This Event is licensed under the Creative Commons BY-SA license. This license allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use. If you remix, adapt, or build upon the material, you must license the modified material under identical terms.

Event: 122

Key Event Title

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

Activation, Glucocorticoid 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

Explore in a Third Party Tool

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
eukaryotic cell

Organ term

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
glucocorticoid receptor activity	glucocorticoid receptor	increased

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
Glucocorticoid Receptor, Activation	MolecularInitiatingEvent	Carlie LaLone (send email)	Open for comment. Do not cite
Network of SSRIs	KeyEvent	Lyle Burgoon (send email)	Open for adoption
GR activation leading to hepatic steatosis	MolecularInitiatingEvent	Chander K. Negi (send email)	Under Development: Contributions and Comments Welcome
GR Agonism Leading to Impaired Fin Regeneration	MolecularInitiatingEvent	Alexander Cole (send email)	Open for citation & comment

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

Term	Scientific Term	Evidence	Link
Vertebrates	Vertebrates	High	NCBI

Life Stages

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

Life stage	Evidence
All life stages	Moderate

Sex Applicability

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

Term	Evidence
Unspecific	High

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 molecular site of action is the glucocorticoid receptor (GR), nuclear receptor part of a superfamily of highly conserved which bind to steroids, sterols, thyroid hormones, retinoids, and orphan receptors (Weikum et al., 2017). In humans, the formal gene name of this receptor is nuclear receptor subfamily 3, group C, member 1 – NR3C1 (Oakley & Cidlowski, 2013). More specifically, the GR agonism occurs through the interaction of a chemical (endogenous compounds such as cortisol, or an external stressor) with the ligand binding domain. In the absence of a ligand, the GR is transcriptionally inactive in the cytoplasm (Barnes, 1998).

Responses at the macromolecular level: Once bound to a hormonal ligand, the GR is translocated from the cytoplasm to the nucleus where the activated GR interacts with genomic glucocorticoid-response elements (GRE) and regulates transcription of associated genes. Interactions with double stranded DNA and transcription factors can cause both activation and repression of downstream genes via directly binding to a consensus site, binding to other transcription factors to form a heterodimer, or homodimerization prior to DNA binding (Oakley & Cidlowski, 2013).

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

Glucocorticoid receptor activation can be measured via bioanalytical tools such as in vitro bioassays where results are typically reported in Dexamethasone-equivalents (DEX-EQ) . However it should be noted that these assays have differences in sensitivity (Cole & Brooks, 2023).

In Vitro Assays Employed in Glucocorticoid Receptor Agonism Detection
Assay	Receptor Organism	Tissue	Citation
TOX21 GR BLA Agonist Ratio	Human	Cervix	Huang et al., 2011
GR CALUX	Human	Osteosarcoma	Been et al., 2021; Macikova et al., 2014; Schriks et al., 2010; Suzuki et al., 2015
Attagene GR TRANS	Human	Liver	Martin et al., 2010; Medvedev et al., 2018; Romanov et al., 2008
Attagene GRe CIS	Human	Liver	Martin et al., 2010; Medvedev et al., 2018; Romanov et al., 2008
CV1-hGR	Human	Kidney	Medlock Kakaley et al., 2019
GR-GeneBlazer	Human	Kidney	Jia et al., 2016
NovaScreen NR hGR	Human	N/A	Knudsen et al., 2011; Sipes et al., 2013
Trout GR1	Trout	Kidney	Kugathas & Sumpter, 2011
Trout GR2	Trout	Kidney	Kugathas & Sumpter, 2011
Indigo hGR	Human	N/A	Cavaillin et al., 2021; Cole et al., 2025
Indigo zfGR	Zebrafish	N/A	Cole et al., 2025

In addition to bioanalytical techniques, induction of GR-regulated genes are also indicative of GR agonism in vivo (Cavallin et al., 2021; Cole et al., 2025; Garland et al., 2019).

