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Event: 1889

Key Event Title

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

Premature initiation of meiosis in fetal male germ cells

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
premature meiosis, male germ cells
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Biological Context

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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

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

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
Ectopic ATRA in fetal testis leads to reduced spem count KeyEvent Arthur Author (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
Vertebrates Vertebrates NCBI
human, mouse, rat human, mouse, rat High NCBI

Life Stages

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

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

Male germ cell fate, fetal life

In male mammals, the XY germ cells initially proliferate during early stages of fetal testis differentiation, then enter a stage of mitotic arrest. Once in this G0/G1 cell cycle phase, the germ cells gradually stop expressing several pluripotency markers and start expressing genes considered characteristic of male germ cell differentiation (Spiller & Bowles, 2019). The mitotically arrested germ cells, now referred to as pro-spermatogonia (McCarrey, 2013), remain quiescent until after birth (McLaren, 1984).

Premature meiosis as Key Event

Germ cells in developing testis enter cell cycle quiescence during fetal life; i.e. they must avoid entering meiosis as germ cells do in the fetal ovary. In the ovaries, germ cell meiosis is initiated by the presence of all-trans retinoic acid (atRA) which induces expression of key pre-meiotic gene Stra8 (Bowles et al, 2006; Koubova et al, 2006). In the testes, atRA is degraded by the CYP26B1 enzyme, and therefore germ cells do not express Stra8 and do not enter meiosis (Bowles et al, 2006; Koubova et al, 2006; MacLean et al, 2007; Spiller et al, 2017; Trautmann et al, 2008). It is not yet clear how atRA concentrations are controlled in the human fetal testis. Regardless, there is evidence that the presence of atRA during human fetal testis development is detrimental to germ cell development (Jørgensen et al, 2015).

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

There are no OECD validated assays for measuring meiotic initiation.

Meiotic factors, such as Stra8, Sycp3, gH2AX mRNA and protein levels can be measured using various probes and antibodies that are commercially available eg. (Bowles et al, 2006).

Indirect measurements in animal models can be performed using the Stra8 promoter element driving expression of reporter protein GFP (Feng et al, 2021). This reporter assay can detect the presence (GFP) or absence (GFP negative) of Stra8 induction in a semi-quantitative manner.

Domain of Applicability

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

Fetal male germ cells must enter cell cycle quiescence (G0/G1 arrest) during fetal life and premature meiosis in gonocytes leads to their removal/death (Spiller et al, 2017). This process is conserved between mice, rats and humans.

References

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

Bowles J, Feng CW, Spiller CM, Davidson TL, Jackson A, Koopman P (2010) FGF9 suppresses meiosis and promotes male germ cell fate in mice. Dev Cell 19: 440-449

Bowles J, Knight D, Smith C, Wilhelm D, Richman J, Mamiya S, Yashiro K, Chawengsaksophak K, Wilson MJ, Rossant J, Hamada H, Koopman P (2006) Retinoid signaling determines germ cell fate in mice. Science 312: 596-600

Feng CW, Burnet G, Spiller CM, Cheung FKM, Chawengsaksophak K, Koopman P, Bowles J (2021) Identification of regulatory elements required for Stra8 expression in fetal ovarian germ cells of the mouse. Development 148: dev194977

Jørgensen A, Nielsen JE, Perlman S, Lundvall L, Mitchell RT, Juul A, Rajpert-De Meyts E (2015) Ex vivo culture of human fetal gonads: manipulation of meiosis signalling by retinoic acid treatment disrupts testis development. Hum Reprod 30: 2351-2363

Koubova J, Menke DB, Zhou Q, Capel B, Griswold MD, Page DC (2006) Retinoic acid regulates sex-specific timing of meiotic initiation in mice. Proc Natl Acad Sci U S A 103: 2474-2479

MacLean G, Li H, Metzger D, Chambon P, Petkovich M (2007) Apoptotic extinction of germ cells in testes of Cyp26b1 knockout mice. Endocrinology 148: 4560-4567

McCarrey JR (2013) Toward a more precise and informative nomenclature describing fetal and neonatal male germ cells in rodents. Biol Reprod 89: 47

McLaren A (1984) Meiosis and differentiation of mouse germ cells. Symp Soc Exp Biol 38: 7-23

Spiller C, Bowles J (2019) Sexually dimorphic germ cell identity in mammals. Curr Top Dev Biol 134: 252-288

Spiller C, Koopman P, Bowles J (2017) Sex Determination in the Mammalian Germline. Annu Rev Genet 51: 265-285

Trautmann E, Guerquin MJ, Duquenne C, Lahaye JB, Habert R, Livera G (2008) Retinoic acid prevents germ cell mitotic arrest in mouse fetal testes. Cell Cycle 7: 656-664