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Event: 2393

Key Event Title

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

Androgen receptor nuclear transcriptional activity in genital-tubercle tissues, reduced

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
AR transcriptional activity in GT tissues, reduced
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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
Cellular

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

Organ 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
Organ term
undifferentiated genital tubercle

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
protein import into nucleus, translocation androgen receptor decreased
regulation of DNA binding androgen decreased

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 OECD Status
AR agonism leads to delayed PPS via reduced FGF expression KeyEvent Travis Karschnik (send email) Under development: Not open for comment. Do not cite

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
mammals mammals High NCBI
Mus musculus Mus musculus High NCBI
Oryctolagus sp. Oryctolagus sp. High NCBI
Homo sapiens Homo sapiens High NCBI

Life Stages

An indication of the the relevant life stage(s) for this KE. More help
Life stage Evidence
Development High
Fetal to Parturition High
Foetal High
Embryo High

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

The event describes a decrease in androgen receptor (AR)-mediated gene transcription in genital tubercle (GT) tissue.  It reflects a state in which AR fails to be activated to as a result of reduced AR translocation to the nucleus, diminished DNA binding to androgen response elements, and/or lower recruitment of transcriptional co-regulators.  

The biological compartment it is measured in are GT tissues, particularly mesenchymal and epithelial cells. 

AR transcriptional activity is involved in differentiation of the GT by regulating genes that control outgrowth and elongation of the tubercle, formation for the penile erectile tissues, ventral urethral closure and patterning, and morphogenesis of external genitalia.

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

Direct evidence with well validated and widely used techniques that strongly correlate with AR activation state.

  • Nuclear AR localization, which is the amount of AR protein in the cell nucleus, can be measured via:
    • Immunohistochemistry
    • Immunofluorescence
    • Western blot
  • AR DNA binding, which measures androgen response elements on chromatin, can be measured via:
    • Chromatin Immunoprecipitation followed by qPCR or seq.

Indirect evidence well validated and widely used techniques that strongly correlate with AR activation state.

  • Expression of AR target genes, which measure either mRNA or protein levels of AR-regulated genes, can be measured via:
    • RT-qPCR
    • RNA-seq
    • In situ hybridization
    • Proteomics

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

Reduced AR nuclear transcriptional activity in genital-tubercle tissues has been measured mammals including humans and rodents (Veyssiere et al., 1985; Agras et al., 2006; Rodriguez et al., 2012).  It’s plausible for any species expressing AR in GT tissue developing into external genitalia. SeqAPASS results for taxonomic conservation within Mammalia is attached for AR (AAA51780.1) as AR-SeqAPASS_Mammalia.xlsx.

Lifestage Applicability

AR transcriptional activity in GT tissues is critical in embryonic and fetal periods.  AR signalling during this time-period influences genital tissue patterning and morphogenesis.

  • Gestation day 18 in rabbits (Veyssiere et al., 1985) 
  • Gestational day 15.5-17.5 (Miyagawa et al., 2009) 
  • Gestation day 14 in mice (Agras et al., 2006)

Sex Applicability

The genital tubercle forms early in embryonic development in males and females.  AR nuclear transcription occurs in that tissue in both males and females although it is the dominant driver of GT differentiation in males and only occurs transiently and at lower levels in females (Sajjad et al., 2004).

References

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

Agras, K., Willingham, E., Liu, B., & Baskin, L. S. (2006). Ontogeny of androgen receptor and disruption of its mRNA expression by exogenous estrogens during morphogenesis of the genital tubercle. The Journal of urology, 176(4), 1883-1888.

Miyagawa, S., Satoh, Y., Haraguchi, R., Suzuki, K., Iguchi, T., Taketo, M. M., ... & Yamada, G. (2009). Genetic interactions of the androgen and Wnt/β-catenin pathways for the masculinization of external genitalia. Molecular endocrinology, 23(6), 871-880

Rodriguez Jr, E., Weiss, D. A., Ferretti, M., Wang, H., Menshenia, J., Risbridger, G., ... & Baskin, L. (2012). Specific morphogenetic events in mouse external genitalia sex differentiation are responsive/dependent upon androgens and/or estrogens. Differentiation, 84(3), 269-279.

Sajjad, Y., Quenby, S., Nickson, P., Lewis-Jones, D. I., & Vince, G. (2004). Immunohistochemical localization of androgen receptors in the urogenital tracts of human embryos. Reproduction, 128(3), 331-339.

Veyssiere, G., Berger, M., Jean-Faucher, C., De Turckheim, M., & Jean, C. (1985). Androgen receptor in genital tubercle of rabbit fetuses and newborns. Ontogeny and properties. Journal of steroid biochemistry, 23(4), 399-404.