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

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          Abstract

          Background

          A 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.

          Objective

          The 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.

          Methods

          Twenty 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.

          Results

          The 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.

          Conclusions

          The 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.

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          Most cited references 33

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          Polybrominated diphenyl ethers in the environment and in people: a meta-analysis of concentrations.

           Ronald Hites (2004)
          Polybrominated diphenyl ethers (PBDEs) are used as flame retardants in many types of consumer products. Perhaps as a result of their widespread use and their lipophilicity, these compounds have become ubiquitous in the environment and in people. This review summarizes PBDE concentrations measured in several environmental media and analyzes these data in terms of relative concentrations, concentration trends, and congener profiles. In human blood, milk, and tissues, total PBDE levels have increased exponentially by a factor of approximately 100 during the last 30 yr; this is a doubling time of approximately 5 yr. The current PBDE concentrations in people from Europe are approximately 2 ng/g lipid, but the concentrations in people from the United States are much higher at approximately 35 ng/g lipid. Current PBDE concentrations in marine mammals from the Canadian Arctic are very low at approximately 5 ng/g lipid, but they have increased exponentially with a doubling time of approximately 7 yr. Marine mammals from the rest of the world have current PBDE levels of approximately 1000 ng/g lipid, and these concentrations have also increased exponentially with a doubling time of approximately 5 yr. Some birds' eggs from Sweden are also highly contaminated (at approximately 2000 ng/g lipid) and show PBDE doubling times of approximately 6 yr. Herring gull eggs from the Great Lakes region now have PBDE concentrations of approximately 7000 ng/g lipid, and these levels have doubled every approximately 3 yr. Fish from Europe have approximately 10 times lower PBDE concentrations than fish from North America. From these and other data, it is clear that the environment and people from North America are very much more contaminated with PBDEs as compared to Europe and that these PBDE levels have doubled every 4-6 yr. Analyses of the relative distributions of the most abundant PBDE congeners (using category averages and principal component analysis) indicated that these patterns cannot yet be used to assign sources to these pollutants.
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            Potent competitive interactions of some brominated flame retardants and related compounds with human transthyretin in vitro.

            Brominated flame retardants such as polybrominated diphenyl ethers (PBDEs), pentabromophenol (PBP), and tetrabromobisphenol A (TBBPA) are produced in large quantities for use in electronic equipment, plastics, and building materials. Because these compounds have some structural resemblance to the thyroid hormone thyroxine (T(4)), it was suggested that they may interfere with thyroid hormone metabolism and transport, e.g., by competition with T(4) on transthyretin (TTR). In the present study, we investigated the possible interaction of several brominated flame retardants with T(4) binding to TTR in an in vitro competitive binding assay, using human TTR and 125 I-T(4) as the displaceable radioligand. Compounds were tested in at least eight different concentrations ranging from 1.95 to 500 nM. In addition, we investigated the structural requirements of these and related ligands for competitive binding to TTR. We were able to show very potent competition binding for TBBPA and PBP (10.6- and 7.1-fold stronger than the natural ligand T(4), respectively). PBDEs were able to compete with T(4)-TTR binding only after metabolic conversion by induced rat liver microsomes, suggesting an important role for hydroxylation. Brominated bisphenols with a high degree of bromination appeared to be more efficient competitors, whereas chlorinated bisphenols were less potent compared to their brominated analogues. These results indicate that brominated flame retardants, especially the brominated phenols and tetrabromobisphenol A, are very potent competitors for T(4) binding to human transthyretin in vitro and may have effects on thyroid hormone homeostasis in vivo comparable to the thyroid-disrupting effects of PCBs.
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              Developmental exposure to brominated diphenyl ethers results in thyroid hormone disruption.

              The objective of the current study was to characterize the effects of DE-71 (a commercial polybrominated diphenyl ether mixture containing mostly tetra- and penta-bromodiphenyl ethers) on thyroid hormones and hepatic enzyme activity in offspring, following perinatal maternal exposure. Primiparous Long-Evans rats were orally administered DE-71 (0, 1, 10, and 30 mg/kg/day) in corn oil from gestation day (GD) 6 to postnatal day (PND) 21. Serum and liver samples obtained from dams (GD 20 and PND 22), fetuses (GD 20), and offspring (PNDs 4, 14, 36, and 90) were analyzed for circulating total serum thyroxine (T(4)) and triiodothyronine (T(3)), or hepatic microsomal ethoxy- and pentoxy-resorufin-O-deethylase (EROD and PROD), and uridine diphosphoglucuronosyl transferase (UDPGT) activity. There were no significant effects of treatment on maternal body weight gain, litter size, or sex ratio, nor were there any effects on any measures of offspring viability or growth. Serum T(4) was reduced in a dose-dependent manner in fetuses on GD 20 (at least 15%) and offspring on PND 4 and PND 14 (50 and 64% maximal in the 10 and 30 mg/kg/day groups, respectively), but recovered to control levels by PND 36. Reduction in serum T(4) was also noted in GD 20 dams (48% at highest dose), as well as PND 22 dams (44% at highest dose). There was no significant effect of DE 71 on T(3) concentrations at any time in the dams or the offspring. Increased liver to body weight ratios in offspring were consistent with induction of EROD (maximal 95-fold), PROD (maximal 26-fold) or UDPGT (maximal 4.7-fold). Induction of PROD was similar in both dams and offspring; however, EROD and UDPGT induction were much greater in offspring compared to dams (EROD = 3.8-fold; UDPGT = 0.5-fold). These data support the conclusion that DE-71 is an endocrine disrupter in rats during development.
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                Author and article information

                Journal
                Environ Health Perspect
                Environmental Health Perspectives
                National Institute of Environmental Health Sciences
                0091-6765
                1552-9924
                January 2009
                1 August 2008
                : 117
                : 1
                : 93-98
                Affiliations
                [1 ] School of Public and Environmental Affairs, Indiana University, Bloomington, Indiana, USA;
                [2 ] Department of Obstetrics and Gynecology, School of Medicine, Indiana University, Indianapolis, Indiana, USA
                Author notes
                Address correspondence to R.A. Hites, School of Public and Environmental Affairs, Indiana University, 1315 E. 10th St., Bloomington, IN 47405 USA. Telephone: (812) 855–0193. Fax: (812) 855–1076. E-mail: HitesR@ 123456indiana.edu

                The authors declare they have no competing financial interests.

                Article
                ehp-117-93
                10.1289/ehp.11660
                2627872
                19165393
                This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original DOI.
                Categories
                Research

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