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: The GR is present in almost every vertebrate cell (Weikum et al., 2017). The evolutionary conservation of GR activation across taxa was examined in silico through the employment of EPA’s Sequence Alignment to Predict Across Species Susceptibility (SeqAPASS) Tool, and 623 orthologs were identified confirming conservation in vertebrate species. Additionally, bioanalytical methods comparing zebrafish (Danio rerio) GR and human GR show conservation of ligand binding and receptor agonism when using dexamethasone and beclomethasone dipropionate. Lastly, the fathead minnow (Pimephales promelas) model has been employed to examine susceptibility to synthetic glucocorticoids in the following in vivo exposure to dexamethasone and beclomethasone dipropionate (Cole et al., 2025).

Through the processes of gene duplication and divergence, the GR and mineralocorticoid receptor (MR) evolved from a corticoid receptor in jawless fish. While only possessing one isoform of MR, teleost fish possess two isoforms of the GR and all three have affinity for endogenous cortisol (Baker et al., 2013). Conservation of susceptibility does not infer similarities in sensitivity which varies based on species, receptor isoform, and tissue (Aedo et al., 2023; Baker et al., 2013; Bury & Sturm, 2007; Gilmour, 2005; Jerez-Cepa et al., 2019; Small & Quiniou, 2018; Stolte et al., 2006)

Figure: Results from (A) Level 1 Sequence Alignment to Predict Cross-Species Susceptibility (SeqAPASS) comparing 1,631 protein sequences to zebrafish glucocorticoid receptor (zfGR). Analysis resulted in 782 ortholog candidates at a susceptibility cut-off of 20.55%. (B) Level 2 SeqAPASS analysis examining the ligand binding domain (LDB) of zfGR which resulted in 784 orthologs at a susceptibility cut-off of 34.47%.

Life Stage Applicability: This MIE is not life stage specific. However, the downstream transcriptional effects of GR agonism may vary based on life stage. (LaLone et al., 2012; Watanabe et al., 2016).

Sex Applicability: This MIE is not sex specific.

References

List of the literature that was cited for this KE description. More help

Aedo, J. E., Zuloaga, R., Aravena-Canales, D., Molina, A., & Valdés, J. A. (2023). Role of glucocorticoid and mineralocorticoid receptors in rainbow trout (Oncorhynchus mykiss) skeletal muscle: A transcriptomic perspective of cortisol action. Frontiers in Physiology, 13, 1048008. https://doi.org/10.3389/fphys.2022.1048008

Baker, M. E., Funder, J. W., & Kattoula, S. R. (2013). Evolution of hormone selectivity in glucocorticoid and mineralocorticoid receptors. The Journal of Steroid Biochemistry and Molecular Biology, 137, 57–70.

Barnes, P. J. (1998). Anti-inflammatory actions of glucocorticoids: Molecular mechanisms. Clinical Science (London, England: 1979), 94(6), 557–572. https://doi.org/10.1042/cs0940557

Been, F., Pronk, T., Louisse, J., Houtman, C., van der Velden-Slootweg, T., van der Oost, R., & Dingemans, M. M. L. (2021). Development of a framework to derive effect-based trigger values to interpret CALUX data for drinking water quality. Water Research, 193. https://doi.org/10.1016/j.watres.2021.116859

Bury, N. R., & Sturm, A. (2007). Evolution of the corticosteroid receptor signalling pathway in fish. General and Comparative Endocrinology, 153(1), 47–56. https://doi.org/10.1016/j.ygcen.2007.03.009

Cavallin, J. E., Battaglin, W. A., Beihoffer, J., Blackwell, B. R., Bradley, P. M., Cole, A. R., Ekman, D. R., Hofer, R. N., Kinsey, J., Keteles, K., Weissinger, R., Winkelman, D. L., & Villeneuve, D. L. (2021). Effects-Based Monitoring of Bioactive Chemicals Discharged to the Colorado River before and after a Municipal Wastewater Treatment Plant Replacement. Environmental Science & Technology, 55(2), 974–984. https://doi.org/10.1021/acs.est.0c05269

Cole, A. R., & Brooks, B. W. (2023). Comparative Endpoint Sensitivity of Bioanalytical Tools for Glucocorticoid Receptor Agonism Surveillance in Aquatic Matrices. ACS ES&T Water, 3(9), 3082–3092. https://doi.org/10.1021/acsestwater.3c00253

