Hydroxylated Polybrominated Diphenyl Ethers Research Articles

Thyroid hormone activities of neutral and anionic hydroxylated polybrominated diphenyl ethers to thyroid receptor β: A molecular dynamics study

Hydroxylated polybrominated diphenyl ethers (OH-PBDEs) have been identified as the strong endocrine disrupting chemicals to humans, which show structural similarity with endogenous thyroid hormones (THs) and thus disrupt the functioning of THs through competitive binding with TH receptors (TRs). Although previous studies have reported the hormone activities of some OH-PBDEs on TH receptor β (TRβ), the interaction mechanism remains unclear. Furthermore, hydroxyl dissociation of OH-PBDEs may alter their TR disrupting activities, which has not yet been investigated in depth. In this work, we selected 18 OH-PBDEs with neutral and anionic forms and performed molecular dynamics (MD) simulations to estimate their binding interactions with the ligand binding domain (LBD) of TRβ. The results demonstrate that most of OH-PBDEs have stronger binding affinities to TRβ-LBD than their anionic counterparts, and the hydroxyl dissociation of ligands differentiate the major driving force for their binding. More Br atoms in OH-PBDEs can result in stronger binding potential with TRβ-LBD. Moreover, 5 hydrophobic residues, including Met313, Leu330, Ile276, Leu346, and Phe272, are identified to have important contributions to bind OH-PBDEs. These results clarify the binding mechanism of OH(O−)-PBDEs to TRβ-LBD at the molecular level, which can provide a solid theoretical basis for accurate assessment of TH disrupting effects of these chemicals.

Formation of hydroxylated polybrominated diphenyl ethers and hydroxylated polybrominated biphenyls during the adsorption of bromophenols by reduced graphene oxide

The widespread use of bromophenols in industrial products has led to their emergence in natural water environments. This study investigated the oxidative coupling reactions of 2,6-dibromophenol (2,6-diBP), 2,4-dibromophenol (2,4-diBP) and 3,5-dibromophenol (3,5-diBP) during the water purification by reduced graphene oxide (rGO). Results showed that rGO markedly promoted the oxidation of three bromophenols (BPs). The oxidation efficiencies of three BPs were related to their homolytic bond dissociation energies and decreased following the order of 2,6-diBP > 2,4-diBP > 3,5-diBP. Mass spectrometry and density functional theory calculation revealed that CO and CC coupling among BPs radicals were the main reaction pathways, with the hydroxylated polybrominated diphenyl ethers (HO-PBDEs) and the hydroxylated polybrominated biphenyls (HO-PBBs) being the main reaction products. The oxidant of the reaction was dissolved oxygen, which was first transformed to the surface-bound reactive oxygen species on graphene defects and then oxidized BPs into HO-PBDEs and HO-PBBs. To our knowledge, this is the first report indicating that HO-PBDEs and HO-PBBs could be generated during the adsorption of BPs by rGO. Given the enhanced toxicity of HO-PBDEs and HO-PBBs, caution should be taken when treating BPs-containing water with rGO.

Formation of 1,3,8-tribromodibenzo-p-dioxin and 2,4,6,8-tetrabromodibenzofuran in the oxidation of synthetic hydroxylated polybrominated diphenyl ethers by iron and manganese oxides under dry conditions.

Hydroxylated polybrominated diphenyl ethers (OH-PBDEs) are ubiquitous and highly toxic emerging endocrine disruptors found in surface and subsurface soils and clay deposits. Seriously, they could be easily transformed to the more toxic dioxins (PBDD/Fs) in photochemical processes and incineration, but the spontaneous formation of PBDD/Fs has rarely been reported. This study focused on the formation of 1,3,8-tribromodibenzo-p-dioxin (1,3,8-TrBDD) and 2,4,6,8-tetrabromodibenzofuran (2,4,6,8-TeBDF) from 2'-OH-BDE-68 and 2,2'-diOH-BB-80 under the oxidization of iron and manganese oxides (goethite and MnOx). Approximately 0.09μmol/kg (2.33%) and 0.17μmol/kg (4.15%) were transformed to 1,3,8-TrBDD and 2,4,6,8-TeBDF by goethite in 8days and a higher conversion 0.15μmol/kg (3.77%) and 0.23μmol/kg (5.74%) were observed for MnOx in 4days. However, the formation of PBDD/Fs, probably proceeding via Smiles rearrangements and bromine elimination processes, was greatly inhibited by the presence of water. Transformation of OH-PBDEs by goethite and MnOx was accompanied by release of Fe and Mn ions and the possible pathways for the formation of reaction products were proposed. In view of the ubiquity of OH-PBDEs and metal oxides in the environment, oxidation of OH-PBDEs mediated by goethite and MnOx is likely an abiotic route for the formation of PBDD/Fs.

