In Silico Approach To Identify Potential Thyroid Hormone Disruptors among Currently Known Dust Contaminants and Their Metabolites

Abstract

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.

Cats’ Internal Exposure to Selected Brominated Flame Retardants and Organochlorines Correlated to House Dust and Cat Food

“…A review article of organic contaminants in settled house dust reported 485 chemicals, including a wide range of compound groups such as PBDEs, PCBs, organophosphate esters, per-and polyfluoroalkyl substances (PFAS), polycyclic aromatic hydrocarbons (PAHs), chlorinated phenols, and pesticides. 36,37 In this study, correlation between cats' internal and external exposure by paired analyses of serum, cat food (matched after each cat's food requirements according to the cat owners), and settled house dust was investigated. Several previous studies have analyzed cat blood for BFRs, [9][10][11]15,[38][39][40][41]15,[38][39][40][41][42] and pesticides.…”

Structure-related interactions of brominated and organophosphate flame retardants and degradation products with thyroxine and human thyroid hormone transport proteins in vitro

“…At the time of selection of this study set of OP triesters and metabolites, no previous studies had yet been published on interactions of OP triester FRs with TH transport proteins. Since then two published studies have observed interactions of select OP triesters with human TTR using a similar in vitro assay to the present methodology, as well as some in silico analyses Zhang et al, 2015). These studies consistently predicted no competition of OP triesters (including the presently-selected TDCIPP, TBOEP, and TPHP) with T4 for binding at the TH binding channel of human TTR in silico or in vivo.…”

“…Several other amino acid residues in the gull TTR binding pocket were predicted to form interactions with the TH and TB-DiPhOBz ligands, however, including: Met-13, Leu-17, Phe-52, Glu-54, Thr-106, Ala-108, Ala-109, Leu-110, Thr-118, Thr-119, and Val-121 (Figure 4-5; Appendix A). These residues align with many of those found to interact with ligands (e.g., OH-BDE congeners) in the human TTR binding pocket (Cao et al, 2010;Zhang et al, 2015).…”

“…Several physical-chemical properties have been identified as important factors in the interactions of endogenous and exogenous ligands with TH transport proteins (and predominantly human TTR). The three most important characteristics identified to-date are 1) presence of an aromatic ring(s), 2) presence of a halogen(s), and 3) presence of a hydroxyl group (and preferably a paraor meta-OH group) (Papa et al, 2013;Zhang et al, 2015). Other notable characteristics include a molecular size of up to 550 g/mol, partial charge, polarity, and hydrophobicity (Lans et al, 1993;Papa et al, 2013;Weiss et al, 2015;Zhang et al, 2015).…”

Thyroid disruption properties of three indoor dust chemicals tested in Silurana tropicalis tadpoles

“…Major groups of chemicals detected in dust include phthalate esters, polychlorinated biphenyls, pesticides, brominated and organophosphate flame retardants, chlorinated paraffins and parabens (Lucattini et al, ). Zhang et al () developed a quantitative structure‐activity relationship model, which predicted 37 dust contaminants and 230 metabolites as potential TTR binders, suggesting that a large number of indoor dust chemicals are capable of interfering with the thyroid system. As TTR binding is only one of several possible mechanisms for thyroid disruption, it is of great importance to study the overall TH‐disrupting potency for indoor dust chemicals.…”