In Silico Analysis of the Conservation of Human Toxicity and Endocrine Disruption Targets in Aquatic Species

Pharmaceuticals and industrial chemicals, both in the environment and in research settings, commonly interact with aquatic vertebrates. Due to their short life-cycles and the traits that can be generalized to other organisms, fish and amphibians are attractive models for the evaluation of toxicity caused by endocrine disrupting chemicals (EDCs) and adverse drug reactions. EDCs, such as pharmaceuticals or plasticizers, alter the normal function of the endocrine system and pose a significant hazard to human health and the environment. The selection of suitable animal models for toxicity testing is often reliant on high sequence identity between the human proteins and their animal orthologs. Herein, we compare in silico the ligand-binding sites of 28 human "side-effect" targets to their corresponding orthologs in Danio rerio, Pimephales promelas, Takifugu rubripes, Xenopus laevis, and Xenopus tropicalis, as well as subpockets involved in protein interactions with specific chemicals. We found that the ligand-binding pockets had much higher conservation than the full proteins, while the peroxisome proliferator-activated receptor γ and corticotropin-releasing factor receptor 1 were notable exceptions. Furthermore, we demonstrated that the conservation of subpockets may vary dramatically. Finally, we identified the aquatic model(s) with the highest binding site similarity, compared to the corresponding human toxicity target.