期刊
TOXICOLOGY LETTERS
卷 285, 期 -, 页码 87-93出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.toxlet.2017.12.030
关键词
Organophosphate esters; Flame retardants; Thyroxine; Human transthyretin; Allosteric interactions
类别
资金
- Chemicals Management Plan (CMP)
- Environment and Climate Change Canada
- National and Engineering Science Research Council (NSERC) of Canada
- NSERC CREATE Program
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-OHTPHP (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.
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