Cole, A. R., Blackwell, B. R., Cavallin, J. E., Collins, J. E., Kittelson, A. R., Shmaitelly, Y. M., Langan, L. M., Villenueve, D. L., & Brooks, B. W. (2025). Comparative Glucocorticoid Receptor Agonism: In Silico, In Vitro, and In Vivo and Identification of Potential Biomarkers for Synthetic Glucocorticoid Exposure. Environmental Toxicology and Chemistry, vgae041. https://doi.org/10.1093/etojnl/vgae041

Garland, M. A., Sengupta, S., Mathew, L. K., Truong, L., de Jong, E., Piersma, A. H., La Du, J., & Tanguay, R. L. (2019). Glucocorticoid receptor-dependent induction of cripto-1 (one-eyed pinhead) inhibits zebrafish caudal fin regeneration. Toxicology Reports, 6, 529–537. https://doi.org/10.1016/j.toxrep.2019.05.013

Gilmour, K. M. (2005). Mineralocorticoid receptors and hormones: Fishing for answers. Endocrinology, 146(1), 44–46.

Huang, R., Xia, M., Cho, M.-H., Sakamuru, S., Shinn, P., Houck, K. A., Dix, D. J., Judson, R. S., Witt, K. L., Kavlock, R. J., Tice, R. R., & Austin, C. P. (2011). Chemical Genomics Profiling of Environmental Chemical Modulation of Human Nuclear Receptors. Environmental Health Perspectives, 119(8), 1142–1148. https://doi.org/10.1289/ehp.1002952

Jerez-Cepa, I., Gorissen, M., Mancera, J. M., & Ruiz-Jarabo, I. (2019). What can we learn from glucocorticoid administration in fish? Effects of cortisol and dexamethasone on intermediary metabolism of gilthead seabream (Sparus aurata L.). Comparative Biochemistry and Physiology Part A: Molecular & Integrative Physiology, 231, 1–10. https://doi.org/10.1016/j.cbpa.2019.01.010

Jia, A., Wu, S., Daniels, K. D., & Snyder, S. A. (2016). Balancing the Budget: Accounting for Glucocorticoid Bioactivity and Fate during Water Treatment. Environmental Science & Technology, 50(6), 2870–2880. https://doi.org/10.1021/acs.est.5b04893

Knudsen, T. B., Houck, K. A., Sipes, N. S., Singh, A. V., Judson, R. S., Martin, M. T., Weissman, A., Kleinstreuer, N. C., Mortensen, H. M., Reif, D. M., Rabinowitz, J. R., Setzer, R. W., Richard, A. M., Dix, D. J., & Kavlock, R. J. (2011). Activity profiles of 309 ToxCast^TM chemicals evaluated across 292 biochemical targets. Toxicology, 282(1), 1–15. https://doi.org/10.1016/j.tox.2010.12.010

Kugathas, S., & Sumpter, J. P. (2011). Synthetic Glucocorticoids in the Environment: First Results on Their Potential Impacts on Fish. Environmental Science & Technology, 45(6), 2377–2383. https://doi.org/10.1021/es104105e

LaLone, C. A., Villeneuve, D. L., Olmstead, A. W., Medlock, E. K., Kahl, M. D., Jensen, K. M., Durhan, E. J., Makynen, E. A., Blanksma, C. A., Cavallin, J. E., Thomas, L. M., Seidl, S. M., Skolness, S. Y., Wehmas, L. C., Johnson, R. D., & Ankley, G. T. (2012). Effects of a glucocorticoid receptor agonist, dexamethasone, on fathead minnow reproduction, growth, and development. Environmental Toxicology and Chemistry, 31(3), 611–622. https://doi.org/10.1002/etc.1729

Macikova, P., Groh, K. J., Ammann, A. A., Schirmer, K., & Suter, M. J.-F. (2014). Endocrine Disrupting Compounds Affecting Corticosteroid Signaling Pathways in Czech and Swiss Waters: Potential Impact on Fish. Environmental Science & Technology, 48(21), 12902–12911. https://doi.org/10.1021/es502711c

