Aop: 398

Title

A descriptive phrase which references both the Molecular Initiating Event and Adverse Outcome.It should take the form “MIE leading to AO”. For example, “Aromatase inhibition leading to reproductive dysfunction” where Aromatase inhibition is the MIE and reproductive dysfunction the AO. In cases where the MIE is unknown or undefined, the earliest known KE in the chain (i.e., furthest upstream) should be used in lieu of the MIE and it should be made clear that the stated event is a KE and not the MIE. More help

Inhibition of ALDH1A (RALDH) causing reduced all-trans retinoic acid levels leading to impaired fertility, females

Short name
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Inhibition of ALDH1A leading to reduced fertility, female

Graphical Representation

A graphical representation of the AOP.This graphic should list all KEs in sequence, including the MIE (if known) and AO, and the pair-wise relationships (links or KERs) between those KEs. More help
Click to download graphical representation template Explore AOP in a Third Party Tool
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Authors

The names and affiliations of the individual(s)/organisation(s) that created/developed the AOP. More help

Monica Kam Draskau, Technical University of Denmark, Denmark

Cassy M. Spiller, University of Queensland, Australia

Hanna K.L. Johansson, Technical University of Denmark, Denmark

Josephine Bowles, University of Queensland, Australia

Louise Ramhøj, Technical University of Denmark, Denmark

Eleftheria M. Panagiotou, Karolinska Institute, Sweden

Pauliina Damdimopoulou, Karolinska Institute, Sweden

Anne-Sofie Ravn Ballegaard, Technical University of Denmark, Denmark

Sofie Christiansen, Technical University of Denmark, Denmark

Terje Svingen, Terchnical University of Denmark, Denmark

Point of Contact

The user responsible for managing the AOP entry in the AOP-KB and controlling write access to the page by defining the contributors as described in the next section.   More help
Cataia Ives   (email point of contact)

Contributors

Users with write access to the AOP page.  Entries in this field are controlled by the Point of Contact. More help
  • Terje Svingen
  • Cataia Ives

Status

Provides users with information concerning how actively the AOP page is being developed, what type of use or input the authors feel comfortable with given the current level of development, and whether it is part of the OECD AOP Development Workplan and has been reviewed and/or endorsed. OECD Status - Tracks the level of review/endorsement the AOP has been subjected to. OECD Project Number - Project number is designated and updated by the OECD. SAAOP Status - Status managed and updated by SAAOP curators. More help
Author status OECD status OECD project SAAOP status
Under development: Not open for comment. Do not cite Under Development 1.97 Included in OECD Work Plan
This AOP was last modified on July 16, 2022 18:37

Revision dates for related pages

Page Revision Date/Time
Inhibition of ALDH1A (RALDH) November 11, 2021 14:48
Decreased all-trans retinoic acid (atRA) concentration February 27, 2022 10:55
Disrupted meiotic initiation of fetal oogonia of the ovary February 27, 2022 10:59
Reduced size of the ovarian follicle pool November 11, 2021 14:57
impaired, Fertility December 02, 2016 09:21
irregularities, ovarian cycle November 29, 2016 19:09
ALDH1A (RALDH), inhibition leads to decreased, atRA concentration November 11, 2021 15:32
decreased, atRA concentration leads to Oocyte meiosis, disrupted February 27, 2022 10:51
Oocyte meiosis, disrupted leads to Ovarian follicle pool, reduced November 11, 2021 15:44
Ovarian follicle pool, reduced leads to irregularities, ovarian cycle November 12, 2021 08:36
irregularities, ovarian cycle leads to impaired, Fertility December 03, 2016 16:37

Abstract

A concise and informative summation of the AOP under development that can stand-alone from the AOP page. The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance. More help

This AOP links inhibition of ALDH1A during fetal life with female infertility in adulthood. A key step in this AOP is a reduction in all-trans retinoic acid (atRA) locally in the fetal ovary, which prevents resident germ cells (oocytes) from entering meiosis. Evidence for this AOP, especially upstream events, draws heavily from mouse studies, both genetic models and from exposure studies (including explanted ovaries). Human evidence is also available, especially for downstream events where the oocyte pool/ovarian reserve is known to directly impact on fertility. In reproductive toxicity (animal studies and human epidemiology) fertility is an apical endpoint of high importance and has strong utility for chemical safety assessments. Infertility can be caused by many, and varied, factors, but this AOP focusses on linking perturbed meiosis through disrupted atRA signaling during development, thus supporting the use of data from in silico and in vitro measurements for interference with nuclear receptor activity (RAR/RXR) and atRA synthesis/expression to infer potential to cause in vivo effects.

