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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

Decreased ALDH1A (RALDH) activity leading to decreased fertility via disrupted meiotic initiation of fetal oogonia

Short name
A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help
Decreased ALDH1A activity leading to decreased fertility
The current version of the Developer's Handbook will be automatically populated into the Handbook Version field when a new AOP page is created.Authors have the option to switch to a newer (but not older) Handbook version any time thereafter. More help
Handbook Version v2.0

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

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

Josephine Bowles, University of Queensland, Australia

Eleftheria M. Panagiotou, Karolinska Institute, Sweden

Pauliina Damdimopoulou, Karolinska Institute, Sweden

Johanna Zilliacus, Karolinska Institute, Sweden

Anna Beronius, Karolinska Institute, Sweden

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
Terje Svingen   (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

Coaches

This field is used to identify coaches who supported the development of the AOP.Each coach selected must be a registered author. More help
  • You Song

OECD Information Table

Provides users with information concerning how actively the AOP page is being developed and whether it is part of the OECD Workplan and has been reviewed and/or endorsed. OECD Project: Assigned upon acceptance onto OECD workplan. This project ID is managed and updated (if needed) by the OECD. OECD Status: For AOPs included on the OECD workplan, ‘OECD status’ tracks the level of review/endorsement of the AOP . This designation is managed and updated by the OECD. Journal-format Article: The OECD is developing co-operation with Scientific Journals for the review and publication of AOPs, via the signature of a Memorandum of Understanding. When the scientific review of an AOP is conducted by these Journals, the journal review panel will review the content of the Wiki. In addition, the Journal may ask the AOP authors to develop a separate manuscript (i.e. Journal Format Article) using a format determined by the Journal for Journal publication. In that case, the journal review panel will be required to review both the Wiki content and the Journal Format Article. The Journal will publish the AOP reviewed through the Journal Format Article. OECD iLibrary published version: OECD iLibrary is the online library of the OECD. The version of the AOP that is published there has been endorsed by the OECD. The purpose of publication on iLibrary is to provide a stable version over time, i.e. the version which has been reviewed and revised based on the outcome of the review. AOPs are viewed as living documents and may continue to evolve on the AOP-Wiki after their OECD endorsement and publication.   More help
OECD Project # OECD Status Reviewer's Reports Journal-format Article OECD iLibrary Published Version
1.97 Under Development
This AOP was last modified on December 18, 2024 09:43

Revision dates for related pages

Page Revision Date/Time
Decreased, ALDH1A (RALDH) enzyme activity December 17, 2024 12:04
Decreased, all-trans retinoic acid (atRA) concentration February 13, 2023 08:04
Disrupted, initiation of meiosis of oogonia in the ovary December 17, 2024 15:31
Decreased, size of the ovarian reserve December 17, 2024 15:22
decreased, Fertility December 17, 2024 15:46
disrupted, ovarian cycle December 17, 2024 15:41
Decreased, ALDH1A activity leads to Decreased, atRA concentration December 18, 2024 03:16
Decreased, atRA concentration leads to Disrupted, meiotic initiation in oocyte December 18, 2024 03:30
Disrupted, meiotic initiation in oocyte leads to Decreased, ovarian reserve December 18, 2024 06:36
Decreased, ovarian reserve leads to disrupted, ovarian cycle December 18, 2024 06:53
disrupted, ovarian cycle leads to decreased, 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

An initial scoping search of open literature was performed using pre-set search terms (appendix A), serving to collate an unbiased catalogue of literature beyond that of the AOP developer’s expertise, as well as content of a Draft Research Report on retinoid signaling and potential links to reproductive toxicity (Nilsson 2020). Based on this literature search (which yielded 97 publications) and expert knowledge, a putative AOP relevant for ovary development and female infertility was identified. A draft AOP including interim KEs and KERs were constructed, followed by preliminary essentiality assessments. Having established which modules to include in the AOP string, all KEs and KERs were developed as described individually.

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 Decreased, ALDH1A (RALDH) enzyme activity Decreased, ALDH1A activity
KE 1881 Decreased, all-trans retinoic acid (atRA) concentration Decreased, atRA concentration
KE 1882 Disrupted, initiation of meiosis of oogonia in the ovary Disrupted, meiotic initiation in oocyte
KE 1883 Decreased, size of the ovarian reserve Decreased, ovarian reserve
KE 405 disrupted, ovarian cycle disrupted, ovarian cycle
AO 406 decreased, Fertility decreased, 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 High

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 High

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 mouse studies, so the taxonomic applicability is strongest for this animal model. Studies have also been done in rats. Evidence for the same mechanisms in humans is less substantiated (Li & Clagett-Dame, 2009; Griswold et al, 2012; Spiller & Bowles, 2022; Jørgensen & Rajpert-De Meyts, 2014).

