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Key Event Title
Suppression, Estrogen receptor (ER) activity
|Level of Biological Organization|
Key Event Components
|estrogen receptor activity||estrogen receptor||decreased|
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP||Point of Contact||Author Status||OECD Status|
|Antiestrogens and ovarian adenomas/granular cell tumors||KeyEvent||Charles Wood (send email)||Under Development: Contributions and Comments Welcome|
|Hypothalamic estrogen receptors inhibition leading to ovarian cancer||MolecularInitiatingEvent||Kalyan Gayen (send email)||Under development: Not open for comment. Do not cite||Under Development|
|Not Otherwise Specified||High|
Key Event Description
Estrogen receptors are produced in all vertebrates and located in either the cell cytoplasm or nucleus(Bondesson et al., 2015; Eick and Thornton, 2011). Estrogen receptors are localized either in cytoplasm, or on the cell surface.
Site of action: Stressors (e.g., clomiphene) act on neuronal cell in the hypothalamus, where it inhibits hypothalamic Estrogen Receptors selectively.
Responses at the macromolecular level: Stressors activate the Estrogen Receptor α in the presence of lower level of estrogen and partially blocks the same for higher level of estrogen and works as antagonist for the Estrogen Receptor β(Trost and Khera, 2014). Stressors appear to act in the brain's pituitary gland to secrete an increased amount of gonadotropins hormone (GnRH) in hypothalamus leading towards increased GnRH level in blood.
Estrogen Receptor α: ERα (Estrogen Receptor α or NR3A1 or ESR1) - A nuclear receptor and it is activated by the estrogen (sex hormone). Estrogen located at chromosome number 6 ( 6q25.1)
Estrogen Receptor β: ERβ (Estrogen Receptor β or NR3A2 or ESR2) – This is also nuclear receptor and activated by the sex hormone estrogen which is located at chromosome number 14 (14q23.2). I ERβ has both N-terminal has DNA binding domain and C-terminal has ligand binding domain. This is localized to the nucleus, cytoplasm, and mitochondria. Selective estrogen receptor modulators (SERM) inhibits the ERβ. Drugs used as SERM are clomiphene, tamoxifen, raloxifene etc.
Biological compartments: Estrogen receptors (ER) are present in the plasma membrane. Both ERα and ERβ have diverse functions depending on cells and organs. ERs have also been loacated in cytoplasmic organelles including mitochondria and the endoplasmic reticulum(Levin, 2009).
General role in biology: Estrogen receptors (both estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ) binds the estrogens to promote the the biological functions of estrogens. Depending upon a balance between ERα and ERβ activities in target organs, estrogen signaling is selectively stimulated or inhibited (Welboren et al., 2009). ERβ has a high degree of sequence homology with the classical estrogen receptor. Interestingly, ERβ is detected in many tissues, including those previously assumed to be estrogen insensitive. In tissues where both ERs are expressed, such as the hypothalamus, uterus, mammary glands, and immune system, ERα promotes proliferation whereas ERβ has pro-apoptotic and pro-differentiating functions(Morani et al., 2008). ERα is present mainly in ovary (thecal cells) where as ERβ is found mainly in ovary (granulosa cells)(Paterni et al., 2014). ERα and ERβ is identical approximately 97% in the DNA-binding domain and approximately 56% in the ligand-binding domain(Dahlman-Wright et al., 2006).
How It Is Measured or Detected
Radioreceptor assay/The estrogen receptor binding assay (using Rat Uterine Cytosol): This assay identifies chemicals that have the potential to interact with the estrogen receptor (ER) in vitro. Principle of this particular assay is based on the competitive protein-binding methods. A radiolabelled ligand and an unlabelled ligand are presented together to a specific receptor. The radioactivity measurement provides the quantitative estimation of the bound and unbound fraction of the ligand with the receptor. All cytosolic estrogen receptor subtypes that are expressed in the specific tissue, including ERα and ERβ are used for the determination of estrogen receptor binding. This assay is simple and rapid to perform when optimal conditions for binding are determined. Assay determines if a ligand/chemical can interact and displace the endogenous hormone 17β-estradiol (Freyberger et al., 2010).
Domain of Applicability
Neuronal cell in Hypothalamus
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Welboren, W.-J., Sweep, F. C., Span, P. N., & Stunnenberg, H. G. (2009). Genomic actions of estrogen receptor?: what are the targets and how are they regulated? Endocrine-related cancer, 16(4), 1073.