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Event: 2082

Key Event Title

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

Hypospadias, increased

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
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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

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

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; 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
specification of animal organ position urethral opening abnormal

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 antagonism leading to hypospadias AdverseOutcome Brendan Ferreri-Hanberry (send email) Under development: Not open for comment. Do not cite
Decreased COUP-TFII in Leydig cells leads to Hypospadias, increased AdverseOutcome Agnes Aggy (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
human Homo sapiens High NCBI
mouse Mus musculus High NCBI
rat Rattus norvegicus High NCBI

Life Stages

An indication of the the relevant life stage(s) for this KE. More help
Life stage Evidence
During development and at adulthood High

Sex Applicability

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

Hypospadias is a congenital condition in which the urethral opening is not at the tip of the penis, usually occurring on the underside of the penis.  Improper reproductive organ formation occurring during development can impact proper reproductive function (see Palermo et al. 2021 for review with focus on exposure to phthalates).  Research in laboratory mammals has focused on signaling and gene expression (van den Driesche et al. 2012; Mendoza-Villarroel et al. 2014)), the levels of steroid compounds necessary for proper reproductive development (Kim et al. 2010; Suzuki et al. 2015; Shi et al. 2024), and the targeted disruption by toxicants during different periods of development (Foster and Harris 2005; Welsh et al. 2008).  In addition, clinical studies in humans affected by hypospadias have attempted to find causative factors (see overview in Foster 2006).

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 observation of hypospadias is possible when individuals don’t have an urethral opening at the tip of the penis.

Domain of Applicability

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

Life Stage: Problems first can be observed during development, with adverse outcome manifesting in mature individuals.

Sex: Applies to males.

Taxonomic: Most representative studies have been done in mammals (humans, lab mice, lab rats) with clinical observations in humans; plausible for all vertebrates.    

Regulatory Significance of the Adverse Outcome

An AO is a specialised KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help


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

Foster, P.M.D. and Harris, M.W.  2005.  Changes in Androgen-Mediated Reproductive Development in Male Rat Offspring Following Exposure to a Single Oral Dose of Flutamide at Different Gestational Ages.  Toxicological Sciences 85: 1024–1032.

Foster, P.M.D.  2006.  Disruption of reproductive development in male rat offspring following in utero exposure to phthalate esters.  International Journal of Andrology 29: 140–147.

Kim, T.S., Jung, K.K., Kim, S.S., Kang, I.H., Baek, J.H., Nam, H.-S., Hong, S.-K., Lee, B.M., Hong, J.T., Oh, K.W., Kim, H.S., Han, S.Y., and Kang, T.S.  2010.  Effects of in Utero Exposure to DI(n-Butyl) Phthalate on Development of Male Reproductive Tracts in Sprague-Dawley Rats.  Journal of Toxicology and Environmental Health, Part A 73(21-22): 1544-1559.

Mendoza-Villarroel, R.E., Robert, N.M., Martin, L.J., Brousseau, C., and Tremblay, J.J.  2014.  The Nuclear Receptor NR2F2 Activates Star Expression and Steroidogenesis in Mouse MA-10 and MLTC-1 Leydig Cells.  Biology of Reproduction 91(1) Article 26: 1-12.

Palermo, C.M., Foreman, J.E., Wikoff, D.S., and Lea, I.  2021.  Development of a putative adverse outcome pathway network for male rat reproductive tract abnormalities with specific considerations for the androgen sensitive window of development.  Current Research in Toxicology 2: 254–271.

Shi, B. He, E., Chang, K., Xu, G., Meng, Q., Xu, H., Chen, Z., Wang, X., Jia, M., Sun, W., Zhao, W., Zhao, H., Dong, L., and Cui, H.  2024.  Genistein prevents the production of hypospadias induced by Di-(2-ethylhexyl) phthalate through androgen signaling and antioxidant response in rats.  Journal of Hazardous Materials 466: 133537.

Suzuki, H., Suzuki, K., and Yamada, G.  2015.  Systematic analyses of murine masculinization processes based on genital sex differentiation parameters.  Development, Growth, and Differentiation 57: 639–647.

van den Driesche, S., Walker, M., McKinnel, C., Scott, HM., Eddie, S.L., Mitchell, R.T., Seckl, J.R., Drake, A.J., Smith, L.B., Anderson, R.A., and Sharpe, R.M.  2012.  Proposed Role for COUP-TFII in Regulating Fetal Leydig Cell Steroidogenesis, Perturbation of Which Leads to Masculinization Disorders in Rodents. Public Library of Science One 7(5): e37064.

Welsh, M., Saunders, P.T.K., Fisken, M., Scott, H.M., Hutchison, G.R., Smith, L.B., and Sharpe, R.M.  2008.  Identification in rats of a programming window for reproductive tract masculinization, disruption of which leads to hypospadias and cryptorchidism.  The Journal of Clinical Investigation 118(4): 1479–1490.

NOTE: Italics symbolize edits from John Frisch