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

Abstract

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.

Developmental neurotoxicity of polybrominated diphenyl ether (PBDE) flame retardants

“…PBDEs can be fetotoxic, but usually at maternally toxic doses, and there is no evidence of teratogenicity. Despite the structural similarities to PCBs, PBDEs do not appear to activate the Ah receptor-AhR nuclear translocator protein-XRE complex, although they can bind to the Ah receptor (Chen and Bunce, 2003;Peters et al 2006;Hamers et al 2006). PBDEs may have endocrine disrupting effects, as they have been shown to interact as antagonists or agonists at androgen, progesterone, and estrogen receptors (Meerts et al 2001;Hamers et al 2006).…”

“…Despite the structural similarities to PCBs, PBDEs do not appear to activate the Ah receptor-AhR nuclear translocator protein-XRE complex, although they can bind to the Ah receptor (Chen and Bunce, 2003;Peters et al 2006;Hamers et al 2006). PBDEs may have endocrine disrupting effects, as they have been shown to interact as antagonists or agonists at androgen, progesterone, and estrogen receptors (Meerts et al 2001;Hamers et al 2006). For example, most PBDEs have antiandrogenic activity in vitro and in vivo (Stoker et al 2005); tetra-to hexa-BDEs have potent estrogenic activity in vitro; heptaBDE and 6-OH-BDE-47, a metabolite of BDE-47, have anti-estrogenic activity (Hamers et al 2006).…”

Chronic exposure to environmental levels of tribromophenol impairs zebrafish reproduction

“…Previous studies on the effects of this chemical revealed that TBP causes developmental neurotoxicity, embryotoxicity, and fetotoxicity in rats (Lyubimov et al, 1998). In addition, it is a potent competitor of the thyroid hormone (thyroxine, T4), which was indicated by the results of the in vitro TTR-binding assay (Legler and Brouwer, 2003;Hamers et al 2006;Suzuki et al, 2008); it showed weak estrogen-like activity in the human breast cancer cellline MCF-7 (Olsen et al, 2002); TBP caused an induction of aromatase activity in human adrenocortical (H295R) cell line (Cantón et al, 2005), and it induces neuroblastoma cell differentiation (Ríos et al, 2003) and disturbs cellular Ca 2+ signaling in neuroendocrine cells (PC12) (Hassenklöver et al, 2006). Exposure to TBP has also been shown to affect the development of zebrafish embryos .…”

Toxicity of tetrabromobisphenol A (TBBPA) in zebrafish (Danio rerio) in a partial life-cycle test

“…LC 50 concentrations reported include 0.51 mg/l (0.9 M) in bluegill sunfish, 0.40 mg/l (0.7 M) in rainbow trout (WHO/IPCS 1995), and a relatively high 3 mg/l (5.5 M) in zebrafish (Lee et al 1993). Evidence for TBBPA toxicity at lower doses is limited and points to modulation of the thyroid and reproductive hormonal systems: TBBPA competes with the in vitro binding of thyroxin to its human plasma-transporter protein, transthyretin (Meerts et al 2000;Hamers et al 2004), and the rat thyroid receptor (Kitamura et al 2002), and increases the response to T3 in cultured GH3 rat pituitary adenoma cells (Kitamura et al 2005a). However, 10 −8 M (54 ng/l) TBBPA and higher may suppress T3-dependent tail shortening in Rana rugosa tadpoles, indicating anti-thyroid activity (Kitamura et al 2005b).…”

“…Cultured MCF-7 breast cancer cells show a weak estrogenic response to TBBPA (Körner et al 1998;Olsen et al 2003), and TBBPA inhibits in vitro estradiol sulfonation (Hamers et al 2004), indicating potential for both direct and indirect estrogenic activity in vivo. Increased uterus weights in ovariectomized mice exposed to TBBPA for 3 days (20 mg/kg/day, intraperitoneal) confirm estrogenicity in vivo (Kitamura et al 2005a).…”