Sulfated metabolites of polychlorinated biphenyls are high-affinity ligands for the thyroid hormone transport protein transthyretin.

Content Provider	Europe PMC
Author	Grimm, Fabian A. Lehmler, Hans-Joachim He, Xianran Robertson, Larry W. Duffel, Michael W.
Copyright Year	2013
Abstract	Background: The displacement of l-thyroxine (T4) from binding sites on transthyretin (TTR) is considered a significant contributing mechanism in polychlorinated biphenyl (PCB)-induced thyroid disruption. Previous research has discovered hydroxylated PCB metabolites (OH-PCBs) as high-affinity ligands for TTR, but the binding potential of conjugated PCB metabolites such as PCB sulfates has not been explored.Objectives: We evaluated the binding of five lower-chlorinated PCB sulfates to human TTR and compared their binding characteristics to those determined for their OH-PCB precursors and for T4.Methods: We used fluorescence probe displacement studies and molecular docking simulations to characterize the binding of PCB sulfates to TTR. The stability of PCB sulfates and the reversibility of these interactions were characterized by HPLC analysis of PCB sulfates after their binding to TTR. The ability of OH-PCBs to serve as substrates for human cytosolic sulfotransferase 1A1 (hSULT1A1) was assessed by OH-PCB–dependent formation of adenosine-3´,5´-diphosphate, an end product of the sulfation reaction.Results: All five PCB sulfates were able to bind to the high-affinity binding site of TTR with equilibrium dissociation constants (Kd values) in the low nanomolar range (4.8–16.8 nM), similar to that observed for T4 (4.7 nM). Docking simulations provided corroborating evidence for these binding interactions and indicated multiple high-affinity modes of binding. All OH-PCB precursors for these sulfates were found to be substrates for hSULT1A1.Conclusions: Our findings show that PCB sulfates are high-affinity ligands for human TTR and therefore indicate, for the first time, a potential relevance for these metabolites in PCB-induced thyroid disruption.
ISSN	00916765
Journal	Environmental Health Perspectives
Volume Number	121
PubMed Central reference number	PMC3672920
Issue Number	6
PubMed reference number	23584369
e-ISSN	15529924
DOI	10.1289/ehp.1206198
Language	English
Publisher	National Institute of Environmental Health Sciences
Publisher Date	2013-04-12
Access Restriction	Open
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Subject Keyword	hydroxylated PCB OH-PCB PCB PCB sulfates polychlorinated biphenyl sulfation thyroid disruption transthyretin
Content Type	Text
Resource Type	Article
Subject	Health, Toxicology and Mutagenesis Public Health, Environmental and Occupational Health