Hamers Timo, Kamstra Jorke H, Sonneveld Edwin, Murk Albertinka J, Kester Monique H A, Andersson Patrik L, Legler Juliette, Brouwer Abraham
Institute for Environmental Studies, Vrije Universiteit Amsterdam, De Boelelaan 1087, 1081 HV Amsterdam, The Netherlands.
Toxicol Sci. 2006 Jul;92(1):157-73. doi: 10.1093/toxsci/kfj187. Epub 2006 Apr 6.
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.
在过去几年中，越来越多的证据表明，一些溴化阻燃剂（BFRs）可能具有内分泌干扰（ED）潜能。本研究的目的是对BFRs的ED潜能进行系统的体外筛选，（1）以阐明BFRs在人类和野生动物中的可能作用模式，（2）对具有相似ED潜能特征的BFRs进行分类。选择了一组27种单独的BFRs作为测试集，包括19种多溴二苯醚同系物、四溴双酚A、六溴环十二烷、2,4,6-三溴苯酚、邻羟基化溴化二苯醚47和四溴双酚A-双（2,3）二溴丙醚。所有BFRs都测试了其与芳烃受体、雄激素受体（AR）、孕激素受体（PR）和雌激素受体相互作用的潜能。此外，所有BFRs都测试了其抑制雌二醇（通过雌二醇磺基转移酶（E2SULT）进行硫酸化）、干扰甲状腺激素3,3',5-三碘甲状腺原氨酸（T3）介导的细胞增殖以及与T3前体甲状腺素竞争结合血浆转运蛋白甲状腺素结合蛋白（TTR）的潜能。体外筛选结果表明，BFRs具有ED潜能，其中一些以前未被描述或仅被少量描述过（AR拮抗、PR拮抗、E2SULT抑制和T3介导效应的增强）。对于一些BFRs，诱导AR拮抗、E2SULT抑制和TTR竞争的潜能高于用作阳性对照的天然配体或临床药物。基于它们在ED特征上的相似性，BFRs被分为五个不同的簇。这些发现支持进一步研究这些与环境相关的BFRs在人类和野生动物中的潜在ED效应。
