Perspectives | Correspondence April 2014 | Volume 122 | Issue 4
Crystallographic Analysis and Mimicking of Estradiol Binding: Interpretation and Speculation
Thomas G. Osimitz,1 Michael L. Dourson,2 A. Wallace Hayes,3 and Sam Kacew4
1Science Strategies, Charlottesville, Virginia, USA; 2Toxicology Excellence for Risk Assessment (TERA), Cincinnati, Ohio, USA; 3Harvard School of Public Health, Boston, Massachusetts, USA; 4McLaughlin Centre for Population Health Risk Assessment, University of Ottawa, Ottawa, Ontario, Canada
Citation: Osimitz TG, Dourson ML, Hayes AW, Kacew S. 2014. Crystallographic Analysis and Mimicking of Estradiol Binding: Interpretation and Speculation. Environ Health Perspect 122:A91; http://dx.doi.org/10.1289/ehp.1307987
This work was supported by the North American Flame Retardant Alliance (NAFRA) Panel of the American Chemistry Council, which previously provided funding for travel expenses and honoraria to the authors as members of NAFRA’s Science Advisory Council. The researchers’ scientific conclusions and professional judgments were not subject to the funder’s control.
Published: 1 April 2014
In their recent article, Gosavi et al. (2013) presented the results of a crystallographic analysis of the binding of tetrabromobisphenol A (TBBPA) and 3-hydroxy-2,2´,4,4´-tetrabromodiphenyl ether (3-OH-BDE-47) to estrogen sulfotransferase (SULT1E1). The authors demonstrated that the tested molecules fit into the same binding pocket as estradiol. However, although the study’s methodology and interpretation of the crystallographic analysis provide insight into how binding might occur in isolated and in vitro systems, they did not provide evidence that the tested molecules would initiate any biological activity with the relevant estrogen receptors (ERs) or proteins in a human body. For example, the ability of TBBPA to interact with the ER and estrogen-related receptors has been evaluated in recombinant yeast strains, mammalian cell–based assays, and tests developed by the Organisation for Economic Co-operation and Development (Lee et al. 2012; Nakagawa et al. 2007; Ogunbayo et al. 2007, 2008; Reistad et al. 2005, 2007; Strack et al. 2007). Those studies found that TBBPA either did not interact with ERs or that it acted as a weak ER agonist/antagonist with a potency orders of magnitude below that of natural ER ligands. In addition, the data presented by Gosavi et al. (2013) did not include the use of controls to validate the methods. The use of both positive controls (such as diethylstilbestrol and ethinyl estradiol) and a negative control (such as testosterone) would provide validation of the analysis and allow for the quantification and comparison of the two test substances in relation to the binding potentials of the controls.
The authors also speculated about the possible additivity of the various brominated flame retardants and their metabolites and suggested that low-dose exposure to multiple low-affinity binding compounds may result in endocrine disruption. However, none of the data presented directly addressed this point.
It is highly complex, not well understood, and speculative to extrapolate data on inhibition of enzymes such as SULT1E1 in in vitro assay systems to endocrine-system modulation of selective gene expression, receptor binding, and activation and the production of adverse effects that would characterize endocrine disruption in vivo by additivity of different chemicals competing on the same receptors. Only through a more complete understanding of target tissue dosimetry, potency of interaction of the chemical of interest with the macromolecule of interest (e.g., SULT1E1), and subsequent events can one address the likelihood of in vivo additivity.
Gosavi RA, Knudsen GA, Birnbaum LS, Pedersen LC. 2013. Mimicking of estradiol binding by flame retardants and their metabolites: a crystallographic analysis. Environ Health Perspect 121:1194–1199; doi: 10.1289/ehp.1306902.
Lee HK, Kim TS, Kim CY, Kang IH, Kim MG, Jung KK, et al. 2012. Evaluation of in vitro screening system for estrogenicity: comparison of stably transfected human estrogen receptor-α transcriptional activation (OECD TG455) assay and estrogen receptor (ER) binding assay. J Toxicol Sci 37(2):431–437.
Ogunbayo OA, Lai PF, Connolly TJ, Michelangeli F. 2008. Tetrabromobisphenol A (TBBPA), induces cell death in TM4 Sertoli cells by modulating Ca2+ transport proteins and causing dysregulation of Ca2+ homeostasis. Toxicol In Vitro 22:943–952.
Reistad T, Mariussen E, Fonnum F. 2005. The effect of a brominated flame retardant, tetrabromobisphenol-A, on free radical formation in human neutrophil granulocytes: the involvement of the MAP kinase pathway and protein kinase C. Toxicol Sci 83:89–100.
Reistad T, Mariussen E, Ring A, Fonnum F. 2007. In vitro toxicity of tetrabromobisphenol-A on cerebellar granule cells: cell death, free radical formation, calcium influx and extracellular glutamate. Toxicol Sci 96:268–278.
Since 1993 the News section of EHP has provided readers with objective, accurate information on timely environmental health topics. After years as one of the most popular features of EHP, and as our main tool for reaching a broader audience, we felt it was time the News had its own home on our website. We are now pleased to present our brand-new page devoted exclusively to EHP News! (more…)
EHP is proud to announce that “Acute Impact of Hourly Ambient Air Pollution on Preterm Birth,” published in EHP on 29 April 2016, has been selected by the Children’s Environmental Health Network (CEHN) as its November 2016 Article of the Month. CEHN Article of the Month summaries discuss the potential policy implications of current children’s environmental health research. The CEHN summary can be viewed here.
If you’re attending the American Public Health Association (APHA) 2016 Annual Meeting and Expo in Denver (October 30–November 2), stop by the NIEHS booth (#1214) in the Exhibition Hall. Children’s Health Editor Martha M. Dimes will be available to discuss EHP submissions, Children’s Health topics, and more.
Featured Children’s Health
Veronica A. Tinney, Jerad M. Denton, Lucy Sciallo-Tyler, and Jerome A. Paulson
Jerome A. Paulson and Claire L. Barnett
Kim G. Harley, Katherine Kogut, Daniel S. Madrigal, Maritza Cardenas, Irene A. Vera, Gonzalo Meza-Alfaro, Jianwen She, Qi Gavin, Rana Zahedi, Asa Bradman, Brenda Eskenazi, and Kimberly L. Parra
Rebecca Massa Nachman, Guangyun Mao, Xingyou Zhang, Xiumei Hong, Zhu Chen, Claire Sampankanpanich Soria, Huan He, Guoying Wang, Deanna Caruso, Colleen Pearson, Shyam Biswal, Barry Zuckerman, Marsha Wills-Karp, and Xiaobin Wang