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ToxSci Advance Access originally published online on April 6, 2006
Toxicological Sciences 2006 92(1):157-173; 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

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

Timo Hamers*,1, Jorke H. Kamstra*, Edwin Sonneveld{dagger}, Albertinka J. Murk{ddagger}, Monique H. A. Kester§, Patrik L. Andersson, Juliette Legler* and Abraham Brouwer*,{dagger}

* Institute for Environmental Studies, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands; {dagger} BioDetection Systems BV, 1098 SM Amsterdam, The Netherlands; {ddagger} Toxicology Section, Wageningen University, 6703 HE Wageningen, The Netherlands; § Erasmus University Medical Center, 3015 GJ Rotterdam, The Netherlands; and Environmental Chemistry, Umeå University, SE-901 87 Umeå, Sweden

Received February 1, 2006; accepted April 1, 2006

Over the last few 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 27 individual BFRs were selected, consisting of 19 polybrominated diphenyl ether congeners, tetrabromobisphenol-A, hexabromocyclododecane, 2,4,6-tribromophenol, ortho-hydroxylated brominated diphenyl ether 47, and tetrabromobisphenol-A–bis(2,3)dibromopropyl ether. All BFRs were tested for their potency to interact with the arylhydrocarbon receptor, androgen receptor (AR), progesterone receptor (PR), and estrogen receptor. In addition, all BFRs were tested for their potency to inhibit estradiol (sulfation by estradiol sulfotransferase (E2SULT), to interfere with thyroid hormone 3,3',5-triiodothyronine (T3)–mediated cell proliferation, and to compete with T3-precursor thyroxine 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 ED effects of these environmentally relevant BFRs in man and wildlife.

Key Words: toxicity profiling; brominated flame retardants; endocrine disruption; hierarchical cluster analysis; principal component analysis.


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