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Event: 1889

Key Event Title

The KE title should describe a discrete biological change that can be measured. It should generally define the biological object or process being measured and whether it is increased, decreased, or otherwise definably altered relative to a control state. For example “enzyme activity, decreased”, “hormone concentration, increased”, or “growth rate, decreased”, where the specific enzyme or hormone being measured is defined. 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. The short name should be less than 80 characters in length. More help
premature meiosis, male germ cells

Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. Note, KEs should be defined within a particular level of biological organization. Only KERs should be used to transition from one level of organization to another. Selection of the level of biological organization defines which structured terms will be available to select when defining the Event Components (below). More help
Level of Biological Organization

Cell term

Further information on Event Components and Biological Context may be viewed on the attached pdf.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. More help

Organ term

Further information on Event Components and Biological Context may be viewed on the attached pdf.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. More help

Key Event Components

Further information on Event Components and Biological Context may be viewed on the attached pdf.Because one of the aims of the AOP-KB is to facilitate de facto construction of AOP networks through the use of shared KE and KER elements, authors are also asked to define their KEs using a set of structured ontology terms (Event Components). In the absence of structured terms, the same KE can readily be defined using a number of synonymous titles (read by a computer as character strings). In order to make these synonymous KEs more machine-readable, KEs should also be defined by one or more “event components” consisting of a biological process, object, and action with each term originating from one of 22 biological ontologies (Ives, et al., 2017; See List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling). 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 signalling 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. 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


This is a structured field used to identify specific agents (generally chemicals) that can trigger the KE. Stressors identified in this field will be linked to the KE in a machine-readable manner, such that, for example, a stressor search would identify this as an event the stressor can trigger. NOTE: intermediate or downstream KEs in one AOP may function as MIEs in other AOPs, meaning that stressor information may be added to the KE description, even if it is a downstream KE in the pathway currently under development.Information concerning the stressors that may trigger an MIE can be defined using a combination of structured and unstructured (free-text) fields. For example, structured fields may be used to indicate specific chemicals for which there is evidence of an interaction relevant to this MIE. By linking the KE description to a structured chemical name, it will be increasingly possible to link the MIE to other sources of chemical data and information, enhancing searchability and inter-operability among different data-sources and knowledgebases. The free-text section “Evidence for perturbation of this MIE by stressor” can be used both to identify the supporting evidence for specific stressors triggering the MIE as well as to define broad chemical categories or other properties that classify the stressors able to trigger the MIE for which specific structured terms may not exist. More help

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected from an ontology. 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

The structured ontology terms for life-stage are more comprehensive than those for taxa, but may still require further description/development and explanation in the free text section. More help
Life stage Evidence
Foetal Moderate

Sex Applicability

The authors must select from one of the following: Male, female, mixed, asexual, third gender, hermaphrodite, or unspecific. 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. For example, the biological state being measured could be the activity of an enzyme, the expression of a gene or abundance of an mRNA transcript, the concentration of a hormone or protein, neuronal activity, heart rate, etc. The biological compartment may be a particular cell type, tissue, organ, fluid (e.g., plasma, cerebrospinal fluid), etc. The role in the biology could describe the reaction that an enzyme catalyses and the role of that reaction within a given metabolic pathway; the protein that a gene or mRNA transcript codes for and the function of that protein; the function of a hormone in a given target tissue, physiological function of an organ, etc. Careful attention should be taken to avoid reference to other KEs, KERs or AOPs. Only describe this KE as a single isolated measurable event/state. This will ensure that the KE is modular and can be used by other AOPs, thereby facilitating construction of AOP networks. 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

One of the primary considerations in evaluating AOPs is the relevance and reliability of the methods with which the KEs can be measured. The aim of this section of the KE description is not to provide detailed protocols, but rather to capture, in a sentence or two, per method, the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements. Methods that can be used to detect or measure the biological state represented in the KE should be briefly described and/or cited. 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).Key considerations regarding scientific confidence in the measurement approach include whether the assay is fit for purpose, whether it provides a direct or indirect measure of the biological state in question, whether it is repeatable and reproducible, and the extent to which it is accepted in the scientific and/or regulatory community. Information can be obtained from the OECD Test Guidelines website and the EURL ECVAM Database Service on Alternative Methods to Animal Experimentation (DB-ALM). ?

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

This free text section should be used to elaborate on the scientific basis for the indicated domains of applicability and the WoE calls (if provided). While structured terms may be selected to define the taxonomic, life stage and sex applicability (see structured applicability terms, above) of the KE, the structured terms may not adequately reflect or capture the overall biological applicability domain (particularly with regard to taxa). Likewise, the structured terms do not provide an explanation or rationale for the selection. The free-text section on evidence for taxonomic, life stage, and sex applicability can be used to elaborate on why the specific structured terms were selected, and provide supporting references and background information.  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.

Evidence for Perturbation by Stressor

Stressor:282 Ketoconazole

Ketoconazole can inhibit CYP26B1 activity in mouse fetal testis, preventing catabolism of ATRA, ultimately leading to increased ATRA concentration and initiation of meiosis in XY germ cells (Bowles et al, 2006).


SU5402 is a chemical antagonist of Fibroblast growth factor receptors. When mouse fetal testes are exposed at 11.5 dpc to SU5402, expression of meiotic markers are increased, suggesting premature initiation of meiosis in XY germ cells (Bowles et al, 2010).


List of the literature that was cited for this KE description. Ideally, the list of references, should conform, to the extent possible, with the OECD Style Guide ( (OECD, 2015). 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