Identification of Thyroid Hormone Disruptors among HO-PBDEs: In Vitro Investigations and Coregulator Involved Simulations.

Some hydroxylated polybrominated diphenyl ethers (HO-PBDEs), that have been widely detected in the environment and tissues of humans and wildlife, bind to thyroid hormone (TH) receptor (TR) and can disrupt functioning of systems modulated by the TR. However, mechanisms of TH disrupting effects are still equivocal. Here, disruption of functions of TH modulated pathways by HO-PBDEs was evaluated by assays of competitive binding, coactivator recruitment, and proliferation of GH3 cells. In silico simulations considering effects of coregulators were carried out to investigate molecular mechanisms and to predict potencies for disrupting functions of the TH. Some HO-PBDEs were able to bind to TR with moderate affinities but were not agonists. In GH3 proliferation assays, 13 out of 16 HO-PBDEs were antagonists for the TH. In silico simulations of molecular dynamics revealed that coregulators were essential for identification of TH disruptors. Among HO-PBDEs, binding of passive antagonists induced repositioning of H12, blocking AF-2 (transactivation function 2) and preventing recruitment of the coactivator. Binding of active antagonists exposed the coregulator binding site, which tended to bind to the corepressor rather than the coactivator. By considering both passive and active antagonisms, anti-TH potencies of HO-PBDEs could be predicted from free energy of binding.

Direct and dissolved oxygen involved photodegradation of MeO-PBDEs in water

Photodegradation has been proved to be a crucial way of elimination for polybrominated diphenyl ethers (PBDEs) and hydroxylated PBDEs (HO-PBDEs). However, it is still unknown whether methoxylated PBDEs (MeO-PBDEs) can also undergo photodegradation. In this study, 4′-MeO-BDE-17, 5-MeO-BDE-47, 5′-MeO-BDE-99, 6-MeO-BDE-47 and 6-MeO-BDE-85 were selected as targets to investigate their photodegradation in water. Meanwhile, the effects of dissolved oxygen on the photoreactions of MeO-PBDEs were also unveiled. Simulated sunlight experiments indicate that 6-MeO-BDE-47 resisted photodegradation for 20h, while other MeO-PBDEs underwent relatively fast photodegradation, which was greatly susceptible to the substitution patterns of methoxyl and bromine. Photo-excited MeO-PBDEs (except 6-MeO-BDE-47) can sensitize dissolved oxygen to generate singlet oxygen (1O2) and superoxide anion radical (O2−). The generated 1O2 cannot degrade the MeO-PBDEs, whereas O2− was reactive with MeO-PBDEs. The contribution of dissolved oxygen to the photodegradation of 4′-MeO-BDE-17 and 6-MeO-BDE-85 was negligible; while the negative contribution was observed for 5-MeO-BDE-47 and 5′-MeO-BDE-99. Hydrodebromination was a crucial photodegradation pathway for MeO-PBDEs (excluding 4′-MeO-BDE-17 and 6-MeO-BDE-47). Eventually, direct photolysis half-lives of MeO-PBDEs except 6-MeO-BDE-47 in the surface waters at 40 N latitude were calculated to be 1.35–3.46d in midsummer and 6.39–17.47d in midwinter.

Hydroxylated and methoxylated polybrominated diphenyl ethers in long-tailed ducks (Clangula hyemalis) and their main food, Baltic blue mussels (Mytilus trossulus × Mytilus edulis).

