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Key Event Title
Binding to estrogen receptor (ER)-α in immune cells
Key Event Components
Key Event Overview
AOPs Including This Key Event
|All life stages||High|
Key Event Description
ERα is expressed in all vertebrates (Eick GN. 2011). ERα was discovered in the late 1960s and was cloned and characterized in 1985 (Melissa C. 2011). ERα is expressed in a variety of immunocompetent cells, including thymocytes, CD4+ (Th1, Th2, Th17, and Tregs) and CD8+ cells and macrophages (Melissa C. 2011, Salem ML. 2004, Robinson DP. 2014). One study examined ERα expression in resting and activated PBMC subsets and found that ERα was expressed at higher levels in thymocytes, CD4+ T cells than B cells (Melissa C. 2011). ERα is a nuclear hormone transcription factor that classically binds with ligand (stressors), further stabilizing dimers that subsequently bind estrogen response elements (ERE) or non-ERE to transactivate or suppress specific target genes (Parker MG. 1993, Goldstein RA. 1993, Sasson S. 1991, Brandt ME. 1997, Carolyn MK. 2001).
How It Is Measured or Detected
The binding affinities of E2 and BPA for ERα can be confirmed by radio receptor assay, and its dimer dissociation is measured using size exclusion chromatography (Brandt ME. 1997, Takayanagi S. 2006, OECD TG440 [in vivo] and TG455 [in vitro]). While the binding affinities of PPT for ERα was determined by competitive radiometric binding assays by chemiluminescence (Kraichely DM. 2000, Carlson KE. 1997).
Domain of Applicability
Since ERα expresses in the cells of a vast variety of (vertebrate) species (Maria B. 2015) and there is common functionality in the immune systems of at least humans and mice, this AOP might be applicable to many mammal species, including humans and rodents. The estrogen receptors are composed of several domains important for hormone binding, DNA binding, dimer formation, and activation of transcription (Green S. 1986, Kumar V. 1986, Warnmark A. 2003). Interspecies sequence identities for the entire ERα are 88.5% (human-mouse), 87.5% (human-rat), and 97.5% (mouse-rat). For the ligand binding domain (ERα-LBD) alone, the interspecies sequence identities are 95.5% (human-mouse), 95.1% (human-rat), and 99.2% (mouse-rat) (White R. 1987).
ERα is widely expressed in most tissue types including most immune cells in males and females (Couse JF. 1997, Chelsea C. 2017). The ERs’ expression patterns and functions vary in a receptor subtype, cell- and tissue-specific manner. In the adult human, large-scale sequencing approaches show that ERα mRNA is detected in numerous human tissues, with the highest levels in the uterus, liver, ovary, muscle, mammary gland, pituitary gland, adrenal gland, spleen and heart, and at lower levels in the prostate, testis, adipose tissue, thyroid gland, lymph nodes and spleen (Fagerberg L. 2014, Sayers EW. 2012) (www.ncbi.nlm.nih.gov/UniGene).
Estrogen level is higher in women than men. Ordinary estrogen levels in women are 20-30 pg/mL during diestrus, 100-200 pg/mL during estrus, and 5000-10000 pg/mL during pregnancy (Offner H. 2000). Therefore, the influence of ligand binding to ERα in immune cells is expressed more strong in women than men, especially high estrogen level period.
Evidence for Perturbation by Stressor
Overview for Molecular Initiating Event
E2 activates ERα and ERβ with the same affinity although they share only 56% similarity in their ligand binding domains (Monroe DG. 2005, Papoutsi Z. 2009). Exposure E2 induced thymic atrophy, and changing T-cell phenotype (decreasing double positive (CD4+CD8+) T cell and increasing double negative (CD4-CD8-) T cell) in thymus (Okasha SA. 2001).
BPA binds to both ERα and ERβ, and ERα binding affinity of BPA is lower than that of ERβ (Takayanagi S. 2006). While these bindings are less than 2000‑fold affinity compared to the binding of estradiol to estrogen receptors (Krishnan AV. 1993).
Propylpyrazoletriol (PPT) is an ERα-selective agonist, which shows 410-fold selectivity for ERα as compared with ERβ (Kraichely DM. 2000, Li J. 2006). Li et al (2006) demonstrated that ovariectomized mice exposed PPT induced severe thymic atrophy, changing T-cell phenotype (CD4/CD8 phenotype profile) in thymus, and a reduction of mature B cell number in spleen. Since these effects by PPT were equal to or greater than E2, ERα plays the predominant role in the upregulation of immune responses.
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- Melissa, C. and Gary, G (2011). Estrogen Receptors in Immunity and Autoimmunity. Clinical Reviews in Allergy & Immunology 40:66-73.
- Salem ML. (2004). Estrogen, a double-edged sword: modulation of Th1- and Th2-mediated inflammations by differential regulation of Th1/Th2 cytokine production. Current Drug Targets - Inflammation & Allergy 3(1): 97-104.
- Robinson DP, Hall, O. J., Nilles, T. L., Bream, J.H. and Klein, S.L. (2014). 17β-estradiol protects females against influenza by recruiting neutrophils and increasing virus-specific CD8 T cell responses in the lungs. Journal of Virology 88 (9): 4711-4720.
- Parker MG, Arbuckle N, Dauvois S, Danielian P, White R. Structure and function of the estrogen receptor. Ann N Y Acad Sci. 1993. 684:119-26.
