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Event: 112

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Antagonism, Estrogen receptor

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. More help
Antagonism, Estrogen receptor
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Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. More help
Level of Biological Organization
Molecular

Cell term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Cell term
hepatocyte

Organ term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling).  The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor).  Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description.  To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons.  If a desired term does not exist, a new term request may be made via Term Requests.  Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Process Object Action
estrogen receptor activity estrogen receptor decreased

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE. Clicking on the name of the AOP will bring you to the individual page for that AOP. More help
AOP Name Role of event in AOP Point of Contact Author Status OECD Status
Estrogen receptor antagonism leading to reproductive dysfunction MolecularInitiatingEvent Evgeniia Kazymova (send email) Open for citation & comment EAGMST Under Review
DNA damage and metastatic breast cancer KeyEvent Agnes Aggy (send email) Under development: Not open for comment. Do not cite

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help

Life Stages

An indication of the the relevant life stage(s) for this KE. More help

Sex Applicability

An indication of the the relevant sex for this KE. More help

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

Site of action: The site of action for the molecular initiating event is the liver (hepatocytes).

Responses at the macromolecular level: Estrogen receptor antagonists have been shown to interact with the ligand binding domain of ERs. However, those interactions occur at different contact sites than those of estrogen agonists, leading to a different conformation in the transactivation domain (Brzozowski et al. 1997; Katzenellenbogen 1996).

Characterization of chemical properties: Two broad categories of ER antagonists have been described. Type I, like tamoxifen act as mixed agonists and antagonists. Type II, like ICI164384 are pure antagonists (Katzenellenbogen 1996). Due to their potential utility for treating estrogen-dependent breast cancers and other estrogen-related disease states as well as concerns regarding endocrine disruption, there is an extensive body of literature on the identification and design of chemical structures that act as ER antagonists (e.g., (Brooks et al. 1987; Brooks and Skafar 2004; Lloyd et al. 2006; Sodero et al. 2012; Vedani et al. 2012; Wang et al. 2006).

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help
  • The BG1luc estrogen receptor transactivation test method for identifying estrogen receptor agonists and antagonists (OECD Test Guideline 457) has been validated by the National Toxicology Program Interagency Center for Evaluation of Alternative Toxicological Methods (NICEATM) and Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) as an appropriate assay for detecting ER antagonism. (OECD, 2012b).
  • Other human ER-based transactivation assays that have been used to detect ERα antagonism include the T47D-Kbluc assay (Wilson et al. 2004); ERα CALUX assay (van der Burg et al. 2010); MELN assay (Witters et al. 2010); and the yeast estrogen screen (YES; (De Boever et al. 2001)). Each of these assays have undergone some level of validation.
  • In aquatic ecotoxicology, vitellogenin synthesis in primary fish liver cells and liver slices has also been used to screen for anti-estrogenic activity (e.g., (Bickley et al. 2009; Navas and Segner 2006; Schmieder et al. 2000; Schmieder et al. 2004; Sun et al. 2010). Although these approaches have generally not been subject to as much formal validation as human ER-based transactivation assays, in the case of fish-specific AOPs linked to this key event, these measures of anti-estrogenicity may be more directly relevant to predicting other key events in the pathway.

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided).  More help

Taxonomic applicability: Steroid receptors, including ER are thought to have evolved in the chordate lineage (Baker 1997, 2003; Thornton 2001). An ER ortholog has been isolated from a mollusk species, but no ER orthologs have been detected in arthropods or nematodes (Thornton et al. 2003). Broadly speaking, most vertebrates can be expected to have functional ERs, while most invertebrates do not, although there may be exceptions within the mollusk lineage and evolutionarily-related organisms.