AOP Development Strategy

Context

Used to provide background information for AOP reviewers and users that is considered helpful in understanding the biology underlying the AOP and the motivation for its development.The background should NOT provide an overview of the AOP, its KEs or KERs, which are captured in more detail below. More help

In mammals, the primordial germ cells are initially ‘bipotential’. They will develop into either oocytes or gonocytes in ovaries or testis, respectively, depending on cues from the somatic environment. Germ cells in the developing testis will enter a quiescent state and reactivate at the onset of puberty. In contrast, germ cells in the developing ovary will enter meiosis (prophase I) during fetal life. A key signaling event for this sexual dimorphic germ cell programming is retinoid signaling, with all-trans retinoic acid (atRA) acting as a meiosis-inducing factor (Spiller & Bowles, 2019).

The source of atRA during ovary development differs to some degree between species. In mice, the adjacent mesonephros, which expresses two enzymes necessary for the final step in atRA production, ALDH1A2 and ALDH1A3, is likely the main source of atRA at early developmental stages (Bowles et al, 2018; Bowles et al, 2006; Koubova et al, 2006; Niederreither et al, 1999). There is also the capacity for atRA to be produced within the ovary itself, due to local expression of the atRA-synthesizing enzyme ALDH1A1 (Bowles et al, 2016; Mu et al, 2013).

In humans, ALDH1A enzymes (ALDH1A, -1B and -1C) are expressed in both testes and ovaries of the developing fetus, which suggest a capacity for de novo synthesis of atRA (Childs et al, 2011; Jørgensen & Rajpert-De Meyts, 2014; le Bouffant et al, 2010), as is also the case in rabbits (Díaz-Hernández et al, 2019). One team studying human fetal ovaries reported a peak of ALDH1A1 expression at the onset of meiosis (le Bouffant et al, 2010), suggesting that meiotic onset in the human ovary depends on provision of atRA at the correct time.  There seems to be conservation from rodent to human in terms of the requirement for atRA to induce the pre-meiotic factor STRA8. However, in mice atRA is produced by adjacent tissue and is present at high concentrations in the ovaries, whereas in human ovaries RA is present at only low levels and is then actively produced to induce meiosis in the ovary (Spiller & Bowles, 2019).

Strategy

Provides a description of the approaches to the identification, screening and quality assessment of the data relevant to identification of the key events and key event relationships included in the AOP or AOP network.This information is important as a basis to support the objective/envisaged application of the AOP by the regulatory community and to facilitate the reuse of its components.  Suggested content includes a rationale for and description of the scope and focus of the data search and identification strategy/ies including the nature of preliminary scoping and/or expert input, the overall literature screening strategy and more focused literature surveys to identify additional information (including e.g., key search terms, databases and time period searched, any tools used). More help

Summary of the AOP

This section is for information that describes the overall AOP. The information described in section 1 is entered on the upper portion of an AOP page within the AOP-Wiki. This is where some background information may be provided, the structure of the AOP is described, and the KEs and KERs are listed. More help

Events:

Molecular Initiating Events (MIE)
An MIE is a specialised KE that represents the beginning (point of interaction between a prototypical stressor and the biological system) of an AOP. More help
Key Events (KE)
A measurable event within a specific biological level of organisation. More help
Adverse Outcomes (AO)
An AO is a specialized KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help
Type Event ID Title Short name
MIE 1880 Inhibition of ALDH1A (RALDH) ALDH1A (RALDH), inhibition
KE 1881 Decreased all-trans retinoic acid (atRA) concentration decreased, atRA concentration
KE 1882 Disrupted meiotic initiation of fetal oogonia of the ovary Oocyte meiosis, disrupted
KE 1883 Reduced size of the ovarian follicle pool Ovarian follicle pool, reduced
KE 405 irregularities, ovarian cycle irregularities, ovarian cycle
AO 406 impaired, Fertility impaired, Fertility

