Synthesis and tentative identification of novel polybrominated diphenyl ether metabolites in human blood

Rydén, Andreas; Nestor, Gustav; Jakobsson, Kristina; Marsh, Göran

doi:10.1016/j.chemosphere.2012.03.076

Cited by 16 publications

(15 citation statements)

References 35 publications

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“…The identities of four mono-OH-BDE metabolites, 3-OH-BDE-100, 5′-OH-BDE-100, 6′-OH-BDE-100, and 4′-OH-BDE-103, were confirmed by matching chromatographic retention times and mass fragmentation patterns to authentic MeO-BDE standards. It is important to note that 3′-OH-BDE-100 has been shown to co-elute with 3-OH-BDE-100 on DB-5 columns . Furthermore, 3′-OH-BDE-100 and 3-OH-BDE-100 will have similar mass fragmentation patterns since they are both meta- OH-pentaBDEs .…”

Section: Resultsmentioning

confidence: 99%

Primary Role of Cytochrome P450 2B6 in the Oxidative Metabolism of 2,2′,4,4′,6-Pentabromodiphenyl Ether (BDE-100) to Hydroxylated BDEs

Gross

Butryn

McGarrigle

et al. 2015

Chem. Res. Toxicol.

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Human exposure to polybrominated diphenyl ethers (PBDEs) through various routes poses deleterious health effects. PBDEs are biotransformed into hydroxylated metabolites (OH-BDEs) via cytochrome P450s (P450s), which may add to their neurotoxic effects. This study characterizes the in vitro metabolism of 2,2',4,4',6-pentabromodiphenyl ether (BDE-100), one of the most abundant PBDE congeners found in humans, by recombinant human P450s and pooled human liver microsomes (HLMs). Ten recombinant P450s were individually incubated with BDE-100 to monitor P450-specific metabolism. P450 2B6 was found to be the predominant enzyme responsible for nearly all formation of six mono-OH-pentaBDE and two di-OH-pentaBDE metabolites. Four metabolites were identified as 3-hydroxy-2,2',4,4',6-pentabromodiphenyl ether (3-OH-BDE-100), 5'-hydroxy-2,2',4,4',6-pentabromodiphenyl ether (5'-OH-BDE-100), 6'-hydroxy-2,2',4,4',6-pentabromodiphenyl ether (6'-OH-BDE-100), and 4'-hydroxy-2,2',4,5',6-pentabromodiphenyl ether (4'-OH-BDE-103) through use of reference standards. The two remaining mono-OH-pentaBDE metabolites were hypothesized using mass spectral fragmentation characteristics of derivatized OH-BDEs, which allowed prediction of an ortho-OH-pentaBDE and a para-OH-pentaBDE positional isomer. Additional information based on theoretical boiling point calculations using COnductor-like Screening MOdel for Realistic Solvents (COSMO-RS) and experimental chromatographic retention times were used to identify the hypothesized metabolites as 2'-hydroxy-2,3',4,4',6-pentabromodiphenyl ether (2'-OH-BDE-119) and 4-hydroxy-2,2',4',5,6-pentabromodiphenyl ether (4-OH-BDE-91), respectively. Kinetic studies of BDE-100 metabolism using P450 2B6 and HLMs revealed Km values ranging from 4.9 to 7.0 μM and 6-10 μM, respectively, suggesting a high affinity toward the formation of OH-BDEs. Compared to the metabolism of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) and 2,2',4,4',5-pentabromodiphenyl ether (BDE-99) reported in previous studies, BDE-100 appears to be more slowly metabolized by P450s due to the presence of a third ortho-substituted bromine atom.

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Section: Resultsmentioning

confidence: 99%

Primary Role of Cytochrome P450 2B6 in the Oxidative Metabolism of 2,2′,4,4′,6-Pentabromodiphenyl Ether (BDE-100) to Hydroxylated BDEs

Gross

Butryn

McGarrigle

et al. 2015

Chem. Res. Toxicol.