Long-tailed ducks (Clangula hyemalis) that breed in northern Europe and western Siberia and commonly winter in the Baltic Sea, are threatened by a significant population decrease. The ducks are, by primarily feeding on Baltic blue mussels (Mytilus trossulus × Mytilus edulis) while wintering in the Baltic Sea, potentially subjected to high levels of toxic hydroxylated polybrominated diphenyl ethers (OH-PBDEs). To assess long-tailed ducks exposure to polybrominated phenols (PBPs), polybrominated anisoles (PBAs), hydroxylated polybrominated diphenyl ethers (OH-PBDEs), their methylated counterparts (MeO-PBDEs) and polybrominated diphenyl ethers (PBDEs), livers of ten long-tailed ducks wintering in the Baltic Sea were analysed. Pattern and levels of analytes in long-tailed ducks (liver) and blue mussels sampled in March and May at nine sites in the Baltic Sea were compared. The geometric mean concentration (ng/g l.w.) in livers of long-tailed ducks and Baltic blue mussels were: Σ(2)PBPs: 0.57 and 48; Σ(2)PBAs: 0.83 and 11; Σ(7)OH-PBDEs: 6.1 and 45; Σ(7)MeO-PBDEs: 3.8 and 69; Σ(7)PBDEs: 8.0 and 7.2, respectively. Based on an estimated daily intake of 450 g fresh blue mussel meat, long-tailed ducks daily dietary intake of brominated substances while foraging in the Baltic Sea in March-May was estimated to; 390 ng Σ(2)PBPs, 90 ng Σ(2)PBAs, 370 ng Σ(7)OH-PBDEs, 590 ng Σ(7)MeO-PBDEs and 59 ng Σ(7)PBDEs. The low levels of PBPs, PBAs, OH-PBDEs and MeO-PBDEs in the long-tailed duck livers compared to blue mussel, despite a continuous daily intake, suggest that these compounds are poorly retained in long-tailed ducks.

Production of hydroxylated polybrominated diphenyl ethers from bromophenols by bromoperoxidase-catalyzed dimerization.

Hydroxylated polybrominated diphenyl ethers (HO-PBDEs) are emerging endocrine-disrupting compounds that are widely present in the marine environment. The origin of HO-PBDEs is generally attributed to metabolism of PBDEs and natural production in the environment. However, it is unclear how HO-PBDEs are produced naturally. Here we report the formation of HO-PBDEs from simple bromophenols (BPs) [e.g., 2,4-dibromophenol (2,4-DBP) and 2,4,6-tribromophenol (2,4,6-TBP)] under the catalysis of bromoperoxidase (BPO) isolated from the common marine red alga Corallina officinalis. Experiments at room temperature showed that BPO readily catalyzes the conversion of 2,4-DBP and 2,4,6-TBP to HO-PBDEs in the presence of Br(-) and H2O2. From analysis of the original forms and their corresponding methylated derivatives, the reaction products were tentatively identified as 2'-HO-BDE-121 and 4'-HO-BDE-121. The formation of HO-PBDEs was likely resulted from the coupling of bromophenoxy radicals generated by the oxidation of BPs via BPO-mediated processes. The presence of Br(-) in the reaction favored the conversion. The production of HO-PBDEs was found to be pH-dependent, and a higher yield was obtained at pH 6.5. In view of the abundance of BPs and C. officinalis in the marine environment, bioconversion of BPs mediated by BPO may be a potential route for the natural production of HO-PBDEs.

Mechanisms of Toxicity of Hydroxylated Polybrominated Diphenyl Ethers (HO-PBDEs) Determined by Toxicogenomic Analysis with a Live Cell Array Coupled with Mutagenesis in Escherichia coli

