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Binding interactions of perfluoroalkyl substances with thyroid hormone transport proteins and potential toxicological
Xiao-Min Ren1, Wei-Ping Qin1, Lin-Ying Cao1
1State Key Laboratory of Environmental Chemistry and Eco-toxicology, Research Center for Eco-environmental Sciences, Chinese Academy of Sciences, 18 Shuangqing Road, Beijing 100085, China.
Abstract:
Perfluoroalkyl 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 3×10(-4) 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 2×10(-4) 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.
Insights
Per- and polyfluoroalkyl substances (PFASs) can disrupt thyroid hormones by binding to transport proteins like transthyretin (TTR) and thyroxine-binding globulin (TBG). Specific PFAS structures show varying affinities, impacting thyroid hormone regulation.
Area of Science:
- Environmental Toxicology
- Endocrinology
- Biochemistry
Background:
- Per- and polyfluoroalkyl substances (PFASs) are environmental contaminants linked to thyroid hormone (TH) disruption in animals.
- The precise molecular mechanisms underlying PFAS-induced thyroid disruption remain poorly understood.
- Thyroid hormones are transported in the blood by specific binding proteins, primarily transthyretin (TTR) and thyroxine-binding globulin (TBG).
Purpose of the Study:
- To investigate the binding affinities of various PFASs to major thyroid hormone transport proteins, TTR and TBG.
- To elucidate the molecular interactions and structural determinants governing PFAS binding to TTR and TBG.
- To assess the potential for PFASs to displace thyroxine (T4) from these transport proteins.
Main Methods:
- A fluorescence displacement assay was employed to quantify the binding affinities of 16 different PFASs to TTR and TBG.
- Structure-activity relationship analysis was performed to identify optimal PFAS characteristics for binding.
- Site-directed mutagenesis and molecular docking simulations were utilized to pinpoint key amino acid residues and binding modes.
Main Results:
- Most tested PFASs bound to TTR, with potencies varying based on chain length and functional group (sulfonate optimal).
- Perfluorotridecanoic acid and perfluorotetradecanoic acid showed weak binding to TBG.
- Specific mutations in TTR (K15G) and TBG (R378G, R381G) significantly reduced PFAS binding, highlighting key residues (K15, R381).
Conclusions:
- PFASs can bind to TTR and, to a lesser extent, TBG, potentially interfering with thyroid hormone transport.
- Binding affinity is influenced by PFAS chemical structure, with medium-chain sulfonated PFASs favoring TTR and longer-chain PFASs favoring TBG.
- These interactions, particularly with TTR, may contribute to thyroid hormone disruption, especially in occupationally exposed populations.
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