API

Event: 122

Key Event Title

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Activation, Glucocorticoid Receptor

Short name

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Activation, Glucocorticoid Receptor

Biological Context

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Level of Biological Organization
Molecular

Cell term

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Cell term
eukaryotic cell


Organ term

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Key Event Components

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Process Object Action
glucocorticoid receptor activity glucocorticoid receptor increased

Key Event Overview


AOPs Including This Key Event

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AOP Name Role of event in AOP
Glucocorticoid Receptor, Activation MolecularInitiatingEvent
Network of SSRIs KeyEvent
GR activation leading to hepatic steatosis MolecularInitiatingEvent
GR Agonism Leading to Impaired Fin Regeneration MolecularInitiatingEvent

Stressors

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Taxonomic Applicability

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Life Stages

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Life stage Evidence
All life stages Moderate

Sex Applicability

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Term Evidence
Mixed Moderate

Key Event Description

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Site of action: The molecular site of action is the glucocorticoid receptor (GR). The GR is a steroid receptor belonging to the nuclear receptor (NR) family of ligand-dependent transcription factors. In the absence of a ligand, the GR is transcriptionally inactive in the cytoplasm. Responses at the macromolecular level: Binding of a hormonal ligand enables GR to translocate into the nucleas where it binds to genomic GC-response elements (GRE) and regulates trascription of associated genes.


How It Is Measured or Detected

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Glucocorticoid activation can be measured in a number of assays as stated by the EPA’s comptox dashboard (https://comptox.epa.gov/dashboard/assay_endpoints?search=NR3C1).

Receptor Transactivation Assays:

  • Indigo Biosciences Human GR reporter assay system. Product Family IB0020 GR
  • Medlock Kakaley EK, Blackwell BR, Cardon MC, Conley JM, Evans N, Feifarek DJ, Furlong ET, Glassmeyer ST, Gray LE Jr, Hartig PC, Kolpin DW, Mills MA, Rosenblum L, Villeneuve DL, Wilson VS. De Facto Water Reuse: Bioassay suite approach delivers depth and breadth in endocrine active compound detection. Sci Total Environ. 2020 Jan 10;699:134297. doi: 10.1016/j.scitotenv.2019.134297. Epub 2019 Sep 4. PubMed PMID: 31683213.
  • Conley JM, Lambright CS, Evans N, Strynar MJ, McCord J, McIntyre BS, Travlos GS, Cardon MC, Medlock-Kakaley E, Hartig PC, Wilson VS, Gray LE Jr. Adverse Maternal, Fetal, and Postnatal Effects of Hexafluoropropylene Oxide Dimer Acid (GenX) from Oral Gestational Exposure in Sprague-Dawley Rats. Environ Health Perspect. 2019 Mar;127(3):37008. doi: 10.1289/EHP4372. PubMed PMID: 30920876;PubMed Central PMCID: PMC6768323.
  • Medlock Kakaley E, Cardon MC, Gray LE, Hartig PC, Wilson VS. Generalized Concentration Addition Model Predicts Glucocorticoid Activity Bioassay Responses to Environmentally Detected Receptor-Ligand Mixtures. Toxicol Sci. 2019 Mar 1;168(1):252-263. doi: 10.1093/toxsci/kfy290. PubMed PMID: 30535411; PubMed Central PMCID: PMC6709530. 
  • Conley JM, Evans N, Cardon MC, Rosenblum L, Iwanowicz LR, Hartig PC, Schenck KM, Bradley PM, Wilson VS. Occurrence and In Vitro Bioactivity of Estrogen, Androgen, and Glucocorticoid Compounds in a Nationwide Screen of United States Stream Waters. Environ Sci Technol. 2017 May 2;51(9):4781-4791. doi:10.1021/acs.est.6b06515. Epub 2017 Apr 12. PubMed PMID: 28401766. 
  • Hartig PC, Bobseine KL, Britt BH, Cardon MC, Lambright CR, Wilson VS, Gray LE Jr. Development of two androgen receptor assays using adenoviral transduction of MMTV-luc reporter and/or hAR for endocrine screening. Toxicol Sci. 2002 Mar;66(1):82-90. PubMed PMID: 11861975.

In addition to invitro assay, induction of glucocorticoid receptor-regulated genes such as annexin a1b, gilz, glula, and fkbp1 are also indicative of GR activation in vivo (Garland et al., 2019).


Domain of Applicability

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Glucocorticoid receptor is fairly conserved across vertebrates. Fish however, have two copies of the gene resulting in two different receptors. Although conserved across species, the sensitivity of the glucocorticoid receptor varies based on species (Solte et al., 2006).

 


Evidence for Perturbation by Stressor


Overview for Molecular Initiating Event

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References

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Garland MA, Sengupta S, Mathew LK, Truong L, Jong ED, Piersma AH, Du JL, Tanguay RL. 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

Solte EH, Lidy Verberg van Kemenade BM, Savelkoul FJ, Flik G. 2006. Evolution of glucocorticoid receptors with different glucocorticoid sensitivity. Journal of Endocrinology 190:17-28. DOI: 10.1677/joe.1.06703