Results of previous studies have indicated that 6-HO-BDE-47, the addition of the hydroxyl (HO) group to the backbone of BDE-47, significantly increased the toxicity of the chemical compared to its postulated precursor analogues, BDE-47 and 6-MeO-BDE-47. However, whether such a result is conserved across polybrominated diphenyl ether (PBDE) congeners was unknown. Here, cytotoxicity of 32 PBDE analogues (17 HO-PBDEs and 15 MeO-PBDEs) was further tested and the underlying molecular mechanism was investigated. A total of 14 of the 17 HO-PBDEs inhibited growth of Escherichia coli during 4 or 24 h durations of exposure, but none of the MeO-PBDEs was cytotoxic at the concentrations tested. 6-HO-BDE-47 and 2-HO-BDE-28 were most potent with 4 h median effect concentrations (EC50) of 12.13 and 6.25 mg/L, respectively, which trended to be lesser with a longer exposure time (24 h). Expression of 30 modulated and validated genes by 6-HO-BDE-47 in a previous study was also observed after exposure to other HO-PBDE analogues. For instance, uhpT was upregulated by 13 HO-PBDEs, and three rRNA operons (rrnA, rrnB, and rrnC) were downregulated by 8 HO-PBDEs. These unanimous responses suggested a potential common molecular signaling modulated by HO-PBDEs. To explore new information on mechanisms of action, this work was extended by testing the increased susceptibility of 182 mutations of transcriptional factors (TFs) and 22 mutations as genes modulated by 6-HO-BDE-47 after exposure to 6-HO-BDE-47 at the 4 h IC50 concentration. Although a unanimous upregulation of uhpT was observed after exposure to HO-PBDEs, no significant shift in sensitivity was observed in uhpT-defective mutants. The 54 genes, selected by cut-offs of 0.35 and 0.65, were determined to be responsible for "organic acid/oxoacid/carboxylic acid metabolic process" pathways, which supported a previous finding.

Molecular docking and molecular dynamics studies on the interactions of hydroxylated polybrominated diphenyl ethers to estrogen receptor alpha

Environmental estrogens have attracted great concerns. Recent studies have indicated that some hydroxylated polybrominated diphenyl ethers (HO-PBDEs) can interact with estrogen receptor (ER), and exhibit estrogenic activity. However, interactions between HO-PBDEs and ER are not well understood. In this work, molecular docking and molecular dynamics (MD) simulations were performed to characterize interactions of two HO-PBDEs (4'-HO-BDE30 and 4'-HO-BDE121) with ERα. Surflex-Dock was employed to reveal the probable binding conformations of the compounds at the active site of ERα; MD simulation was used to determine the detailed binding process. The driving forces of the binding between HO-PBDEs and ERα were van der Waals and electrostatic interactions. The decomposition of the binding free energy indicated that the hydrogen bonds between the residues Glu353, Gly521 and ligands were crucial for anchoring the ligands into the active site of ERα and stabilizing their conformations. The results showed that different interaction modes and different specific interactions with some residues were responsible for the different estrogenic activities of the two HO-PBDEs.

Dioxin-like Potency of HO- and MeO- Analogues of PBDEs’ the Potential Risk through Consumption of Fish from Eastern China

Polybrominated diphenyl ethers (PBDEs) and their analogues, such as hydroxylated PBDE (HO-PBDEs) and methoxylated PBDE (MeO-PBDEs) are of interest due to their wide distribution, bioaccumulation and potential toxicity to humans and wildlife. While information on the toxicity/biological potencies of PBDEs was available, information on analogues of PBDEs was limited. Dioxin-like toxicity of 34 PBDEs analogues was evaluated by use of the H4IIE-luc, rat hepatoma transactivation bioassay in 384-well plate format at concentrations ranging from 0 to 10 000 ng/mL. Among the 34 target analogues of PBDEs studied here, 19 activated the aryl hydrocarbon receptor (AhR) and induced significant dioxin-like responses in H4IIE-luc cells. Efficacies of the analogues of PBDEs ranged from 5.0% to 101.8% of the maximum response caused by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD-max) and their respective 2,3,7,8-TCDD potency factors (ReP(H4IIE-luc)) ranged from 7.35 × 10(-12) to 4.00 × 10(-4), some of which were equal to or more potent than some mono-ortho-substituted PCBs (TEF-(WHO) = 3 × 10(-5)). HO-PBDEs exhibited greater dioxin-like activity than did the corresponding MeO-PBDEs. Analogues of PBDEs were detected mostly in marine organisms. Of these 11 detected analogues of PBDEs, 6 were found to have measurable dioxin-like potency. Though some analogues of PBDEs exhibited significant dioxin-like potency as measured by responses of the H4IIE-luc transactivation assay, concentrations of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) equivalents ((PBDEs analogues)TEQ(H4IIE-luc)), calculated as the sum of the product of concentrations of individual PBDE and their ReP(H4IIE-luc), were less than the tolerance limit proposed by European Union and the oral reference dose (RfD) derived by U.S. Environmental Protection Agency, respectively. (Hazard Quotients (HQ) < 0.005) Additional investigations should be conducted to evaluate the toxic potencies of these chemicals, especially for 2'-MeO-BDE-28, 4-HO-BDE-90, 6-HO-BDE-47, and 6-MeO-BDE-47, which had been detected in other environmental media, including human blood.