Relationships Between Two Key Events (Including MIEs and AOs)

This table summarizes all of the KERs of the AOP and is populated in the AOP-Wiki as KERs are added to the AOP.Each table entry acts as a link to the individual KER description page. More help

Network View

This network graphic is automatically generated based on the information provided in the MIE(s), KEs, AO(s), KERs and Weight of Evidence (WoE) summary tables. The width of the edges representing the KERs is determined by its WoE confidence level, with thicker lines representing higher degrees of confidence. This network view also shows which KEs are shared with other AOPs. More help

Prototypical Stressors

A structured data field that can be used to identify one or more “prototypical” stressors that act through this AOP. Prototypical stressors are stressors for which responses at multiple key events have been well documented. More help

Life Stage Applicability

The life stage for which the AOP is known to be applicable. More help
Life stage Evidence
During development and at adulthood Moderate

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected.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. More help
Term Scientific Term Evidence Link
mouse Mus musculus High NCBI
rat Rattus norvegicus Moderate NCBI
human Homo sapiens Moderate NCBI

Sex Applicability

The sex for which the AOP is known to be applicable. More help
Sex Evidence
Female Moderate

Overall Assessment of the AOP

Addressess the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and Weight of Evidence (WoE) for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). More help

The majority of evidence supporting this AOP is derived from mouse studies, both in vitro (fetal ovary cultures) and in vivo (incl. genetic mouse models). There is also evidence from humans (in vitro ovary cultures), yet it is also recognized that there are some differences between mice and humans with regard to atRA synthesis, expression and potential role in meiotic initiation. Notably, an important link, yet not described as a separate key event, is the role for Stra8 in meiotic initiation alongside the established role for atRA to control Stra8 expression via RAR/RXR.

The evidence linking MIE with KE1 is considered as strong and regarded as canonical knowledge. Likewise, evidence for the downstream key events linking reduced oocyte pool/ovarian reserve with reduced fertility is very strong and regarded as canonical knowledge. The weak link in the overall AOP is the connection between reduced atRA levels and fertility via loss of oocytes during development. To strengthen this link, more evidence must be obtained; nevertheless, the remaining links are very strong and can be used to assess the impact of chemical stressors on female fertility. Yet, caution should be exercised with directly linking inhibition of ALDH1A2 with reduced fertility.

Domain of Applicability

Addressess the relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context. More help
  • Sex: This AOP applies to females. atRA is also involved in meiosis of testicular gonocytes, but this occurs postnatally. In the female ovaries, atRA induces meiosis of oocytes during gestation, thus the spatiotemporal expression of atRA in the ovaries are tightly controlled. Finally, as this AOP is concerned with establishing the ovarian reserve/follicle pool through mechanisms that are unique to ovaries, restricting the AOP to female only is appropriate.
  • Life stages: This AOP spans the period from mid- to late-gestation in mammals, all the way to adulthood where fertility is manifested. The upstream event pertains to fetal/neonatal life stages, whereas the downstream events pertain to adult reproductive life stages. 
  • Taxonomy: Strongest evidence for the role of atRA in regulating oocyte entry into meiosis stems from moue studies, so the taxonomic applicability is strongest for this animal model. Evidence also exists for the same modes of action being relevant across mammalian species, including human (Kalampokas et al, 2014), albeit the evidence for taxonomic applicability is still weaker.

Essentiality of the Key Events

The essentiality of KEs can only be assessed relative to the impact of manipulation of a given KE (e.g., experimentally blocking or exacerbating the event) on the downstream sequence of KEs defined for the AOP. Consequently, evidence supporting essentiality is assembled on the AOP page, rather than on the independent KE pages that are meant to stand-alone as modular units without reference to other KEs in the sequence. The nature of experimental evidence that is relevant to assessing essentiality relates to the impact on downstream KEs and the AO if upstream KEs are prevented or modified. This includes: Direct evidence: directly measured experimental support that blocking or preventing a KE prevents or impacts downstream KEs in the pathway in the expected fashion. Indirect evidence: evidence that modulation or attenuation in the magnitude of impact on a specific KE (increased effect or decreased effect) is associated with corresponding changes (increases or decreases) in the magnitude or frequency of one or more downstream KEs. More help

The critical first stage of this AOP is the lack of atRA in ovaries at the stage where oocytes need to enter meiosis during gestation. Failure to enter meiosis at the correct time during development is detrimental to oocyte development and ultimately this will compromise the follicle pool in adulthood; a non-renewable source for producing viable eggs for fertilization. However, reduced atRA is not defined as the MIE in this AOP, as atRA synthesis by the action of ALDH1A enzymes is required, and this synthesis step is a potential vulnerable point for chemical perturbation. 

