US EPA

3009236 

Journal Article 

In silico approach to identify potential thyroid hormone disruptors among currently known dust contaminants and their metabolites 

Zhang, J; Kamstra, JH; Ghorbanzadeh, M; Weiss, JM; Hamers, T; Andersson, PL 

2015 

1 

Environmental Science & Technology
ISSN: 0013-936X
EISSN: 1520-5851 

49 

16 

10099-10107 

English 

26207645 

10.1021/acs.est.5b01742 

WOS:000359891700082 

https://search.proquest.com/docview/1712558167?accountid=171501
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Thyroid hormone disrupting chemicals (THDCs) interfere with the thyroid hormone system and may induce multiple severe physiological disorders. Indoor dust ingestion is a major route of THDCs exposure in humans, and one of the molecular targets of these chemicals is the hormone transporter transthyretin (TTR). To virtually screen indoor dust contaminants and their metabolites for THDCs targeting TTR, we developed a quantitative structure-activity relationship (QSAR) classification model. The QSAR model was applied to an in-house database including 485 organic dust contaminants reported from literature data and their 433 in silico derived metabolites. The model predicted 37 (7.6%) dust contaminants and 230 (53.1%) metabolites as potential TTR binders. Four new THDCs were identified after testing 23 selected parent dust contaminants in a radio-ligand TTR binding assay; 2,2',4,4'-tetrahydroxybenzophenone, perfluoroheptanesulfonic acid, 3,5,6-trichloro-2-pyridinol, and 2,4,5-trichlorophenoxyacetic acid. These chemicals competitively bind to TTR with 50% inhibition (IC50) values at or below 10 μM. Molecular docking studies suggested that these THDCs interacted similarly with TTR via the residue Ser117A, but their binding poses were dissimilar to the endogenous ligand T4. This study identified new THDCs using an in silico approach in combination with bioassay testing and highlighted the importance of metabolic activation for TTR binding. 

Meteorological & Geoastrophysical Abstracts; Toxicology Abstracts; Environment Abstracts; Residues; Environmental sciences; Hormones; Structure-activity relationships; Ingestion; Databases; Metabolites; Classification; Thyroxine; Physiology; Thyroid hormones; Thyroid; Physiological disorders; transthyretin; Bioassays; Indoor environments; Data processing; Chemicals; Contaminants; Metabolic activation; X 24360:Metals; ENA 02:Toxicology & Environmental Safety; M2 551.5:General (551.5)