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Relationship: 2527

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

increased atRA concentration leads to premature meiosis, male germ cells

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes. Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

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 Do not cite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

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 KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help
Term Scientific Term Evidence Link
mouse Mus musculus High NCBI
rat Rattus norvegicus Moderate NCBI
human Homo sapiens Low NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Male High

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help
Term Evidence
Fetal Moderate

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

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.

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER.  For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

The majority of evidence for this KER is derived from rodent studies. Gonad explants are predominantly used for evidence supporting this KER in humans.

The overall strength of evidence will be evaluated upon further studies of relevant literature included from the literature search.

Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help

In mammalian germ cells, expression of the pre-meiotic marker Stimulated by retinoic acid gene 8 (Stra8) is a critical factor for meiotic onset and progression (Baltus et al, 2006; Bowles et al, 2006; Feng et al, 2021; Koubova et al, 2014; Koubova et al, 2006). In male mice lacking Stra8, the germ cells fail to initiate meiosis at puberty (Anderson et al, 2008), which has also been shown to be the case in the fetal female (Baltus et al, 2006) underlining that Stra8 seems to be required for correct meiotic initiation in both sexes. Though the mechanistic details of the spatiotemporal regulation of Stra8 are yet unclear, robust evidence suggests that atRA is a main regulator of Stra8 expression (Griswold et al, 2012). Germ cells from embryos from pregnant vitamin A (the precursor of atRA) deficient rats fail to upregulate Stra8 and enter meiosis (Li & Clagett-Dame, 2009) and several functional atRA response elements have been identified within the Stra8 promoter (Feng et al, 2021).

In the fetal male, somatic expression of the cytochrome P450 (CYP) enzyme CYP26B1 ensures atRA degradation, thus avoiding initiation of meiosis (Bowles et al, 2018; Bowles et al, 2006; Koubova et al, 2006; Li et al, 2009; MacLean et al, 2007). However, if atRA is not cleared effectively, male germ cells will initiate expression of Stra8, and aberrantly enter meiosis (Bowles et al, 2006; Koubova et al, 2006).

Genetic deletion of Cyp26b1 in mice increases endogenous atRA levels in the fetal testis and the germ cells abnormally start to express Stra8 and enter meiosis (Bowles et al, 2006; MacLean et al, 2007). Exogenous atRA can stimulate male germ cells to induce Stra8 expression and meiosis in mouse testis explants (Bowles et al, 2006; Koubova et al, 2006; Trautmann et al, 2008).

This effect seems to be conserved in humans, though limited studies are available. A key difference, however, has been the observation that CYP26B1 is expressed at equal or even higher levels in the fetal ovary than in the fetal human testis (Childs et al, 2011; Jørgensen et al, 2012). This is in contrast to the sexually dimorphic expression patterns observed in fetal rodents. Lastly, in accordance with the above mentioned rodent studies, single cell suspension cultures of human fetal testes showed increased STRA8 expression in response to exogenous atRA, however, no effect was observed on the gene expression of meiosis markers SYCP3 and DMC1 (Childs et al, 2011).

Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

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).

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help
Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help

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.

Time-scale
Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help
Known Feedforward/Feedback loops influencing this KER
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

References

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

Anderson EL, Baltus AE, Roepers-Gajadien HL, Hassold TJ, de Rooij DG, van Pelt AMM, Page DC (2008) Stra8 and its inducer, retinoic acid, regulate meiotic initiation in both spermatogenesis and oogenesis in mice. Proc Natl Acad Sci U S A 105: 14976-14980

Aoki T, Takada T (2012) Bisphenol A modulates germ cell differentiation and retinoic acid signaling in mouse ES cells. Reprod Toxicol 34: 463-470

Baltus AE, Menke DB, Hu YC, Goodheart ML, Carpenter AE, de Rooij DG, Page DC (2006) In germ cells of mouse embryonic ovaries, the decision to enter meiosis precedes premeiotic DNA replication. Nat Genet 38: 1430-1434

Bellutti L, Abby E, Tourpin S, Messiaen S, Moison D, Trautmann E, Guerquin MJ, Rouiller-Fabre V, Habert R, Livera G (2019) Divergent Roles of CYP26B1 and Endogenous Retinoic Acid in Mouse Fetal Gonads. Biomolecules 9: 536

Bowles J, Feng CW, Inseson J, Miles K, Spiller CM, Harley VR, Sinclair AH, Koopman P (2018) Retinoic Acid Antagonizes Testis Development in Mice. Cell Rep 24: 1330-1341

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

Chassot AA, Le Rolle M, Jolivet G, Stevant I, Guigonis JM, Da Silva F, Nef S, Pailhoux E, Schedl A, Ghyselinck NB, Chaboissier MC (2020) Retinoic acid synthesis by ALDH1A proteins is dispensable for meiosis initiation in the mouse fetal ovary. Sci Adv 6: eaaz1261

Childs AJ, Cowan G, Kinnell HL, Anderson RA, Saunders PTK (2011) Retinoic Acid signalling and the control of meiotic entry in the human fetal gonad. PLoS One 6: e20249

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

Griswold MD, Hogarth CA, Bowles J, Koopman P (2012) Initiating meiosis: the case for retinoic acid. Biol Reprod 86: 35

Jørgensen A, Nielsen JE, Blomberg Jensen M, Græm N, Rajpert-De Meyts E (2012) Analysis of meiosis regulators in human gonads: a sexually dimorphic spatio-temporal expression pattern suggests involvement of DMRT1 in meiotic entry. Mol Hum Reprod 18: 523-534

Koubova J, Hu YC, Bhattacharyya T, Soh YQS, Gill ME, Goodheart ML, Hogarth CA, Griswold MD, Page DC (2014) Retinoic acid activates two pathways required for meiosis in mice. PLoS Genet 10: e1004541

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

Kumar S, Chatzi C, Brade T, Cunningham TJ, Zhao X, Duester G (2011) Sex-specific timing of meiotic initiation is regulated by Cyp26b1 independent of retinoic acid signalling. Nat Commun 2: 151

Li H, Clagett-Dame M (2009) Vitamin A deficiency blocks the initiation of meiosis of germ cells in the developing rat ovary in vivo Biol Reprod 81: 996-1001

Li H, MacLean G, Cameron D, Clagett-Dame M, Petkovich M (2009) Cyp26b1 expression in murine Sertoli cells is required to maintain male germ cells in an undifferentiated state during embryogenesis. PLoS One 4: e7501

Livera G, Rouiller-Fabre V, Durand P, Habert R (2000a) Multiple effects of retinoids on the development of Sertoli, germ, and Leydig cells of fetal and neonatal rat testis in culture. Biol Reprod 62: 1303-1314

Livera G, Rouiller-Fabre V, Valla J, Habert R (2000b) Effects of retinoids on the meiosis in the fetal rat ovary in culture. Mol Cell Endocrinol 165: 225-231

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

Miyauchi H, Ohta H, Nagaoka S, Nakaki F, Sasaki K, Hayashi K, Yabuta Y, Nakamura T, Yamamoto T, Saitou M (2017) Bone morphogenetic protein and retinoic acid synergistically specify female germ-cell fate in mice. EMBO J 36: 3100-3119

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

Vernet N, Condrea D, Mayere C, Féret B, Klopfenstein M, Magnant W, Alunni V, Teletin M, Souali-Crespo S, Nef S, Mark M, Ghyselinck NB (2020) Meiosis occurs normally in the fetal ovary of mice lacking all retinoic acid receptors. Sci Adv 6: eaaz1139