- Goldstein RA, Katzenellenbogen JA, Wolynes PG, et al. Three-dimensional model for the hormone binding domains of steroid receptors. Proc Natl Acad Sci. 1993;90 (21):9949-53.
- Sasson S. Equilibrium binding analysis of estrogen agonists and antagonists: relation to the activation of the estrogen receptor. Pathol Biol (Paris). 1991;39(1):59-69.
- Brandt ME, Vickery LE. Cooperativity and dimerization of recombinant human estrogen receptor hormone-binding domain. J Biol Chem. 1997;272(8):4843-9.
- Carolyn MK. Estrogen receptor interaction with estrogen response elements. Nucleic Acids Res. 2001 Jul 15; 29(14): 2905-2919.
- Takayanagi, S. Tokunaga, T., et al. (2006). Endocrine disruptor bisphenol A strongly binds to human estrogen-related receptor γ (ERRγ) with high constitutive activity. Toxicology Letters, 167 (2):95-105.
- OECD Guideline for the Testing of Chemicals [Test No. 440: Uterotrophic Bioassay in Rodents]
- OECD Guideline for the Testing of Chemicals [Test No. 455: Performance-Based Test Guideline for Stably Transfected Transactivation In Vitro Assays to Detect Estrogen Receptor Agonists and Antagonists]
- Kraichely, DM. Sun, J. Katzenellenbogen, JA. Katzenellenbogen, BS. (2000). Conformational changes and coactivator recruitment by novel ligands for estrogen receptor-α and estrogen receptor-β: correlations with biological character and distinct differences among SRC coactivator family members. Endocrinology, 141 (10):3534–3545.
- Carlson, KE. Choli, I. Gee, A. Katzenellenbogen, BS. Katzenellenbogen, JA. (1997) Altered Ligand Binding Properties and Enhanced Stability of a Constitutively Active Estrogen Receptor: Evidence That an Open Pocket Conformation Is Required for Ligand Interaction. Biochemistry, 36:14897-14905.
- Maria, B., Ruixin, H., Chin-Yo, L., Cecilia, W., Jan-Ake, G. (2015). Estrogen receptor signaling during vertebrate development. Biochim Biophys Acta 1849: 142-151.
- Green S, Walter P, Chambon P, et al. Human oestrogen receptor cDNA: sequence, expression and homology to v-erb-A. Nature. 1986; 320:134-139.
- Kumar V, Green S, Chambon P, et al. Localisation of the oestradiol-binding and putative DNA-binding domains of the human oestrogen receptor. The EMBO journal. 1986; 5: 2231-2236.
- Warnmark A, Treuter E, Gustafsson JA, et al. Activation functions 1 and 2 of nuclear receptors: molecular strategies for transcriptional activation. Molecular endocrinology (Baltimore, Md). 2003; 17:1901-1909.
- White, R., Lees, JA., Needham, M., Ham, J. and Parker, M. (1987). Structural Organization and Expression of the Mouse Estrogen Receptor. Molecular Endocrinology 1 (10): 735-744.
- Couse JF, Lindzey J, Grandien K, Gustafsson JA, Korach KS. (1997) Tissue distribution and quantitative analysis of estrogen receptor-alpha (ERalpha) and estrogen receptor-beta (ERbeta) messenger ribonucleic acid in the wild-type and ERalphaknockout mouse. Endocrinology 138(11):4613-4621.
- Fagerberg L, Hallstrom BM, Edlund K, et al. Analysis of the human tissue- specific expression by genome-wide integration of transcriptomics and antibody-based proteomics. Molecular & cellular proteomics. 2014; 13:397-406.
- Sayers EW, Barrett T, Federhen S, et al. Database resources of the National Center for Biotechnology Information. Nucleic acids research. 2012; 40: D13-25.
- Offner H, Adlard K, Zamora A, Vandenbark AA. Estrogen potentiates treatment with T-cell receptor protein of female mice with experimental encephalomyelitis. J Clin Invest. 2000;105(10):1465-72.
- Monroe DG, Secreto FJ, Subramaniam M, Getz BJ, Khosla S, Spelsberg TC. Estrogen receptor alpha and beta heterodimers exert unique effects on estrogen- and tamoxifen-dependent gene expression in human U2OS osteosarcoma cells. Molecular endocrinology (Baltimore, Md). 2005; 19:1555–1568.
- Papoutsi Z, Zhao C, Putnik M, Gustafsson JA, Dahlman-Wright K. Binding of estrogen receptor alpha/beta heterodimers to chromatin in MCF-7 cells. J Mol Endocrinol. 2009; 43:65-72.
- Okasha SA, Ryu S, Do Y, McKallip RJ, Nagarkatti M, Nagarkatti PS. Evidence for estradiol-induced apoptosis and dysregulated T cell maturation in the thymus. Toxicology. 2001, 163 (1):49-62.
- Takayanagi S, Tokunaga T, Liu X, Okada H, Matsushima A, Shimohigashi Y. Endocrine disruptor bisphenol A strongly binds to human estrogen-related receptor γ (ERRγ) with high constitutive activity. Toxicology Letters, 2006, 167 (2):95-105.
- Krishnan, AV., Stathis, P., Permuth, S. F., Tokes, L. and Feldman, D. (1993). Bisphenol-A: an estrogenic substance is released from polycarbonate flasks during autoclaving. Endocrinology 132; 2279-2286.
- Li, J., McMurray, RW. (2006). Effects of estrogen receptor subtype-selective agonists on immune functions in ovariectomized mice. International Immunopharmacology, 6 (9):1413-1423.