Combined 3D-QSAR, molecular docking and molecular dynamics study on thyroid hormone activity of hydroxylated polybrominated diphenyl ethers to thyroid receptors β

Several recent reports suggested that hydroxylated polybrominated diphenyl ethers (HO-PBDEs) may disturb thyroid hormone homeostasis. To illuminate the structural features for thyroid hormone activity of HO-PBDEs and the binding mode between HO-PBDEs and thyroid hormone receptor (TR), the hormone activity of a series of HO-PBDEs to thyroid receptors β was studied based on the combination of 3D-QSAR, molecular docking, and molecular dynamics (MD) methods. The ligand- and receptor-based 3D-QSAR models were obtained using Comparative Molecular Similarity Index Analysis (CoMSIA) method. The optimum CoMSIA model with region focusing yielded satisfactory statistical results: leave-one-out cross-validation correlation coefficient (q2) was 0.571 and non-cross-validation correlation coefficient (r2) was 0.951. Furthermore, the results of internal validation such as bootstrapping, leave-many-out cross-validation, and progressive scrambling as well as external validation indicated the rationality and good predictive ability of the best model. In addition, molecular docking elucidated the conformations of compounds and key amino acid residues at the docking pocket, MD simulation further determined the binding process and validated the rationality of docking results.

Different photolysis kinetics and photooxidation reactivities of neutral and anionic hydroxylated polybrominated diphenyl ethers

Hydroxylated polybrominated diphenyl ethers (HO-PBDEs) pose potential ecological risks due to their endocrine disrupting effects and extensive sources. It is of great importance to know their environmental transformation for the purpose of ecological risk assessment. Photodegradation is an important transformation pathway of HO-PBDEs. As HO-PBDEs ionize in natural waters, the photochemical reactivities of both neutral and anionic HO-PBDEs need to be unveiled. In this study, six HO-PBDEs were selected as model compounds. Their direct photolysis rate constants (kd), quantum yields (Φ), light absorptions (A), second-order reaction rate constants with 1O2 (k1O2) and OH (kOH) at different pH were determined, as well as these parameters for the neutral and anionic HO-PBDEs. The kd, Φ, A, k1O2 and kOH for the anions are much higher than those for the neutral molecules and vary with the bromination degree. Molecular parameters computed with the density functional theory (DFT) were employed to construct structure–reactivity equations. The ether bond strength, the frontier molecular orbital energy and the charge distribution were found to be the intrinsic structural characters governing the photochemical reactivities. The half-lives range from 0.7 to 60.1h for the photodegradation including the direct photolysis and the reactions with 1O2 and OH in surface waters at 45°N latitude under the continuous solar irradiation of sunny noon on 15 July. Direct photolysis is the dominant pathway. The photochemical reactivities of other HO-PBDEs at a given pH can also be estimated based on the structure–reactivity equations, which is important for the ecological risk assessment of HO-PBDEs.

