This Event is licensed under the Creative Commons BY-SA license. This license allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use. If you remix, adapt, or build upon the material, you must license the modified material under identical terms.

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
Hypospadias
Explore in a Third Party Tool

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

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
penis

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
embryonic organ development penis 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 Terje Svingen (send email) Under development: Not open for comment. Do not cite
Decreased COUP-TFII in Leydig cells leads to Hypospadias, increased AdverseOutcome John Frisch (send email) Under development: Not open for comment. Do not cite
Decreased testosterone synthesis leading to hypospadias AdverseOutcome Terje Svingen (send email) Under development: Not open for comment. Do not cite
5α-reductase inhibition leading to hypospadias AdverseOutcome Terje Svingen (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
Perinatal 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 malformation of the penis where the urethral opening is displaced from the tip of the glans, usually on the ventral side on the phallus. Most cases of hypospadias are milder where the urethral opening still appears on the glans proper or on the most distal part of the shaft. In more severe cases, the opening may be more proximally placed on the shaft or even as low as the scrotum or the perineum.

In addition to the misplacement of the urethral opening, hypospadias is associated with an absence of ventral prepuce, an excess of dorsal preputial tissue, and in some cases a downward curvature of the penis (chordee).  Patients with hypospadias may need surgical repairment depending on severity, with more proximal hypospadias patients in most need of surgeries to achieve optimal functional and cosmetic results (Baskin, 2000; Baskin & Ebbers, 2006; Mattiske & Pask, 2021). The incidence of hypospadias varies greatly between countries, from 1:100 to 1:500 of newborn boys (Skakkebaek et al., 2016), and the global prevalence seems to be increasing (Paulozzi, 1999; Springer et al., 2016; Yu et al., 2019).

The external genitalia arise from the biphasic genital tubercle during fetal development. Androgens (testosterone and dihydrotestosterone) drive formation of the male external genitalia. In humans, the urethra develops by fusion of two endoderm-derived urethral folds. Disruption of genital tubercle differentiation results in an incomplete urethra, i.e. hypospadias.  (Baskin, 2000; Baskin & Ebbers, 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

In humans, hypospadias is diagnosed clinically by physical examination of the infant and is at first recognized by the absence of ventral prepuce and concurrent excess dorsal prepuce (Baskin, 2000). Hypospadias may be classified according to the location of the urethral meatus: Glandular, subcoronal, midshaft, penoscrotal, scrotal, and perineal (Baskin & Ebbers, 2006).

In mice and rats, macroscopic assessment of hypospadias may be performed postnatally, and several OECD test guidelines require macroscopic examination of genital abnormalities in in vivo toxicity studies (TG 414, 416, 421/422, 443). The guidelines do not define hypospadias or how to identify them. Fetal and neonatal identification of hypospadias may require microscopic examination for proper evaluation of the pathology. This can be done by scanning electron microscopy (Uda et al., 2004), or by histological assessment in which the presence of the urethral opening in proximal, transverse sections (for example co-occuring with the os penis or corpus cavernosum), indicates hypospadias (Mahawong et al., 2014; Sinclair et al., 2017; Vilela et al., 2007). In a semiquantitative, histologic approach, the number of transverse sections of the penis with internalization of the urethra was related to the total length of the penis, achieving a percentage of urethral internalization. In this study, ≤89% of urethral internalization was defined as indicative of mild hypospadias (Stewart et al., 2018).

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: Numerous studies have shown an association in humans between in utero exposure to endocrine disrupting chemicals and hypospadias. In mice and rats, in utero exposure to several endocrine disrupting chemicals, in particular estrogens and antiandrogens, have been shown to cause hypospadias in male offspring at different frequencies (Mattiske & Pask, 2021).

Life stage applicability: Penis development is finished prenatally in humans, and hypospadias is diagnosed at birth (Baskin & Ebbers, 2006). In rodents, penis development is not fully completed until weeks after birth, but hypospadias may be identified in early postnatal life as well, and in some cases in late gestation (Sinclair et al., 2017).

Sex applicability: Hypospadias is primarily used in reference to malformation of the male external genitalia. 

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

In the OECD guidelines for developmental and reproductive toxicology, several test endpoints include examination of structural abnormalities with special attention to the organs of the reproductive system. These are: Test No. 414 ‘Prenatal Developmental Toxicity Study’ (OECD, 2018a); Test No. 416 ‘Two-Generation Reproduction Toxicity’ (OECD, 2001) and Tests No. 421/422 ‘Reproduction/Developmental Toxicity Screening Test’ (OECD, 2016a, 2016b). In Test No. 443 ‘Extended One-Generation Reproductive Toxicity Study’ (OECD, 2018b), hypospadias is specifically mentioned as a genital abnormality to note.

References

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

Baskin, L. S. (2000). Hypospadias and urethral development. The Journal of Urology, 163(3), 951–956.

