Organophosphate triesters and selected metabolites enhance binding of thyroxine to human transthyretin in vitro

Katie L. Hill, Timo Hamers, Jorke H. Kamstra, William G. Willmore, Robert J. Letcher*

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review

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The toxicological properties of organophosphate (OP) triesters that are used as flame retardants and plasticizers are currently not well understood, though increasing evidence suggests they can affect the thyroid system. Perturbation of thyroid hormone (TH) transport is one mechanism of action that may affect thyroid function. The present study applied an in vitro competitive protein binding assay with thyroxine (T4) and human transthyretin (hTTR) transport protein to determine the potential for the OP triesters, TDCIPP (tris(1,3-dichloro-2-propyl) phosphate), TBOEP (tris(butoxyethyl) phosphate), TEP (triethyl phosphate), TPHP (triphenyl phosphate), p-OH-TPHP (para-hydroxy triphenyl phosphate), and the OP diester DPHP (diphenyl phosphate), to competitively displace T4 from hTTR. Enhancement of T4 binding to hTTR, rather than the hypothesized competition, was observed for the six OP esters and in a concentration-dependent manner. For example, T4-hTTR binding was significantly increased at concentrations of TBOEP as low as 64 nM, and up to 184% of controls at 5000 nM. A plausible explanation of these results, which to our knowledge has not been previously reported, may be allosteric interactions of the OP esters with hTTR allowing T4 to access the second site of the TH binding pocket. These in vitro results suggest a novel mechanism of OP ester toxicity via T4 binding enhancement, and possible dysregulation of T4-hTTR interactions.

Original languageEnglish
Pages (from-to)87-93
Number of pages7
JournalToxicology Letters
Early online date3 Jan 2018
Publication statusPublished - 15 Mar 2018


This study was financially supported by the Chemicals Management Plan (CMP; Environment and Climate Change Canada (to R.J.L.) , a Discovery Grant from the National and Engineering Science Research Council (NSERC) of Canada (to R.J.L. and W.G.W.), and the NSERC CREATE Program (to R.J.L. and W.G.W.).

FundersFunder number
Chemicals Management Plan
Natural Sciences and Engineering Research Council of Canada
Environment and Climate Change Canada


    • Allosteric interactions
    • Flame retardants
    • Human transthyretin
    • Organophosphate esters
    • Thyroxine


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