Photochemical Formation of Brominated Dioxins and Other Products of Concern from Hydroxylated Polybrominated Diphenyl Ethers (OH-PBDEs)

The photochemical conversion of selected hydroxylated polybrominated diphenyl ethers (OH-PBDEs) to dioxins and other products was investigated. OH-PBDEs, which are both transformation products of polybrominated diphenyl ethers and naturally occurring compounds, undergo direct photolysis to yield a number of products that may have a higher toxicity than their parent. The compounds investigated were 6-OH-PBDE 99, 6'-OH-PBDE 100, and 6'-OH-PBDE 118. Of special interest was 6'-OH-PBDE 118, a potential transformation product of PBDE 153 that is capable of photochemically generating 2,3,7,8-tetrabromodibenzo-p-dioxin, the most toxic brominated dioxin congener. Photolysis experiments were conducted at two different pH values to assess the photochemical behavior of both the phenol and phenolate form of the compounds. The percent conversion to dioxin and other photoproducts was determined and the natural product, 6-OH-PBDE 99, was found to have the highest conversion to dioxin (7%). The reaction quantum yields ranged from 0.027 to 0.16 across all photolysis conditions. In addition, it is shown that all three compounds are capable of photochemically generating other compounds of concern, including brominated phenols and a dibenzofuran.

Structure–activity relationship study on the binding of PBDEs with thyroxine transport proteins

Molecular docking and three-dimensional quantitative structure-activity relationships (3D-QSAR) were used to develop models to predict binding affinity of polybrominated diphenyl ether (PBDE) compounds to the human transthyretin (TTR). Based on the molecular conformations derived from the molecular docking, predictive comparative molecular similarity indices analysis (CoMSIA) models were developed. The results of CoMSIA models were as follows: leave-one-out (LOO) cross-validated squared coefficient q² (LOO) = 0.827 (full model, for all 28 compounds); q² (LOO) = 0.752 (split model, for 22 compounds in the training set); leave-many-out (LMO) cross-validated squared coefficient q² (LMO, two groups) = 0.723 ± 0.100 (full model, for all 28 compounds); q² (LMO, five groups) = 0.795 ± 0.030 (full model, for all 28 compounds); and the predictive squared correlation coefficient r²(pred) = 0.928 (for six compounds in the test set). The developed CoMSIA models can be used to infer the activities of compounds with similar structural characteristics. In addition, the interaction mechanism between hydroxylated polybrominated diphenyl ethers (HO-PBDEs) and the TTR was explored. Hydrogen bonding with amino acid residues Asp74, Ala29, and Asn27 may be an important determinant for HO-PBDEs binding to TTR. Among them, forming hydrogen bonds with amino acid residues Asp74 might exert a more important function.

Halogenated Phenolic Contaminants Inhibit the In Vitro Activity of the Thyroid-Regulating Deiodinases in Human Liver

Halogenated contaminants, particularly brominated flame retardants, disrupt circulating levels of thyroid hormones (THs), potentially affecting growth and development. Disruption may be mediated by impacts on deiodinase (DI) activity, which regulate the levels of active hormones available to bind to nuclear receptors. The goal of this study was to develop a mass spectrometry-based method for measuring the activity of DIs in human liver microsomes and to examine the effect of halogenated phenolic contaminants on DI activity. Thyroxine (T4) and reverse triiodothyronine (rT3) deiodination kinetics were measured by incubating pooled human liver microsomes with T4 or rT3 and monitoring the production of T3, rT3, 3,3'-diiodothyronine, and 3-monoiodothyronine by liquid chromatography tandem mass spectrometry. Using this method, we examined the effects of several halogenated contaminants, including 2,2',4,4',5-pentabromodiphenyl ether (BDE 99), several hydroxylated polybrominated diphenyl ethers (OH-BDEs), tribromophenol, tetrabromobisphenol A, and triclosan, on DI activity. The Michaelis constants (K(M)) of rT3 and T4 deiodination were determined to be 3.2 ± 0.7 and 17.3 ± 2.3μM. The V(max) was 160 ± 5.8 and 2.8 ± 0.10 pmol/min.mg protein, respectively. All studied contaminants inhibited DI activity in a dose-response manner, with the exception of BDE 99 and two OH-BDEs. 5'-Hydroxy 2,2',4,4',5-pentabromodiphenyl ether was found to be the most potent inhibitor of DI activity, and phenolic structures containing iodine were generally more potent inhibitors of DI activity relative to brominated, chlorinated, and fluorinated analogues. This study suggests that some halogenated phenolics, including current use compounds such as plastic monomers, flame retardants, and their metabolites, may disrupt TH homeostasis through the inhibition of DI activity in vivo.

