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Event: 1889
Key Event Title
Premature initiation of meiosis in fetal male germ cells
Short name
Exploration Options for Key Events
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Biological Context
| Level of Biological Organization |
|---|
| Cellular |
Cell term
Organ term
Key Event Components
Key Event Overview
AOPs Including This Key Event
| 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 Do not cite |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
Life Stages
| Life stage | Evidence |
|---|---|
| Foetal | Moderate |
Sex Applicability
| Term | Evidence |
|---|---|
| Male | High |
Key Event Description
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
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
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.