  • MIE (Inhibition, ALDH1A): atRA is synthesized from dietary vitamin A in a two-step enzymatic process, where ALDH1A is responsible for the second, irreversible oxidation of retinal to atRA (Chatzi et al, 2013; Shannon et al, 2017).
  • KE1 (Decreased atRA): Although ALDH1A enzymes can make different retinoid metabolites (9-cis, 13-cis, all-trans), atRA is considered the only active metabolite in mammals (Krężel et al, 2019). atRA acts locally in tissues as a paracrine, short-range, signaling molecule (Teletin et al, 2017). In the mouse, atRA is synthesized in the adjacent mesonephros and diffuses into the gonad proper to establish local concentrations required for organogenesis (Chassot et al, 2020; Kumar et al, 2011), including prompting oocytes to enter meiosis (Bowles et al, 2006; Koubova et al, 2006). In humans, atRA appears to be synthesized locally in the ovary. This KE is essential for this AOP as represents the essential link between ALDH1A inhibition by chemicals with reduced fertility in adult females.
  • KE2 (disrupted meiosis): The downstream KE of this AOP, reduced follicle pool, can arise from multiple events, of which disrupted meiosis is only one. Nevertheless, disrupted meiosis is essential for this AOP in that it is the clear rational link between inhibited retinoid signaling and reduced fertility via diminished ovarian reserve. For meiosis to initiate in the mouse, oocytes need to express Stra8 (Baltus et al, 2006), a factor that is regulated by atRA via retinoid receptors RAR/RXR (Bowles et al, 2016; Bowles et al, 2006; Feng et al, 2021; Koubova et al, 2006). Although the role for atRA for initiating meiosis in humans is still under some debate, the role for Stra8 appears essential also for human oocytes to initiate meiosis (Childs et al, 2011).
  • KE3 (reduced ovarian reserve): In mammals, it is broadly accepted that females are born with a set number of follicles, termed the ovarian reserve, which is dependent on proper development, including meiotic initiation, during fetal life (Grive & Freiman, 2015). A large number of oocytes are lost during ovarian/oocyte development to ensure a quality ovarian reserve. However, a minimum amount of oocytes are required to establish and maintain adult reproductive function. Therefore this KE represents an essential step in the AOP, since falling below a critical number of follicles will lead to disrupted ovary function and irregular cyclicity (as normally occurs during menopause).
  • KE4 (irregular ovarian cycle): Female fertility depends on the ovarian cycle to produce competent follicles for ovulation and fertilization. Thus, this KE is an essential step in determining fertility status.  
  • AO impaired fertility, female: Fertility represents the capability to reproduce and as such is the essential AO of this AOP. It is measurable both at the individual and population level. Although the AO of this AOP (ID 406) describe impaired fertility independent of sex, the AOP is specific to females as it involves oocyte/ovary development and function.  

Evidence Assessment

Addressess the biological plausibility, empirical support, and quantitative understanding from each KER in an AOP. More help

Biological Plausibility, coherence, and consistency of the experimental evidence

The role for ALDH1A2 in the synthesis of atRA is well established as an essential component of regulating regional expression of retinoid species during development. It is also well established that atRA is an inducer of meiosis in germ cells in mice; however, there is some debate about the essentiality of atRA in this process in human fetal ovaries. The requirement for oocytes to enter the first phase of meiosis during fetal development is also well established, hence the biological plausibility linking meiotic failure with loss of oocytes at later developmental stages is strong.