Formation of 2′-hydroxy-2,3′,4,5′-tetrabromodipheyl ether (2′-HO-BDE68) from 2,4-dibromophenol in aqueous solution under simulated sunlight irradiation

Hydroxylated polybrominated diphenyl ethers (HO-PBDEs) have received significant attention due to their toxicities and universal presence in the environmental matrices. However, their origins are not fully understood. We explored the feasibility of the generation of HO-PBDEs through photochemical processes from bromophenol, a commonly detected pollutant with anthropogenic source in freshwater and natural source in the marine environment. The results showed that when 2,4-dibromophenol (2,4-diBP) was irradiated in aquatic solutions under simulated sunlight, significant amounts of 2′-hydroxy-2,3′,4,5′-tetrabromodipheyl ether (2′-HO-BDE68) were rapidly formed as the dimeric product of 2,4-diBP. The formation of 2′-HO-BDE68 intensified with the increase of light intensity and with the initial concentration increase of 2,4-diBP, whereas it weakened with an increase in pH. Moreover, Fe(III) and fulvic acid played important roles in the formation of 2′-HO-BDE68. This study provides important insight into a possible source of HO-PBDEs from bromophenols in natural aquatic systems through photochemical approaches.

Hormone Activity of Hydroxylated Polybrominated Diphenyl Ethers on Human Thyroid Receptor-β: In Vitro and In Silico Investigations

BackgroundHydroxylated polybrominated diphenyl ethers (HO-PBDEs) may disrupt thyroid hormone status because of their structural similarity to thyroid hormone. However, the molecular mechanisms of interactions with thyroid hormone receptors (TRs) are not fully understood.ObjectivesWe investigated the interactions between HO-PBDEs and TRβ to identify critical structural features and physicochemical properties of HO-PBDEs related to their hormone activity, and to develop quantitative structure–activity relationship (QSAR) models for the thyroid hormone activity of HO-PBDEs.MethodsWe used the recombinant two-hybrid yeast assay to determine the hormone activities to TRβ and molecular docking to model the ligand–receptor interaction in the binding site. Based on the mechanism of action, molecular structural descriptors were computed, selected, and employed to characterize the interactions, and finally a QSAR model was constructed. The applicability domain (AD) of the model was assessed by Williams plot.ResultsThe 18 HO-PBDEs tested exhibited significantly higher thyroid hormone activities than did PBDEs (p < 0.05). Hydrogen bonding was the characteristic interaction between HO-PBDE molecules and TRβ, and aromaticity had a negative effect on the thyroid hormone activity of HO-PBDEs. The developed QSAR model had good robustness, predictive ability, and mechanism interpretability.ConclusionsHydrogen bonding and electrostatic interactions between HO-PBDEs and TRβ are important factors governing thyroid hormone activities. The HO-PBDEs with higher ability to accept electrons tend to have weak hydrogen bonding with TRβ and lower thyroid hormone activities.

Photochemical decomposition of dissolved hydroxylated polybrominated diphenyl ethers under various aqueous conditions

The area of fire protection has grown over the last decades with an increasing use of brominated flame retardants (BFRs). Some of the BFRs are phenolic compounds as applied, e.g. tetrabromobisphenol A and 2,4,6-tribromophenol. Others, like the polybrominated diphenyl ethers (PBDEs), can be metabolized to phenolic compounds, i.e. polybrominated phenoxyphenols (OH-PBDEs). OH-PBDEs, have to our knowledge never been commercially produced, but some are well known natural products, and found in high concentrations in biota. The present study is aimed to determine the susceptibility of OH-PBDEs to undergo photolysis when dissolved in water and to compare their reactivity with a couple of PBDE congeners. A previously developed method for studies of photolysis was applied and adapted to include OH-PBDEs in water at pH 7 and 11, water/methanol and water/hydrogen peroxide. The results indicate a change in reaction rates for the photolysis of OH-PBDE in different aqueous media and pH dependence. The results from the present study show that hydroxylated compounds rapidly undergo photolytic transformations in water. The OH-PBDEs are more rapidly transformed then PBDE congeners with similar numbers of bromine substituents. All the OH-PBDEs, independent of structure, are rapidly transformed, with approx. the same rate, when hydrogen peroxide is present, indicating another route of reaction. Polybrominated dibenzo- p-dioxins (PBDDs) are indicated as transformation products upon photolysis of OH-PBDEs with a favorable bromine substitution pattern.

