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Key Event Title
Antagonism, Estrogen receptor
|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|
|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 Do not cite|
Key Event Description
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
- 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
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.
- 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.