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“…2′-Hydroxy-2,4,4′-tribromodiphenyl ether (2′-OH-BDE28); 2′-hydroxy-2,3′,4,4′-tetrabromodiphenyl ether (2′-OH-BDE66); 2′-hydroxy-2,3′,4,5′-tetrabromodiphenyl ether (2′-OH-BDE68); 2-hydroxy-2′,3,4,4′,5-pentabromodiphenyl ether (2-OH-BDE123); 3-hydroxy-2,2′,4,4′-tetrabromodiphenyl ether (3-OH-BDE47); 3-hydroxy-2,2′,4,4′,5,5′-hexabromodiphenyl ether (3-OH-BDE153); 3′-hydroxy-2,2′,4,4′,5,6′-hexabromodiphenyl ether (3′-OH-BDE154); 3-hydroxy-2,2′,4,4′,6,6′-hexabromodiphenyl ether (3-OH-BDE155); 5-hydroxy-2,2′,4,4′-tetrabromodiphenyl ether (5-OH-BDE47); 6-hydroxy-2,2′,4,4′-tetrabromodiphenyl ether (6-OH-BDE47); 6′-hydroxy-2,2′4,5′-tetrabromodiphenyl ether (6′-OH-BDE49); 6-hydroxy-2,2′,3,4,4′-pentabromodiphenyl ether (6-OH-BDE85); 6-hydroxy-2,2′,3,4′,5-pentabromodiphenyl ether (6-OH-BDE90); 6-hydroxy-2,2′,4,4′,5-pentabromodiphenyl ether (6-OH-BDE99); 6-hydroxy-2,2′,3,4,4′,5-hexabromodiphenyl ether (6-OH-BDE137); 2′-hydroxy-6′-chloro-2,3′,4,5′-tetrabromodiphenyl ether (2′-OH-6′-Cl-BDE68); 6-hydroxy-5-chloro-2,2′,4,4′-tetrabromodiphenyl ether (6-OH-5-Cl-BDE47) were synthesized at Stockholm University as described elsewhere [29,30,31]. Carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (FCCP) (≥98% purity) was purchased from Sigma-Aldrich (St. Louis, MO, USA).…”

Section: Methodsmentioning

confidence: 99%

Effects of Hydroxylated Polybrominated Diphenyl Ethers in Developing Zebrafish Are Indicative of Disruption of Oxidative Phosphorylation

Legradi¹,

Pomeren

Dahlberg

et al. 2017

IJMS

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Hydroxylated polybrominated diphenyl ethers (OH-PBDEs) have been detected in humans and wildlife. Using in vitro models, we recently showed that OH-PBDEs disrupt oxidative phosphorylation (OXPHOS), an essential process in energy metabolism. The goal of the current study was to determine the in vivo effects of OH-PBDE reported in marine wildlife. To this end, we exposed zebrafish larvae to 17 OH-PBDEs from fertilisation to 6 days of age, and determined developmental toxicity as well as OXPHOS disruption potential with a newly developed assay of oxygen consumption in living embryos. We show here that all OH-PBDEs tested, both individually and as mixtures, resulted in a concentration-dependant delay in development in zebrafish embryos. The most potent substances were 6-OH-BDE47 and 6′-OH-BDE49 (No-Effect-Concentration: 0.1 and 0.05 µM). The first 24 h of development were the most sensitive, resulting in significant and irreversible developmental delay. All substances increased oxygen consumption, an effect indicative of OXPHOS disruption. Our results suggest that the induced developmental delay may be caused by disruption of OXPHOS. Though further studies are needed, our findings suggest that the environmental concentrations of some OH-PBDEs found in Baltic Sea wildlife in the Baltic Sea may be of toxicological concern.