Hydroxylated Metabolites of Polybrominated Diphenyl Ethers in Human Blood Samples from the United States

BackgroundA previous study from our laboratory showed that polybrominated diphenyl ethers (PBDEs) were metabolized to hydroxylated PBDEs (HO-PBDEs) in mice and that para-HO-PBDEs were the most abundant and, potentially, the most toxic metabolites.ObjectiveThe goal of this study was to determine the concentrations of HO-PBDEs in blood from pregnant women, who had not been intentionally or occupationally exposed to these flame retardants, and from their newborn babies.MethodsTwenty human blood samples were obtained from a hospital in Indianapolis, Indiana, and analyzed for both PBDEs and HO-PBDEs using electron-capture negative-ionization gas chromatographic mass spectrometry.ResultsThe metabolite pattern of HO-PBDEs in human blood was quite different from that found in mice; 5-HO-BDE-47 and 6-HO-BDE-47 were the most abundant metabolites of BDE-47, and 5′-HO-BDE-99 and 6′-HO-BDE-99 were the most abundant metabolites of BDE-99. The relative concentrations between precursor and corresponding metabolites indicated that BDE-99 was more likely to be metabolized than BDE-47 and BDE-100. In addition, three bromophenols were also detected as products of the cleavage of the diphenyl ether bond. The ratio of total hydroxylated metabolites relative to their PBDE precursors ranged from 0.10 to 2.8, indicating that hydroxylated metabolites of PBDEs were accumulated in human blood.ConclusionsThe quite different PBDE metabolite pattern observed in humans versus mice indicates that different enzymes might be involved in the metabolic process. Although the levels of HO-PBDE metabolites found in human blood were low, these metabolites seemed to be accumulating.

In Vitro Estrogenicity of Polybrominated Diphenyl Ethers, Hydroxylated PBDEs, and Polybrominated Bisphenol A Compounds

Polybrominated diphenyl ethers (PBDEs) are used in large quantities as additive flame retardants in plastics and textile materials. PBDEs are persistent compounds and have been detected in wildlife and in human adipose tissue and plasma samples. In this study, we investigated the (anti)estrogenic potencies of several PBDE congeners, three hydroxylated PBDEs (HO-PBDEs), and differently brominated bisphenol A compounds in three different cell line assays based on estrogen receptor (ER)-dependent luciferase reporter gene expression. In human T47D breast cancer cells stably transfected with an estrogen-responsive luciferase reporter gene construct (pEREtata-Luc), 11 PBDEs showed estrogenic potencies, with concentrations leading to 50% induction (EC(50)) varying from 2.5 to 7.3 microM. The luciferase induction of the most potent HO-PBDE [2-bromo-4-(2,4,6-tribromophenoxy)phenol] exceeded that of estradiol (E(2)), though at concentrations 50,000 times higher. As expected, brominated bisphenol A compounds with the lowest degree of bromination showed highest estrogenic potencies (EC(50) values of 0.5 microM for 3-monobromobisphenol A). In an ER alpha-specific, stably transfected human embryonic kidney cell line (293-ER alpha-Luc), the HO-PBDE 4-(2,4,6-tribromophenoxy)phenol was a highly potent estrogen with an EC(50) < 0.1 microM and a maximum 35- to 40-fold induction, which was similar to E(2). In an analogous ER beta-specific 293-ER betas-Luc cell line, the agonistic potency of the 4-(2,4,6-tribromophenoxy)phenol was much lower (maximum 50% induction compared to E(2)), but EC(50) values were comparable. These results indicate that several pure PBDE congeners, but especially HO-PBDEs and brominated bisphenol A-analogs, are agonists of both ER alpha and ER beta receptors, thus stimulating ER-mediated luciferase induction in vitro. These data also suggest that in vivo metabolism of PBDEs may produce more potent pseudoestrogens.