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ToxSci Advance Access published online on April 6, 2006
Toxicological Sciences, doi:10.1093/toxsci/kfj187
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© The Author 2006. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received February 1, 2006
Accepted April 3, 2006

In Vitro Toxicology

In Vitro Profiling of the Endocrine Disrupting Potency of Brominated Flame Retardants

Timo Hamers 1 *, Jorke H. Kamstra 1, Edwin Sonneveld 2, Albertinka J. Murk 3, Monique H.A. Kester 4, Patrik L. Andersson 5, Juliette Legler 1, and Abraham Brouwer 6

1 Institute for Environmental Studies (IVM); Amsterdam, The Netherlands
2 BioDetection Systems BV (BDS); Amsterdam, The Netherlands
3 Wageningen University - Toxicology Section; Wageningen, The Netherlands
4 Erasmus University Medical Center; Rotterdam, The Netherlands
5 Umeå University - Environmental Chemistry; Umeå, Sweden
6 Institute for Environmental Studies (IVM); Amsterdam, The Netherlands; BioDetection Systems BV (BDS); Amsterdam, The Netherlands

* To whom correspondence should be addressed.
Timo Hamers, E-mail: timo.hamers{at}ivm.vu.nl


  Abstract

Over the last years, increasing evidence has become available that some brominated flame retardants (BFRs) may have endocrine disrupting (ED) potencies. The goal of the current study was to perform a systematic in vitro screening of the ED potencies of BFRs (1) to elucidate possible modes of action of BFRs in man and wildlife, and (2) to classify BFRs with similar profiles of ED potencies. A test set of twenty-seven individual BFRs was selected, consisting of nineteen polybrominated diphenylethers (PBDE) congeners, tetrabromobisphenol-A (TBBPA), hexabromocyclododecane (HBCD), 2,4,6-tribromophenol (246-TBP), ortho-hydroxylated BDE-47 (6OH-BDE-47), and TBBPA-bis(2,3)dibromopropylether (TBBPA-DBPE). All BFRs were tested for their potency to interact with the arylhydrocarbon receptor (AhR), androgen receptor (AR), progesterone receptor (PR), and estrogen receptor (ER). In addition, all BFRs were tested for their potency to inhibit estradiol (E2) sulfation by E2-sulfotransferase (E2SULT), to interfere with thyroid hormone 3,3‘,5-triiodothyronine (T3) mediated cell proliferation, and to compete with T3-precursor thyroxine (T4) for binding to the plasma transport protein transthyretin (TTR). The results of the in vitro screening indicated that BFRs have ED potencies, some of which had not or only marginally been described before (AR-antagonism, PR-antagonism, E2SULT inhibition, and potentiation of T3-mediated effects). For some BFRs, the potency to induce AR-antagonism, E2SULT inhibition and TTR competition was higher than for natural ligands or clinical drugs used as positive controls. Based on their similarity in ED profiles, BFRs were classified into five different clusters. These findings support further investigation of the potential endocrine disrupting effects of these environmentally relevant BFRs in man and wildlife.

Keywords: Toxicity profiling; Brominated Flame Retardants; Endocrine Disruption; Hierarchical Cluster Analysis; Principal Component Analysis.
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