References

List of the literature that was cited for this KE description. More help
  • Brzozowski AM, Pike AC, Dauter Z, Hubbard RE, Bonn T, Engstrom O, et al. 1997. Molecular basis of agonism and antagonism in the oestrogen receptor. Nature 389:753-758.
  • Katzenellenbogen B. 1996. Estrogen receptors: Bioactivities and interactions with cell signaling pathways. Biology of Reproduction 54:287-293.
  • Brooks SC, Wappler NL, Corombos JD, Doherty LM, Horwitz JP. 1987. Estrogen structure-fuction relationships. Berlin:Walter de Gruyter & Co., 443-466.
  • Brooks SC, Skafar DF. 2004. From ligand structure to biological activity: Modified estratrienes and their estrogenic and antiestrogenic effects in mcf-7 cells. Steroids 69:401-418.
  • Lloyd DG, Smith HM, O'Sullivan T, Knox AS, Zisterer DM, Meegan MJ. 2006. Antiestrogenically active 2-benzyl-1,1-diarylbut-2-enes: Synthesis, structure-activity relationships and molecular modeling study for flexible estrogen receptor antagonists. Medicinal chemistry 2:147-168.
  • Sodero AC, Romeiro NC, da Cunha EF, de Oliveira Magalhaaes U, de Alencastro RB, Rodrigues CR, et al. 2012. Application of 4d-qsar studies to a series of raloxifene analogs and design of potential selective estrogen receptor modulators. Molecules 17:7415-7439.
  • Vedani A, Dobler M, Smiesko M. 2012. Virtualtoxlab - a platform for estimating the toxic potential of drugs, chemicals and natural products. Toxicology and applied pharmacology 261:142-153.
  • Wang CY, Ai N, Arora S, Erenrich E, Nagarajan K, Zauhar R, et al. 2006. Identification of previously unrecognized antiestrogenic chemicals using a novel virtual screening approach. Chemical research in toxicology 19:1595-1601.
  • Denny JS, Tapper MA, Schmieder PK, Hornung MW, Jensen KM, Ankley GT, et al. 2005. Comparison of relative binding affinities of endocrine active compounds to fathead minnow and rainbow trout estrogen receptors. Environmental toxicology and chemistry / SETAC 24:2948-2953.
  • 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-alpha transcriptional activation (oecd tg455) assay and estrogen receptor (er) binding assay. The Journal of toxicological sciences 37:431-437.
  • Rider CV, Hartig PC, Cardon MC, Lambright CR, Bobseine KL, Guillette LJ, Jr., et al. 2010. Differences in sensitivity but not selectivity of xenoestrogen binding to alligator versus human estrogen receptor alpha. Environmental toxicology and chemistry / SETAC 29:2064-2071.
  • OECD. 2012b. Test no. 457: Bg1luc estrogen receptor transactivation test method for identifying estrogen receptor agonists and antagonists:OECD Publishing.
  • Wilson VS, Bobseine K, Gray LE, Jr. 2004. Development and characterization of a cell line that stably expresses an estrogen-responsive luciferase reporter for the detection of estrogen receptor agonist and antagonists. Toxicological sciences : an official journal of the Society of Toxicology 81:69-77.
  • van der Burg B, Winter R, Weimer M, Berckmans P, Suzuki G, Gijsbers L, et al. 2010. Optimization and prevalidation of the in vitro eralpha calux method to test estrogenic and antiestrogenic activity of compounds. Reproductive toxicology 30:73-80.
  • Witters H, Freyberger A, Smits K, Vangenechten C, Lofink W, Weimer M, et al. 2010. The assessment of estrogenic or anti-estrogenic activity of chemicals by the human stably transfected estrogen sensitive meln cell line: Results of test performance and transferability. Reproductive toxicology 30:60-72.
  • De Boever P, Demare W, Vanderperren E, Cooreman K, Bossier P, Verstraete W. 2001. Optimization of a yeast estrogen screen and its applicability to study the release of estrogenic isoflavones from a soygerm powder. Environmental health perspectives 109:691-697.
  • Bickley LK, Lange A, Winter MJ, Tyler CR. 2009. Evaluation of a carp primary hepatocyte culture system for screening chemicals for oestrogenic activity. Aquatic toxicology 94:195-203.
  • Navas JM, Segner H. 2006. Vitellogenin synthesis in primary cultures of fish liver cells as endpoint for in vitro screening of the (anti)estrogenic activity of chemical substances. Aquatic toxicology 80:1-22.
  • Schmieder P, Tapper M, Linnum A, Denny J, Kolanczyk R, Johnson R. 2000. Optimization of a precision-cut trout liver tissue slice assay as a screen for vitellogenin induction: Comparison of slice incubation techniques. Aquatic toxicology 49:251-268.
  • Schmieder PK, Tapper MA, Denny JS, Kolanczyk RC, Sheedy BR, Henry TR, et al. 2004. Use of trout liver slices to enhance mechanistic interpretation of estrogen receptor binding for cost-effective prioritization of chemicals within large inventories. Environmental science & technology 38:6333-6342.
  • Sun L, Wen L, Shao X, Qian H, Jin Y, Liu W, et al. 2010. Screening of chemicals with anti-estrogenic activity using in vitro and in vivo vitellogenin induction responses in zebrafish (danio rerio). Chemosphere 78:793-799.
  • Baker ME. 1997. Steroid receptor phylogeny and vertebrate origins. Molecular and cellular endocrinology 135:101-107.
  • Baker ME. 2003. Evolution of adrenal and sex steroid action in vertebrates: A ligand-based mechanism for complexity. BioEssays : news and reviews in molecular, cellular and developmental biology 25:396-400.
  • Thornton JW. 2001. Evolution of vertebrate steroid receptors from an ancestral estrogen receptor by ligand exploitation and serial genome expansions. Proceedings of the National Academy of Sciences of the United States of America 98:5671-5676.
  • Thornton JW, Need E, Crews D. 2003. Resurrecting the ancestral steroid receptor: Ancient origin of estrogen signaling. Science 301:1714-1717.