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Crystallographic Analysis and Mimicking of Estradiol Binding: Interpretation and Speculation

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Crystallographic Analysis and Mimicking of Estradiol Binding: Interpretation and Speculation Crystallographic Analysis and Mimicking of Estradiol Binding: Interpretation and Speculation The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Osimitz, Thomas G., Michael L. Dourson, A. Wallace Hayes, and Sam Kacew. 2014. “Crystallographic Analysis and Mimicking of Estradiol Binding: Interpretation and Speculation.” Environmental Health Perspectives 122 (4): A91. doi:10.1289/ehp.1307987. http:// dx.doi.org/10.1289/ehp.1307987. Published Version doi:10.1289/ehp.1307987 Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:12185816 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA All EHP content is accessible to individuals with disabilities. Fully accessible (Section 508–compliant) HTML versions of these articles are available at Perspectives | Correspondence http://dx.doi.org/10.1289/ehp.1307987 and http://dx.doi.org/10.1289/ehp.1307987R. The correspondence section is a public forum and, as such, is not peer-reviewed. EHP is not responsible Crystallographic Analysis and for the accuracy, currency, or reliability of personal opinion expressed herein; it is the sole responsibility of Mimicking of Estradiol Binding: the authors. EHP neither endorses nor disputes their published commentary. Pedersen et al. Respond http://dx.doi.org/10.1289/ehp.1307987R Crystallographic Analysis and Previous studies have addressed the Mimicking of Estradiol Binding: production of adverse effects that would biological effects of brominated flame retar­ Interpretation and Speculation characterize endocrine disruption in vivo by dants (Birnbaum and Staskal 2004; Koike additivity of different chemicals competing et al. 2013; Mariussen and Fonnum 2003; http://dx.doi.org/10.1289/ehp.1307987 on the same receptors. Only through a more Ogunbayo et al. 2008), including a 2­year In their recent article, Gosavi et al. (2013) complete understanding of target tissue bioassay study performed by the National presented the results of a crystallographic dosimetry, potency of interaction of the Toxicology Program (NTP), which demon­ analysis of the binding of tetrabromo­ chemical of interest with the macro molecule strated that tetra bromo bisphenol A (TBBPA) bisphenol A (TBBPA) and 3­hydroxy­ of interest (e.g., SULT1E1), and subsequent can induce aggressive uterine tumors in rats 2,2´,4,4´­tetrabromo diphenyl ether events can one address the likelihood of (NTP 2013). As pointed out by Osimitz (3­OH­BDE­47) to estrogen sulfotransferase in vivo additivity. et al., TBBPA has been shown to bind poorly (SULT1E1). The authors demonstrated that This work was supported by the North to the estrogen receptor, providing the impe­ the tested mole cules fit into the same bind­ American Flame Retardant Alliance (NAFRA) tus to study other pathways such as disrup­ ing pocket as estradiol. However, although Panel of the American Chemistry Council, which tion of steroid transport and metabolism. the study’s methodology and interpreta­ previously provided funding for travel expenses Other groups have demonstrated the ability tion of the crystallographic analysis provide and honoraria to the authors as members of TBBPA and flame retardant metabolites to insight into how binding might occur in of NAFRA’s Science Advisory Council. The inhibit estrogen sulfotransferase (SULT1E1), isolated and in vitro systems, they did not researchers’ scientific conclusions and professional with IC (median inhibitory concentration) judgments were not subject to the funder’s control. 50 provide evidence that the tested molecules values near the Km for estradiol (Hamers would initiate any biological activity with Thomas G. Osimitz,1 Michael L. Dourson,2 et al. 2008; Kester et al. 2002; Zhang et al. the rele vant estrogen receptors (ERs) or pro­ A. Wallace Hayes,3 and Sam Kacew 4 1998). Our work (Gosavi et al. 2013) was teins in a human body. For example, the 1Science Strategies, Charlottesville, Virginia, USA; focused solely on understanding the struc­ ability of TBBPA to inter act with the ER 2Toxicology Excellence for Risk Assessment (TERA), tural mechanism by which these compounds Cincinnati, Ohio, USA; 3Harvard School of Public and estrogen­related receptors has been Health, Boston, Massachusetts, USA; 4McLaughlin bind to and inhibit SULT1E1’s ability to evaluated in recombi nant yeast strains, Centre for Population Health Risk Assessment, metabolize estradiol. The results of our work mammalian cell–based assays, and tests University of Ottawa, Ottawa, Ontario, Canada demonstrate that TBBPA and the 3­OH developed