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Event: 2214

Key Event Title

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

Decreased, Insulin-like peptide 3 (INSL3)

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

Decreased, INSL3

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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
gene expression		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
Decreased INSL3 leads to Increased, cryptorchidism	KeyEvent	John Frisch (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	Moderate	NCBI

Life Stages

An indication of the the relevant life stage(s) for this KE. More help

Life stage	Evidence
Development	Moderate

Sex Applicability

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

Term	Evidence
Unspecific	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

Insulin-like peptide 3 (INSL3) has been studied for roles during development. In animals that have a sexually dimorphic position of gonads, a key developmental pathway is reproductive tissue and organ development that differs between males and females. Improper signaling inhibits sexual differentiation of reproductive tissue resulting in abnormal reproductive organs. Particularly focus for INSL3 has been placed on decreased INSL3 gene expression in Leydig cells and failure of male development of the cranial suspensory ligament and the gubernaculum, resulting in cryptorchidism (Nef and Parada 1999, Zimmerman et al. 1999, Kaftanovskaya et al. 2011). Evidence suggests that INSL3 activates the GREAT (LGR8) receptor (Bogatcheva et al. 2003). Targeted disruption of INSL3 through toxicant exposure has been used in laboratory mammal studies to further investigate resulting effects (from phthalates see Wilson et al. 2004; Wilson et al. 2007).

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

INSL3 is measured by changes in gene expression (via real time PCR) and protein (via Western blotting or enzyme immunoassays) levels.

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: Predominantly studied during development; likely present during all lifestages.

Sex: Applies to both males and females.

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

References

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

Bogatcheva, N.V., Truong, A., Feng, S., Engel, W., Adham, I.M., and Agoulnik, A.I. 2003. GREAT/LGR8 Is the Only Receptor for Insulin-Like 3 Peptide. Molecular Endocrinology 17(12):2639–2646.

Kaftanovskaya, E.M., Feng, S., Huang, Z., Tan, Y., Barbara, A.M., Kaur, S., Troung, A., Gorlov, I.P., and Agoulnik, A.I. 2011. Suppression of Insulin-Like3 Receptor Reveals the Role of β-Catenin and Notch Signaling in Gubernaculum Development. Molecular Endocrinology 25: 170–183.

Nef, S. and Parada, L.F. 1999. Cryptorchidism in mice mutant for Insl3. Nature Genetics 22: 295-299.

Wilson, V.S., Lambright, C., Furr, J., Ostby, J., Wood, C., Held, G., and Gray, Jr., L.E. 2004. Phthalate ester-induced gubernacular lesions are associated with reduced insl3 gene expression in the fetal rat testis. Toxicology Letters 146: 207–215.

Wilson, V.S., Howdeshell, K.L., Lambright, C.S., Furr, J., and Gray, Jr., L.E. 2007. Differential expression of the phthalate syndrome in male Sprague–Dawley and Wistar rats after in utero DEHP exposure. Toxicology Letters 170: 177–184.

Zimmermann, S., Steding, G., Emmen, J.M.A., Brinkmann, A.O., Nayernia, K., Holstein, A.F., Engel, W., and Adham, I.M. 1999. Targeted Disruption of the Insl3 Gene Causes Bilateral Cryptorchidism. Molecular Endocrinology 13(5): 681-691.

NOTE: Italics symbolize edits from John Frisch