Baskin, L. S., & Ebbers, M. B. (2006). Hypospadias: Anatomy, etiology, and technique. In Journal of Pediatric Surgery (Vol. 41, Issue 3, pp. 463–472). https://doi.org/10.1016/j.jpedsurg.2005.11.059

Mahawong, P., Sinclair, A., Li, Y., Schlomer, B., Rodriguez, E., Ferretti, M. M., Liu, B., Baskin, L. S., & Cunha, G. R. (2014). Prenatal diethylstilbestrol induces malformation of the external genitalia of male and female mice and persistent second-generation developmental abnormalities of the external genitalia in two mouse strains. Differentiation, 88(2–3), 51–69. https://doi.org/10.1016/j.diff.2014.09.005

Mattiske, D. M., & Pask, A. J. (2021). Endocrine disrupting chemicals in the pathogenesis of hypospadias; developmental and toxicological perspectives. In Current Research in Toxicology (Vol. 2, pp. 179–191). Elsevier B.V. https://doi.org/10.1016/j.crtox.2021.03.004

OECD. (2001). Test No. 416: Two-Generation Reproduction Toxicity. In OECD Guidelines for the Testing of Chemicals, Section 4. OECD Publishing. https://doi.org/10.1787/9789264070868-en

OECD. (2016a). Test No. 421: Reproduction/Developmental Toxicity Screening Test. In OECD Guidelines for the Testing of Chemicals, Section 4. OECD Publishing. https://doi.org/10.1787/9789264264380-en

OECD. (2016b). Test No. 422: Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test. In OECD Guidelines for the Testing of Chemicals, Section 4. OECD Publising. https://doi.org/10.1787/9789264264403-en

OECD. (2018a). Test No. 414: Prenatal Developmental Toxicity Study. In OECD Guidelines for the Testing of Chemicals, Section 4. OECD Publishing. https://doi.org/10.1787/9789264070820-en

OECD. (2018b). Test No. 443: Extended One-Generation Reproductive Toxicity Study. In OECD Guidelines for the Testing of Chemicals, Section 4. OECD Publishing. https://doi.org/10.1787/9789264185371-en

Paulozzi, L. J. (1999). International Trends in Rates of Hypospadias and Cryptorchidism. Environmental Health Perspectives, 107(4), 297–302. https://doi.org/10.1289/ehp.99107297

Sinclair, A. W., Cao, M., Pask, A., Baskin, L., & Cunha, G. R. (2017). Flutamide-induced hypospadias in rats: A critical assessment. Differentiation, 94, 37–57. https://doi.org/10.1016/j.diff.2016.12.001

Skakkebaek, N. E., Rajpert-De Meyts, E., Buck Louis, G. M., Toppari, J., Andersson, A.-M., Eisenberg, M. L., Jensen, T. K., Jørgensen, N., Swan, S. H., Sapra, K. J., Ziebe, S., Priskorn, L., & Juul, A. (2016). Male Reproductive Disorders and Fertility Trends: Influences of Environment and Genetic Susceptibility. Physiological Reviews, 96(1), 55–97. https://doi.org/10.1152/physrev.00017.2015.-It

Springer, A., van den Heijkant, M., & Baumann, S. (2016). Worldwide prevalence of hypospadias. Journal of Pediatric Urology, 12(3), 152.e1-152.e7. https://doi.org/10.1016/j.jpurol.2015.12.002

Stewart, M. K., Mattiske, D. M., & Pask, A. J. (2018). In utero exposure to both high- and low-dose diethylstilbestrol disrupts mouse genital tubercle development. Biology of Reproduction, 99(6), 1184–1193. https://doi.org/10.1093/biolre/ioy142

Uda, A., Kojima, Y., Hayashi, Y., Mizuno, K., Asai, N., & Kohri, K. (2004). Morphological features of external genitalia in hypospadiac rat model: 3-dimensional analysis. The Journal of Urology, 171(3), 1362–1366. https://doi.org/10.1097/01.JU.0000100140.42618.54

Vilela, M. L. B., Willingham, E., Buckley, J., Liu, B. C., Agras, K., Shiroyanagi, Y., & Baskin, L. S. (2007). Endocrine Disruptors and Hypospadias: Role of Genistein and the Fungicide Vinclozolin. Urology, 70(3), 618–621. https://doi.org/10.1016/j.urology.2007.05.004

Yu, X., Nassar, N., Mastroiacovo, P., Canfield, M., Groisman, B., Bermejo-Sánchez, E., Ritvanen, A., Kiuru-Kuhlefelt, S., Benavides, A., Sipek, A., Pierini, A., Bianchi, F., Källén, K., Gatt, M., Morgan, M., Tucker, D., Canessa, M. A., Gajardo, R., Mutchinick, O. M., … Agopian, A. J. (2019). Hypospadias Prevalence and Trends in International Birth Defect Surveillance Systems, 1980–2010. European Urology, 76(4), 482–490. https://doi.org/10.1016/j.eururo.2019.06.027