through environmental toxins and pollutants, this study provides insights into the influence of different types of PFAS on protein function.