Event: 1710

Key Event Title


Binding to estrogen receptor (ER)-α in immune cells

Short name


Binding to estrogen receptor (ER)-α

Biological Context


Level of Biological Organization

Cell term


Organ term


Organ term
immune system

Key Event Components


Process Object Action

Key Event Overview

AOPs Including This Key Event


AOP Name Role of event in AOP
Binding to ER-α leading to exacerbation of SLE MolecularInitiatingEvent



Taxonomic Applicability


Term Scientific Term Evidence Link
Homo sapiens Homo sapiens High NCBI
Mus musculus Mus musculus High NCBI

Life Stages


Life stage Evidence
All life stages High

Sex Applicability


Term Evidence

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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