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Event: 122
Key Event Title
Activation, Glucocorticoid Receptor
Short name
Biological Context
Level of Biological Organization |
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Molecular |
Cell term
Cell term |
---|
eukaryotic cell |
Organ term
Key Event Components
Process | Object | Action |
---|---|---|
glucocorticoid receptor activity | glucocorticoid receptor | increased |
Key Event Overview
AOPs Including This Key Event
AOP Name | Role of event in AOP | Point of Contact | Author Status | OECD 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 Do not cite | |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
Term | Scientific Term | Evidence | Link |
---|---|---|---|
Vertebrates | Vertebrates | High | NCBI |
Life Stages
Life stage | Evidence |
---|---|
All life stages | Moderate |
Sex Applicability
Term | Evidence |
---|---|
Unspecific | High |
Key Event Description
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
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).
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
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
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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.
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