Staff Publications

Staff Publications

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    'Staff publications' is the digital repository of Wageningen University & Research

    'Staff publications' contains references to publications authored by Wageningen University staff from 1976 onward.

    Publications authored by the staff of the Research Institutes are available from 1995 onwards.

    Full text documents are added when available. The database is updated daily and currently holds about 240,000 items, of which 72,000 in open access.

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Record number 430325
Title New Approaches to Assess the Transthyretin Binding Capacity of Bioactivated Thyroid Hormone Disruptors
Author(s) Montano, M.; Cocco, E.; Guignard, C.; Marsh, G.; Hoffmann, L.; Bergman, A.; Gutleb, A.C.; Murk, A.J.
Source Toxicological sciences 130 (2012)1. - ISSN 1096-6080 - p. 94 - 105.
DOI https://doi.org/10.1093/toxsci/kfs228
Department(s) Sub-department of Toxicology
WIMEK
Publication type Refereed Article in a scientific journal
Publication year 2012
Keyword(s) polybrominated diphenyl ethers - brominated flame retardants - bears ursus-maritimus - in-vitro - thyroxine-binding - liver-microsomes - polychlorinated-biphenyls - transport proteins - bisphenol-a - fatty-acids
Abstract Polychlorinated biphenyls (PCBs) and polybrominated diphenyl-ethers (PBDEs) are metabolized into hydroxylated metabolites (OH-PCBs/PBDEs), which can disrupt the thyroid hormone homeostasis. Binding of these metabolites to transport proteins such as transthyretin (TTR) is an important mechanism of their toxicity. Several methods to quantify the competitive thyroxine (T4) displacement potency of pure metabolites exist. However, quantification of the potency of in vitro metabolized PCBs and PBDEs has drawbacks related to the coextraction of compounds disturbing the T4-TTR competitive binding assay. This study identifies and quantifies the major coextractants namely cholesterol, saturated and nonsaturated fatty acids (SFA and NSFA) at levels above 20 nmol per mg equivalent protein following various extraction methods. Their TTR binding potency was analyzed in a downscaled, nonradioactive fluorescence displacement assay. At concentration factors needed for TTR competitive binding, at least 10µM of these coextracts is present, whereas individual SFA and NSFA disturb the assay from 0.3µM. The effectiveness of the in vitro metabolism and extraction of the model compounds CB 77 and BDE 47 was chemically quantified with a newly developed chromatographic method analyzing silylated derivatives of the OH-metabolites and coextractants. A new method to selectively extract metabolites and limit coextraction of disturbing compounds to less than 5 nmol per mg equivalent protein is presented. It is now possible to make a dose-response curve up to 50% inhibition with bioactivated CB 77 and BDE 47. The toxic potencies of bioactivated persistent organic pollutants (POPs) should be taken into account to prevent serious underestimation of their hazard and risk
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