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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

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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
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

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
Mixed	Moderate

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). 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

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 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
Androgen receptor assays using adenoviral transduction of MMTV-luc reporter and/or hAR for endocrine screening of surface water samples (Hartig et al, 2002).

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

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

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).

References

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

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

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.