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Relationship: 2527
Title
increased atRA concentration leads to premature meiosis, male germ cells
Upstream event
Downstream event
AOPs Referencing Relationship
| AOP Name | Adjacency | Weight of Evidence | Quantitative Understanding | Point of Contact | Author Status | OECD Status |
|---|---|---|---|---|---|---|
| Increased (ectopic) concentration of all-trans retinoic acid (ATRA) if fetal testis leading to reduced sperm count, males | adjacent | Moderate | Low | Arthur Author (send email) | Under development: Not open for comment. Do not cite |
Taxonomic Applicability
Sex Applicability
| Sex | Evidence |
|---|---|
| Male | High |
Life Stage Applicability
| Term | Evidence |
|---|---|
| Fetal | Moderate |
Germs cells undergo meiotic cell division to produce haploid sperm or eggs from diploid gonocytes or oocytes, respectively. Meiotic entry occurs during fetal life in germ cells of ovaries but postnatally in germ cells of testes (Spiller et al, 2017). During late fetal life, germ cells in testes remain in a state of mitotic quiescence and it isn’t until prior to puberty that they initiate meiotic entry.
All-trans retinoic acid (atRA) is suggested to induce meiosis in both males and females at the appropriate life stages. atRA prompts germ cells of the developing ovary to initiate first round of meiosis during fetal life, whereas male germ cells in the developing testis is prevented from entering meiosis until puberty by the effective breakdown of atRA by CYP26 enzymes. In the absence of atRA, fetal male germ cells enter cell cycle quiescence (Spiller et al, 2017). If, however, atRA is ectopically expressed in the fetal testis, premature meiotic initiation is induced in fetal male germ cells, which ultimately disrupts gonocyte development.
| ID | Experimental Design | Species | Upstream Observation | Downstream Observation | Citation (first author, year) | Notes |
|---|
| Title | First Author | Biological Plausibility |
Dose Concordance |
Temporal Concordance |
Incidence Concordance |
|---|
Biological Plausibility
Dose Concordance Evidence
Temporal Concordance Evidence
Incidence Concordance Evidence
Uncertainties and Inconsistencies
Mouse deletion model for the atRA synthesis enzymes Aldh1a1, Aldh1a2 and Aldh1a3 showed decreased expression of Stra8 in double (Aldh1a2/3) and triple (Aldh1a1/2/3) knockouts, although ultimately germ cells were observed undergoing meiosis in these ovaries, suggesting redundant role for atRA (Chassot et al, 2020; Kumar et al, 2011). Similarly, transgenic mice lacking the three atRA nuclear receptors (RAR-a, -b, -g) showed reduced levels of Stra8, although ultimately germ cells were observed undergoing meiosis and were capable of producing live offspring (Vernet et al, 2020). Whether or not these models led to impaired fertility (such as sub-fertility) has not been elucidated and the size of their oocyte pools were not determined.
Gain of function mouse ovary models for CYP26A1 and CYP26B1 shows that CYP26B1 can prevent oocytes from entering meiosis (as in, failure to induce Stra8 expression), whereas CYP26A1 does not have the same effect despite being a potent atRA degrading enzyme. This suggests that factor(s) in addition to atRA are required for meiosis induction (Bellutti et al, 2019).
There is a very limited quantitative understanding of this KER other than the knowledge that when germ cells, from either testis or ovary, are cultured in the presence of atRA, at concentrations as low as 10nM, Stra8 expression is rapidly induced (Spiller & Bowles, 2019).
Response-response Relationship
In vitro and ex vivo, it has been conclusively shown that low levels of exogenous atRA can induce germ cells to enter meiosis in mice (Bowles et al, 2006) and rats (Livera et al, 2000b) and, similarly, that it is necessary to achieve meiosis in in-vitro-derived oocytes via PGCLCs (Miyauchi et al, 2017). Yet, its exact role in vivo is debated.
Whilst the relative levels of endogenous atRA produced by the ovary (for any species) remains unknown, similarly, the quantitative relationship between atRA levels and induction of meiosis also remains unclear. As such, the quantitative understanding of how much atRA needs to be reduced to prevent germ cells from entering meiosis in vivo is rated low.