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      Hydroxylated Metabolites of the Polybrominated Diphenyl Ether Mixture DE-71 Are Weak Estrogen Receptor-α Ligands

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          Polybrominated diphenyl ethers (PBDEs) are widely found in the environment and are suspected endocrine disruptors. We previously identified six hydroxylated metabolites of PBDE (OH-PBDEs) in treated mice.


          We tested the hypothesis that OH-PBDEs would interact with and alter activity of estrogen receptor-α (ER-α).


          We tested estrogenicity using two assays: 3H-estradiol ( 3H-E 2) displacement from recombinant ER-α and induction of reporter gene (ERE-luciferase) in cultured cells. We incubated the PBDE mixture DE-71 with rat liver microsomes and tested the resultant metabolite mixture for estrogenic activity. We also determined relative estrogenic potential of individual hydroxylated PBDE congeners.


          Reporter gene activity was increased by DE-71 that had been subjected to microsomal metabolism. DE-71 did not displace E 2 from ER-α, but all six of the OH-PBDE metabolites did. para-Hydroxylated metabolites displayed a 10- to 30-fold higher affinity for ER-α compared with ortho-hydroxylated PBDEs, and one produced a maximal effect 30% higher than that produced by E 2. Coadministration of E 2 and DE-71, or certain of its metabolites, yielded reporter activity greater than either chemical alone. Two ortho-OH-PBDEs were antiestrogenic in the reporter assay.


          The observations—that the DE-71 mixture did not displace 3H-E 2 from ER-α while the hydroxylated metabolites did—suggest that the weak estrogenic effects of DE-71 are due to metabolic activation of individual congeners. However, the behavior of DE-71 and its metabolites, when co-administered with E 2, suggest a secondary, undetermined mechanism from classical ER-α activation.

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          Most cited references 68

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          Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta.

          The rat estrogen receptor (ER) exists as two subtypes, ER alpha and ER beta, which differ in the C-terminal ligand binding domain and in the N-terminal transactivation domain. In this study we investigated the messenger RNA expression of both ER subtypes in rat tissues by RT-PCR and compared the ligand binding specificity of the ER subtypes. Saturation ligand binding analysis of in vitro synthesized human ER alpha and rat ER beta protein revealed a single binding component for 16 alpha-iodo-17 beta-estradiol with high affinity [dissociation constant (Kd) = 0.1 nM for ER alpha protein and 0.4 nM for ER beta protein]. Most estrogenic substances or estrogenic antagonists compete with 16 alpha-[125I]iodo-17 beta-estradiol for binding to both ER subtypes in a very similar preference and degree; that is, diethylstilbestrol > hexestrol > dienestrol > 4-OH-tamoxifen > 17 beta-estradiol > coumestrol, ICI-164384 > estrone, 17 alpha-estradiol > nafoxidine, moxestrol > clomifene > estriol, 4-OH-estradiol > tamoxifen, 2-OH-estradiol, 5-androstene-3 beta, 17 beta-diol, genistein for the ER alpha protein and dienestrol > 4-OH-tamoxifen > diethylstilbestrol > hexestrol > coumestrol, ICI-164384 > 17 beta-estradiol > estrone, genistein > estriol > nafoxidine, 5-androstene-3 beta, 17 beta-diol > 17 alpha-estradiol, clomifene, 2-OH-estradiol > 4-OH-estradiol, tamoxifen, moxestrol for the ER beta protein. The rat tissue distribution and/or the relative level of ER alpha and ER beta expression seems to be quite different, i.e. moderate to high expression in uterus, testis, pituitary, ovary, kidney, epididymis, and adrenal for ER alpha and prostate, ovary, lung, bladder, brain, uterus, and testis for ER beta. The described differences between the ER subtypes in relative ligand binding affinity and tissue distribution could contribute to the selective action of ER agonists and antagonists in different tissues.
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            Long-term human breast carcinoma cell lines of metastatic origin: preliminary characterization.

            Nineteen human breast carcinoma cell lines have been established as continuous cultures during the past 6 years in our laboratory. This preliminary report is designed to list the lines by their designated code numbers (MDA-MB) and present a brief summary of their morphological, cytogenetic and biochemical characteristics. Sixteen of our lines were obtained from pleural effusions, two from brain metastases, and one from pericardial fluid. All lines have been shown to be distinct entities and are uncontaminated by HeLa cells or each other. A lq marker chromosome is present in all but one of the lines examined.
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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.

                Author and article information

                Environ Health Perspect
                Environmental Health Perspectives
                National Institute of Environmental Health Sciences
                October 2008
                27 May 2008
                : 116
                : 10
                : 1315-1321
                [1 ] Department of Pharmacology and Toxicology
                [2 ] Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, Indiana, USA
                Author notes
                Address correspondence to R.M. Bigsby, Department of Obstetrics and Gynecology, Indiana University School of Medicine, 975 W. Walnut St. (IB360), Indianapolis, IN 46202-5121 USA. Telephone: (317) 274-8970. Fax: (317) 278-2884. E-mail: rbigsby@ 123456iupui.edu
                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.


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