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“…17 Additionally, CTDs have been detected in several sediment cores from wastewater impacted lakes, indicated that CTDs are present in wastewater impacted surface waters. [21][22][23][24][25][26][27][28][29] OH-BDEs are of environmental concern because they have been shown to be endocrine disruptors and neurotoxins with potency equivalent to or greater than PBDEs. 19,20 Due to the extent that polybrominated diphenyl ethers (PBDEs) are found in environmental matrices, transformation products of PBDEs have also become a concern.…”

Section: Introductionmentioning

confidence: 99%

“…OH-BDEs derived from the transformation of PBDEs are suggested to arise from metabolism of PBDEs by animals, oxidation of PBDEs by hydroxyl radicals in the atmosphere, and biological processing during wastewater treatment. [21][22][23][24][25][26][27][28][29] OH-BDEs are of environmental concern because they have been shown to be endocrine disruptors and neurotoxins with potency equivalent to or greater than PBDEs. 30,31 Toxic effects that have been reported include uncoupling of oxidative phosphorylation, 32 indirect estrogenic effects in rats, 33 and effects on hormone transport.…”

Section: Introductionmentioning

confidence: 99%

Triclosan, chlorinated triclosan derivatives, and hydroxylated polybrominated diphenyl ethers (OH-BDEs) in wastewater effluents

Hensley

Kerrigan

Pang

et al. 2015

Environ. Sci.: Water Res. Technol.

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Various halohydroxydiphenyl ethers, including triclosan, chlorinated triclosan derivatives (CTDs), and hydroxylated polybrominated diphenyl ethers (OH-BDEs), are present in aquatic systems. While it is well established that wastewater effluents are a source of triclosan and CTDs, the evidence for OH-BDEs being in wastewater is limited. In this work, pre-and post-disinfection effluent samples were taken from four activated sludge plants, two using chlorine and two using ultraviolet (UV) disinfection. Triclosan levels ranged from 36-465 ng L −1 and CTD levels were non-detect to 27 ng L −1 . While CTDs were generally higher in the plants using chlorine, they were also present in the UV plants, likely due to chlorine residual in the drinking water. Of the five target OH-BDE congeners (selected because they produce dioxins upon photolysis), three were detected. When detected the levels were generally 1-10 ng L −1 , but some samples had levels as high as 100 ng L −1 . Three different analytical methods were used to quantify OH-BDEs, and the levels were comparable using the different methods. Results were inconclusive as to the effect of disinfection method on OH-BDE levels. This study confirms that wastewater is a source of selected OH-BDEs to surface waters, but the overall loading is likely small. Further experiments and analyses are required to determine if the OH-BDEs are formed during the wastewater treatment process.Environ. Sci.: Water Res. Technol. This journal isTreated wastewater is a source of emerging contaminants to aquatic systems, and these compounds may have adverse environmental impacts. This work reveals that halohydroxydiphenyl ethers, such as triclosan and selected hydroxylated polybrominated diphenyl ethers (OH-BDEs) are present in wastewater effluents. The OH-BDE levels approach those of chlorinated triclosan derivatives. Wastewater effluent serves a source of OH-BDEs, and thus potentially brominated dioxins, to aquatic systems.*LODs and LOQs of analytes for each sample analyzed are summarized in the appendix; NDnot detected (LOD but

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Synthesis and tentative identification of novel polybrominated diphenyl ether metabolites in human blood

Cited by 16 publications

References 35 publications

Primary Role of Cytochrome P450 2B6 in the Oxidative Metabolism of 2,2′,4,4′,6-Pentabromodiphenyl Ether (BDE-100) to Hydroxylated BDEs

Primary Role of Cytochrome P450 2B6 in the Oxidative Metabolism of 2,2′,4,4′,6-Pentabromodiphenyl Ether (BDE-100) to Hydroxylated BDEs

Effects of Hydroxylated Polybrominated Diphenyl Ethers in Developing Zebrafish Are Indicative of Disruption of Oxidative Phosphorylation

Triclosan, chlorinated triclosan derivatives, and hydroxylated polybrominated diphenyl ethers (OH-BDEs) in wastewater effluents

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