Martin, M. T., Dix, D. J., Judson, R. S., Kavlock, R. J., Reif, D. M., Richard, A. M., Rotroff, D. M., Romanov, S., Medvedev, A., Poltoratskaya, N., Gambarian, M., Moeser, M., Makarov, S. S., & Houck, K. A. (2010). Impact of Environmental Chemicals on Key Transcription Regulators and Correlation to Toxicity End Points within EPA’s ToxCast Program. Chemical Research in Toxicology, 23(3), 578–590. https://doi.org/10.1021/tx900325g

Medlock Kakaley, E., Cardon, M. C., Gray, L. E., Hartig, P. C., & Wilson, V. S. (2019). Generalized Concentration Addition Model Predicts Glucocorticoid Activity Bioassay Responses to Environmentally Detected Receptor-Ligand Mixtures. Toxicological Sciences, 168(1), 252–263. https://doi.org/10.1093/toxsci/kfy290

Medvedev, A., Moeser, M., Medvedeva, L., Martsen, E., Granick, A., Raines, L., Zeng, M., Makarov, S., Houck, K. A., & Makarov, S. S. (2018). Evaluating biological activity of compounds by transcription factor activity profiling. Science Advances, 4(9), eaar4666. https://doi.org/10.1126/sciadv.aar4666

Oakley, R. H., & Cidlowski, J. A. (2013). The Biology of the Glucocorticoid Receptor: New Signaling Mechanisms in Health and Disease. The Journal of Allergy and Clinical Immunology, 132(5), 1033–1044. https://doi.org/10.1016/j.jaci.2013.09.007

Romanov, S., Medvedev, A., Gambarian, M., Poltoratskaya, N., Moeser, M., Medvedeva, L., Gambarian, M., Diatchenko, L., & Makarov, S. (2008). Homogeneous reporter system enables quantitative functional assessment of multiple transcription factors. Nature Methods, 5(3), 253–260. https://doi.org/10.1038/nmeth.1186

Schriks, M., van Leerdam, J. A., van der Linden, S. C., van der Burg, B., van Wezel, A. P., & de Voogt, P. (2010). High-Resolution Mass Spectrometric Identification and Quantification of Glucocorticoid Compounds in Various Wastewaters in The Netherlands. Environmental Science & Technology, 44(12), 4766–4774. https://doi.org/10.1021/es100013x

Sipes, N. S., Martin, M. T., Kothiya, P., Reif, D. M., Judson, R. S., Richard, A. M., Houck, K. A., Dix, D. J., Kavlock, R. J., & Knudsen, T. B. (2013). Profiling 976 ToxCast Chemicals across 331 Enzymatic and Receptor Signaling Assays. Chemical Research in Toxicology, 26(6), 878–895. https://doi.org/10.1021/tx400021f

Small, B. C., & Quiniou, S. M. A. (2018). Characterization of two channel catfish, Ictalurus punctatus, glucocorticoid receptors and expression following an acute stressor. Comparative Biochemistry and Physiology Part A: Molecular & Integrative Physiology, 216, 42–51. https://doi.org/10.1016/j.cbpa.2017.11.011

Stolte, E. H., Kemenade, B. M. L. V. van, Savelkoul, H. F. J., & Flik, G. (2006). Evolution of glucocorticoid receptors with different glucocorticoid sensitivity. Journal of Endocrinology, 190(1), 17–28. https://doi.org/10.1677/joe.1.06703

Suzuki, G., Sato, K., Isobe, T., Takigami, H., Brouwer, A., & Nakayama, K. (2015). Detection of glucocorticoid receptor agonists in effluents from sewage treatment plants in Japan. Science of The Total Environment, 527–528, 328–334. https://doi.org/10.1016/j.scitotenv.2015.05.008

Watanabe, Y., Grommen, S. V. H., & De Groef, B. (2016). Corticotropin-releasing hormone: Mediator of vertebrate life stage transitions? General and Comparative Endocrinology, 228, 60–68. https://doi.org/10.1016/j.ygcen.2016.02.012

Weikum, E. R., Knuesel, M. T., Ortlund, E. A., & Yamamoto, K. R. (2017). Glucocorticoid receptor control of transcription: Precision and plasticity via allostery. Nature Reviews Molecular Cell Biology, 18(3), 159–174. https://doi.org/10.1038/nrm.2016.152