Although non-meiotic oocytes can survive in germ cell nests and during nest breakdown, they will ultimately be eliminated from the oocyte pool of competent follicles. There is therefore a direct link between meiotic entry and fertility during adulthood. Thus, this AOP provides a plausible chain of events linking reduced atRA during fetal life with reduced ovarian reserve and fertility during reproductive age. The strength of the downstream KEs and KER – reduced ovarian reserve and reduced fertility – is very well documented and thus the biological plausibility is very strong. Evidence for a direct link between the AO and perturbed atRA synthesis, or reduced atRA levels, during early development comes mainly from mouse studies; yet the relationship is regarded biologically plausible also in humans, but with weight of evidence not being as strong. 

Concordance of dose-response relationships

The quantitative understanding of dose-response relationships in this AOP is limited. 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. Nevertheless, it is has been conclusively shown that low levels of exogenous atRA can induce mouse and rat germ cells to enter meiosis both in vitro and ex vivo (Bowles et al, 2006; Livera et al, 2000). Likewise, atRA is necessary to achieve meiosis in in vitro-derived oocytes via PGCLCs (Miyauchi et al, 2017).

Temporal concordance among the key events and the adverse outcome

This AOP bridges two different life stages: fetal/perinatal and adult/reproductive age. The adverse outcome is the result of perturbation taking place during early stages of ovary development. In mice, rats and humans, the oocytes must enter meiosis prophase in order to establish the follicle pool/ovarian reserve postnatally. Thus, the AOP focusses on chemical perturbations during fetal life, which occurs around E13-E16 in mice and E15-E18 is rats, or first trimester in humans (Peters, 1970), but the adverse outcome does not manifest until adulthood. 

There is strong temporal concordance between the various key events, from inhibition of ALDH1A2 (RALDH2) that leads to reduced atRA synthesis. In turn, atRA must be present in the fetal ovaries at the time when oocytes are supposed to enter meiosis mid-gestation in mice (or first trimester in human). With a significant reduction in available atRA the oocytes will not enter meiosis, ultimately leading to the downstream key event of loss of oocytes beyond what is normal. The number of oocytes, or the oocyte pool/ovarian reserve, in turn will affect ovary function and fertility at reproductive stages, hence the temporal sequence of events is rational based on the biological process.

Strength, consistency, and specificity of association of adverse effect and initiating event

In mice, there is strong evidence to support the view that atRA is an inducer of meiosis in germ cells, with consistent results from in vitro (PGCLCs), ex vivo (ovary cultures) and in vivo studies as listed under KE 2477. There is strong evidence showing the importance of RA for female fertility, but this relates to many aspects of reproductive development and function from fetal life to adulthood, including maintaining pregnancy (Clagett-Dame & Knutson, 2011). Thus, it can be difficult to distill exactly how atRA-controlled meiotic entry of oocytes directly link to reduced fertility. Nevertheless, a direct relationship is strongly supported by the fact that Stra8-depleted mice are infertile with small ovaries lacking oocytes (Baltus et al, 2006) and that Stra8 induction in germ cells is controlled by atRA in mice, rats and humans (Bowles et al, 2006; Childs et al, 2011; Koubova et al, 2006; Livera et al, 2000). Furthermore, vitamin A-deficient (VAD) mice display delayed or failed meiotic entry of fetal oocytes depending on level of Vitamin A deficiency (Li & Clagett-Dame, 2009).

Uncertainties, inconsistencies and data gaps

In mice, there is strong evidence to support the view that atRA is important for initiating meiosis in germ cells (Bowles et al, 2016; Spiller et al, 2017; Teletin et al, 2017). Some studies suggest that atAR is not critical but important for meiotic entry under normal physiological conditions by evidencing meiosis in Aldh1a1, Aldh1a2 and Aldh1a3 ablated mice, individually and in tandem (Bellutti et al, 2019; Chassot et al, 2020; Kumar et al, 2011); however, additional studies have shown redundant roles between all three Aldha isoforms which can compensate for deletion of one or two (Bowles et al, 2016). More specifically, both double (Aldh1a2/3) and triple (Aldh1a1/2/3) knockout mouse models display reduced Stra8 expression in oocytes, yet oocytes eventually go through meiosis, which could suggest a redundant role for atRA for meiosis in the ovaries (Chassot et al, 2020; Kumar et al, 2011). A similar phenotype with reduced Stra8 expression but eventual meiotic initiation is seen for deletion of atRA receptors RAR-α, -β, -γ) in mice (Vernet et al, 2020). But, although RAR knockouts were also capable of producing offspring, it remains unclear if any of the above-mentioned mouse models display impaired fertility or whether the size of their oocyte pools are affected.

