title: Biosensor discovery of thyroxine transport disrupting chemicals.
abstract: Ubiquitous chemicals may interfere with the thyroid system that is essential in the development and physiology of vertebrates. We applied a surface plasmon resonance (SPR) biosensor-based screening method for the fast screening of chemicals with thyroxine (T4) transport disrupting activity. Two inhibition assays using the main thyroid hormone transport proteins, T4 binding globulin (TBG) and transthyretin (TTR), in combination with a T4-coated biosensor chip were optimized and automated for screening chemical libraries. The transport protein-based biosensor assays were rapid, high throughput and bioeffect-related. A library of 62 chemicals including the natural hormones, polychlorinated biphenyls (PCBs), polybrominated diphenylethers (PBDEs) and metabolites, halogenated bisphenol A (BPA), halogenated phenols, pharmaceuticals, pesticides and other potential environmentally relevant chemicals was tested with the two assays. We discovered ten new active compounds with moderate to high affinity for TBG with the TBG assay. Strikingly, the most potent binding was observed with hydroxylated metabolites of the brominated diphenyl ethers (BDEs) BDE 47, BDE 49 and BDE 99, that are commonly found in human plasma. The TTR assay confirmed the activity of previously identified hydroxylated metabolites of PCBs and PBDEs, halogenated BPA and genistein. These results show that the hydroxylated metabolites of the ubiquitous PBDEs not only target the T4 transport at the TTR level, but also, and to a great extent, at the TBG level where most of the T4 in humans is circulating. The optimized SPR biosensor-based transport protein assay is a suitable method for high throughput screening of large libraries for potential thyroid hormone disrupting compounds.
authors.affiliation: RIKILT-Institute of Food Safety, Wageningen UR, Wageningen, The Netherlands. gerardo.marchesini@wur.nl
authors.forename: Gerardo R
authors.initials: GR
authors.lastname: Marchesini
authors.forename: Anastasia
authors.initials: A
authors.lastname: Meimaridou
authors.forename: Willem
authors.initials: W
authors.lastname: Haasnoot
authors.forename: Eline
authors.initials: E
authors.lastname: Meulenberg
authors.forename: Faywell
authors.initials: F
authors.lastname: Albertus
authors.forename: Mineyuki
authors.initials: M
authors.lastname: Mizuguchi
authors.forename: Makoto
authors.initials: M
authors.lastname: Takeuchi
authors.forename: Hubertus
authors.initials: H
authors.lastname: Irth
authors.forename: Albertinka J
authors.initials: AJ
authors.lastname: Murk
mesh_terms: D001331:Automation; D015374:Biosensing Techniques; D052244:Endocrine Disruptors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D011228:Prealbumin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011485:Protein Binding; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D015203:Reproducibility of Results; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship; D020349:Surface Plasmon Resonance; D013974:Thyroxine / Q000378:metabolism*; D013975:Thyroxine-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D052244:Endocrine Disruptors; D011228:Prealbumin; D011994:Recombinant Proteins; D054852:Small Molecule Libraries; D013975:Thyroxine-Binding Proteins; D013974:Thyroxine