by the Organisation for Economic E-mail: [email protected] metabolite of BDE­47, although structur­ Co­operation and Development (Lee et al. ally different, bind in a simi lar manner at 2012; Nakagawa et al. 2007; Ogunbayo REFERENCES the estradiol binding site. This work suggests et al. 2007, 2008; Reistad et al. 2005, 2007; that these compounds could have an additive Strack et al. 2007). Those studies found that Gosavi RA, Knudsen GA, Birnbaum LS, Pedersen LC. 2013. effect on the inhibition of this enzyme. We Mimicking of estradiol binding by flame retardants TBBPA either did not interact with ERs or and their metabolites: a crystallographic analysis. wholeheartedly agree with Osimitz et al. that that it acted as a weak ER agonist/antagonist Environ Health Perspect 121:1194–1199; doi:10.1289/ the results of our work warrant future studies with a potency orders of magnitude below ehp.1306902. addressing the potential additive effect of Lee HK, Kim TS, Kim CY, Kang IH, Kim MG, Jung KK, et al. 2012. that of natural ER ligands. In addition, the Evaluation of in vitro screening system for estrogenicity: these compounds on steroid metabolism in data presented by Gosavi et al. (2013) did comparison of stably transfected human estrogen target tissues. not include the use of controls to validate receptor-α transcriptional activation (OECD TG455) assay The authors declare that they have no actual or and estrogen receptor (ER) binding assay. J Toxicol Sci the methods. The use of both positive con­ 37(2):431–437. potential competing financial interests. trols (such as diethylstilbestrol and ethinyl Nakagawa Y, Suzuki T, Ishii H, Ogata A. 2007. Biotransformation Lars C. Pedersen,1 Linda S. Birnbaum,2 estradiol) and a negative control (such as and cytotoxicity of a brominated flame retardant, tetra- Rajendrakumar A. Gosavi,1 and bromo bisphenol A, and its analogues in rat hepatocytes. 2 testosterone) would provide validation of Xenobiotica 37:693–708. Gabriel A. Knudsen the analysis and allow for the quantifica­ Ogunbayo OA, Jensen KT, Michelangeli F. 2007. The inter- 1Laboratory of Structural Biology, National Institute tion and comparison of the two test sub­ action of the brominated flame retardant: tetrabromo- of Environmental Health Sciences, National Institutes stances in relation to the binding potentials bisphenol A with phospholipid membranes. Biochim of Health, Department of Health and Human Biophys Acta 1768:1559–1566. Services, Research Triangle Park, North Carolina, of the controls. Ogunbayo OA, Lai PF, Connolly TJ, Michelangeli F. 2008. USA; 2Laboratory of Toxicology and Toxicokinetics, The authors also speculated about the Tetrabromobisphenol A (TBBPA), induces cell death in National Cancer Institute, National Institutes of 2+ possible additivity of the various brominated TM4 Sertoli cells by modulating Ca transport proteins Health, Department of Health and Human Services, and causing dysregulation of Ca2+ homeostasis. Toxicol flame retardants and their metabolites and Research Triangle Park, North Carolina, USA In Vitro 22:943–952. E-mail: [email protected] suggested that low­dose exposure to mul­ Reistad T, Mariussen E, Fonnum F. 2005. The effect of a bromi- tiple low­affinity binding compounds may nated flame retardant, tetrabromobisphenol-A, on free radical formation in human neutrophil granulocytes: the result in endocrine disruption. However, involvement of the MAP kinase pathway and protein REFERENCES none of the data presented directly addressed kinase C. Toxicol Sci 83:89–100. this point. Reistad T, Mariussen E, Ring A, Fonnum F. 2007. In vitro toxicity Birnbaum LS, Staskal DF. 2004. Brominated flame retardants: of tetrabromobisphenol-A on cerebellar granule cells: cause for concern? Environ Health Perspect 112:9–17; It is highly complex, not well under­ cell death, free radical formation, calcium influx and doi:10.1289/ehp.6559. stood, and speculative to extrapolate data extra cellular glutamate. Toxicol Sci 96:268–278. Gosavi RA, Knudsen GA, Birnbaum LS, Pedersen LC. 2013. on inhibition of enzymes such as SULT1E1 Strack S, Detzel T, Wahl M, Kuch B, Krug HF. 2007. Cytotoxicity Mimicking of estradiol binding by flame retardants and of TBBPA and effects on proliferation, cell cycle and their metabolites: a crystallographic analysis. Environ in in vitro assay systems to endocrine­system MAPK pathways in mammalian cells. Chemosphere Health Perspect 121:1194–1199; doi:10.1289/ehp.1306902. modulation of selective gene expression, 67:S405–S411. Hamers T, Kamstra JH, Sonneveld E, Murk AJ, Visser TJ, receptor binding, and activation and the Van Velzen MJM, et al. 2008. Biotransformation of Environmental Health Perspectives • VOLUME 122 | NUMBER 4 | April 2014 A 91 Correspondence
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