Known Modulating Factors

Modulating factors (MFs) may alter the shape of the response-response function that describes the quantitative relationship between two KES, thus having an impact on the progression of the pathway or the severity of the AO.The evidence supporting the influence of various modulating factors is assembled within the individual KERs. More help

Quantitative Understanding

Optional field to provide quantitative weight of evidence descriptors.  More help

This AOP is still largely qualitative, as the quantitative understanding between chemical potency and perturbation of KEs are insufficient. This relates to the dose-response relationship between concentrations of atRA in the ovary relative to meiotic initiation of oocytes. It also relates to the relationship between number of lost oocytes during development relative to the oocyte pool/ovarian reserve, as there naturally is a large loss of oocytes during development.

Considerations for Potential Applications of the AOP (optional)

Addressess potential applications of an AOP to support regulatory decision-making.This may include, for example, possible utility for test guideline development or refinement, development of integrated testing and assessment approaches, development of (Q)SARs / or chemical profilers to facilitate the grouping of chemicals for subsequent read-across, screening level hazard assessments or even risk assessment. More help

References

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

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, Feng CW, Miles K, Inseson J, Spiller CM, Koopman P (2016) ALDH1A1 provides a source of meiosis-inducing retinoic acid in mouse fetal ovaries. Nat Commun 7: 10845

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

Chatzi C, Cunningham TJ, Duester G (2013) Investigation of retinoic acid function during embryonic brain development using retinaldehyde-rescued Rdh10 knockout mice. Dev Dyn 242: 1056-1065

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

Clagett-Dame M, Knutson D (2011) Vitamin A in Reproduction and Development. Nutrients 3: 385-428

Díaz-Hernández V, Caldelas I, Merchant-Larios H (2019) Gene Expression in the Supporting Cells at the Onset of Meiosis in Rabbit Gonads. Sex Dev 13: 125-136

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

Grive KJ, Freiman RN (2015) The developmental origins of the mammalian ovarian reserve. Development 142: 2554-2563

Jørgensen A, Rajpert-De Meyts E (2014) Regulation of meiotic entry and gonadal sex differentiation in the human: normal and disrupted signaling. Biomol Concepts 5: 331-341

Kalampokas T, Shetty A, Maheswari A (2014) Vitamin A Deficiency and Female Fertility Problems: A Case Report and Mini Review of the Literature. J Women's Health Care 3: 6

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

Krężel W, Rühl R, de Lera AR (2019) Alternative retinoid X receptor (RXR) ligands. Mol Cell Endocrinol 491: 110436

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

le Bouffant R, Guerquin MJ, Duquenne C, Frydman N, Coffigny H, Rouiller-Fabre V, Frydman R, Habert R, Livera G (2010) Meiosis initiation in the human ovary requires intrinsic retinoic acid synthesis. Hum Reprod 25: 2579-2590

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

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

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

Mu X, Wen J, Guo M, Wang J, Li G, Wang Z, Teng Z, Cui Y, Xia G (2013) Retinoic acid derived from the fetal ovary initiates meiosis in mouse germ cells. J Cell Physiol 228: 627-639

Niederreither K, Subbarayan V, Dollé P, Chambon P (1999) Embryonic retinoic acid synthesis is essential for early mouse post-implantation development. Nat Genet 21: 444-448

Peters H (1970) Migration of gonocytes into the mammalian gonad and their differentiation. Philos Trans R Soc Lond B Biol Sci 259: 91-101

Shannon SR, Moise AR, Trainor PA (2017) New insights and changing paradigms in the regulation of vitamin A metabolism in development. Wiley Interdiscip Rev Dev Biol 6: 10.1002/wdev.1264

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

Teletin M, Vernet N, Ghyselinck NB, Mark M (2017) Roles of Retinoic Acid in Germ Cell Differentiation. Curr Top Dev Biol 125: 191-225

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