Binding interactions of perfluoroalkyl substances with thyroid hormone transport proteins and potential toxicological implications

Abstract

A B S T R A C TPerfluoroalkyl substances (PFASs) have been shown to cause abnormal levels of thyroid hormones (THs) in experimental animals, but the molecular mechanism is poorly understood. Here, a fluorescence displacement assay was used to determine the binding affinities of 16 PFASs with two major TH transport proteins, transthyretin (TTR) and thyroxine-binding globulin (TBG). Most of the tested PFASs bound TTR with relative potency (RP) values of 3 Â 10 À4 to 0.24 when compared with that of the natural ligand thyroxine, whereas fluorotelomer alcohols did not bind. Only perfluorotridecanoic acid and perfluorotetradecanoic acid bound TBG, with RP values of 2 Â 10 À4 when compared with that of thyroxine. Based on these results, it was estimated that displacement of T4 from TTR by perfluorooctane sulfonate and perfluorooctanoic acids would be significant for the occupationally exposed workers but not the general population. Structure-binding analysis revealed that PFASs with a medium chain length and a sulfonate acid group are optimal for TTR binding, and PFASs with lengths longer than 12 carbons are optimal for TBG binding. Three mutant proteins were prepared to examine crucial residues involved in the binding of PFASs to TH transport proteins. TTR with a K15G mutation and TBG with either a R378G or R381G mutation showed decreased binding affinity to PFASs, indicating that these residues play key roles in the interaction with the compounds. Molecular docking showed that the PFASs bind to TTR with their acid group forming a hydrogen bond with K15 and the hydrophobic chain towards the interior. PFASs were modeled to bind TBG with their acid group forming a hydrogen bond with R381 and the hydrophobic chain extending towards R378. The findings aid our understanding of the behavior and toxicity of PFASs on the thyroid hormone system.

Multi‐spectroscopic and molecular dynamics simulations investigation of the binding mechanism of polybrominated diphenyl ethers to hen egg white lysozyme

“…All water molecules and other ligands were removed from the structure of HEWL and then Gasteiger charges were assigned and polar hydrogens were added to HEWL using Autodock 4.2 . During the docking process, the proteins were kept rigid while all torsional bonds of small molecules were free . The dimensions of the grid box were set as 70 Å × 70 Å × 70 Å with a default grid spacing of 0.375 Å.…”

Application of the Key Characteristics of Carcinogens to Per and Polyfluoroalkyl Substances

“…PFOA and other PFAS may modulate hormonal signaling and endogenous circulating hormone levels through interaction with serum proteins that facilitate the transport of various endogenous and exogenous substances, including hormones and xenobiotic compounds [186,187]. For example, most PFAS, but not fluorotelomers, bind thyroid hormone transport proteins such as transthyretin [188,189]. Exposure to PFOA and PFOS reduced T4 levels in adult rats as well as circulating T3 and T4 levels in pregnant dams and/or offspring exposed to PFOS, PFHxS, PFBS, and GenX [167,168,[190][191][192].…”

“…Animal Biosassay In Vitro PFOA Association: [153]; [154]; [155]; [156]; [157] Association: reviewed in [164]; [91]; [165]; [166]; [169]; [170]; [173]; [175]; [191]; [61] No association: [174] Association: [176]; [158]; [175]; [181]; [188]; [189]; [193]; [179]; [180] No association: [182] Long-chain PFAS a PFOS Association: [154]; [155]; [156]; [157]; [160]; reviwed in [163] No Association: [153] Association: [191]; [192] Association: [177]; [175]; [181]; [188]; [189]; [193]; [179]; [180] No association: [182] PFHxS Association: [159]; reviwed in [163] No association: [...…”

“…Association: [156]; [160] Association: [188]; [189]; [180] No association: [179] PFDoA Association: [188]; [189]; [179] No association: [180]…”

“…PFTrDA Association: [189] PFTeDA Association: [188]; [189]; [179] 8:2 FTOH Association: [184]; [185] No association: [188] 8:2 monoPAP Association: [184]; [185] 8:2 diPAP Association: [184] 8:2 triPAP Association: [184] 10:2 diPAP Association: [184] Short-chain PFAS b PFBS Association: [190] Association: [175]; [188]; [189]; [179]; [180] No association: [182] PFHxA…”