Homology modeling to screen for potential binding of contaminants to thyroid hormone receptor and transthyretin in glaucous gull (Larus hyperboreus) and herring gull (Larus argentatus)

Geir W Gabrielsen,Ingebrigt Sylte,Bjørn M Jenssen,Kurt Kristiansen,Eldbjørg S Heimstad,Silje Mæhre,Åse-Karen Mortensen

doi:10.1016/j.comtox.2020.100120

Abstract

Thyroid hormone disrupting chemicals (THDCs) are of major concern in ecotoxicology. With the increased number of emerging chemicals on the market there is a need to screen for potential THDCs in a cost-efficient way, and in silico modeling is an alternative to address this issue. In this study homology modeling and docking was used to screen a list of 626 compounds for potential thyroid hormone disrupting properties in two gull species. The tested compounds were known contaminants or emerging contaminants predicted to have the potential to reach the Arctic. Models of transthyretin (TTR) and thyroid hormone receptor α and β (TRα and TRβ) from the Arctic top predator glaucous gull (Larus hyperboreus) and temperate predator herring gull (Larus argentatus) were constructed and used to predict the binding affinity of the compounds to the thyroid hormone (TH) binding sites. The modeling predicted that 28, 4 and 330 of the contaminants would bind to TRα, TRβ and TTR respectively. These compounds were in general halogenated, aromatic and had polar functional groups, like that of THs. However, the predicted binders did not necessarily have all these properties, such as the per- and polyfluoroalkyl substances that are not aromatic and still bind to the proteins.

Highlights

Certain environmental pollutants have chemical structures resembling thyroid hormones (THs)
In the thyroid hormone receptors (TRs) there was only one amino acid that differed between the chicken and gull sequences: an aspartate in chicken was changed to glutamate in gull TRα outside of the ligand binding pocket (BP)
The present study shows that compounds with high binding affinity to human TTR (hTTR) in some cases had high scores, and low binding affinity in the gull TTR (gTTR) models

Summary

Introduction

Certain environmental pollutants have chemical structures resembling thyroid hormones (THs). Hydroxyl-polybrominated diphenyl ethers (OH-PBDEs), hydroxylpolychlorinated biphenyls (OH-PCBs), per- and polyfluoroalkyl substances (PFASs), bisphenol A (BPA), tetrabromo-BPA (TBBPA) and halogenated phenols are among the compounds reported to bind to the TH binding site in human TTR (hTTR) and/or TR (hTR) (see Fig. 1 for illustrations of molecular structure for these groups of chemicals) [1,2,3,4]. These compounds may reduce serum TH concentrations by displacing THs from the transport proteins, increasing hepatic excretion. The isoforms differ in ligand affinity and specificity and are differentially expressed in different organs [8]

Methods

Results

Conclusion