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Biosensor discovery of thyroxine transport disrupting chemicals

Posted Jul 01 2009 5:02pm
Marchesini GR et al.
Toxicol Appl Pharmacol. 2008 Oct 1;232(1):150- 60. Epub 2008 Jul 2.
http://www.sciencedirect.com/science

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.
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