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

Event

Direct evidence

Uncertainties, inconsistencies, and contradictory evidence

MIE 1880

Decreased, ALDH1A activity

LOW: There is direct experimental evidence from KO studies that ALDH1A is essential for atRA synthesis. Some studies on KO and inhibition of ALDH1A show an effect on initiation of meiosis in ovary but there are contradictory studies.

  • KO of ALDH1A isoforms blocks atRA synthesis in vivo in mice (Niederreither et al, 1999, Dupé et al, 2003; Fan et al, 2003; Molotkov & Duester, 2003).
  • KO of ALDH1A1 results in delayed germ cell meiosis in mouse fetal embryos (Bowles et al., 2016).
  • Inhibition of ALDH1A2 in mouse ovary culture results in failure to induce expression of meiotic marker Stra8 and subsequent germ cell loss (Rosario et al, 2020).
  • Inhibition of ALDH1A in mouse ovary cultures blocked germ cell meiotic entry (Mu et al, 2013).
  • Inhibition of ALDH1 partially inhibits meiotic entry in human fetal ovaries (Le Bouffant et al, 2010)

KO of ALDH1A2 and double knockout of ALDH1A2 and ALDH1A3 showed no reduction of Stra8 expression in fetal ovary and ALDH1A2 knockout did not prevent meiotic initiation (Kumar et al., 2012).

Triple KO of ALDH1A1-3 showed a reduced Stra8 expression in fetal ovary but the knockout did not prevent meiotic initiation (Chassot,et al, 2020).

These results indicate that atRA synthesis is not the only determinant for initiation of meiosis in oocytes as discussed in Spiller & Bowles, 2022 and Shimada and Ishiguro, 2023.

KE1881

Decreased atRA concentration

LOW: Some studies show that atRA is essential for initiation of meiosis in ovary but there are contradictory studies.

  • Oocytes fail to enter meiosis in ovaries of vitamin A deficient rats due to atRA deficiency (Li & Clagett-Dame, 2009)
  • Inhibition of RAR in mouse embryonic ovary cultures results in failure to induce Stra8 expression (Bowles et al, 2006; Koubova et al, 2006; Minkina et al, 2017).
  • atRA activates meiosis-related gene network in mouse embryonic stem cells (Aoki & Takada, 2012), increases meiosis resumption in mouse oocytes (Tahaei et al, 2011), promote germ cell meiotic initiation in cultured fetal human ovaries (Le Bouffant et al, 2010), mouse ovaries (Livera et al, 2000), and chicken ovaries (Yu et al, 2013) and camel oocytes (Saadeldin et al, 2019). RAR agonist accelerates meiotic entry in mouse fetal oocytes (Livera et al, 2000).

Triple knockout of RAR-α, -β, -γ showed a reduced Stra8 expression in fetal ovary but the knockout did not prevent meiotic initiation (Vernet et al, 2020).

Mutation of two retinoic acid response elements (RAREs) in the Stra8 promoter in mice reduced Stra8 expression in fetal ovary but did not prevent meiotic initiation (Feng et al, 2021).

These results, together with the studies on ALDH1A KO, described above indicate that atRA is not the only determinant for initiation of meiosis in oocytes as discussed in Spiller & Bowles, 2022 and Shimada & Ishiguro, 2023.

KE1882

Disrupted, initiation of meiosis in oogonia

HIGH: There is direct evidence from experimental studies that disruption of meiosis in ovary results in reduced fertility.

  • In mice, ablation of Stra8 prevents oocytes from entering meiosis in the fetal ovaries and mature females are infertile (Baltus et al, 2006; Zhou et al, 2008).
  • Mutation in Atm, a gene involved in recombination during meiosis, results in complete loss of primary oocytes in mice, and greatly reduced follicle pool in humans (Adelfalk et al, 2011; Agamanolis & Greenstein, 1979; Aguilar et al, 1968; Xu et al, 1996).
  • Mutation to Fanca and Fancd2 genes that are involved in recombination lead to oocyte degeneration and subfertility in mice (Cheng et al, 2000; Houghtaling et al, 2003; Wong et al, 2003).
  • Mice with Lhx8 ablation display total loss of oocytes. Lhx8-/- mice maintain oocytes during fetal development, but loose the oocytes shortly after birth by autophagy, likely because the oocytes have failed to enter meiosis in utero (Choi et al, 2008; D'Ignazio et al, 2018).

KE1883

Decreased size of the ovarian reserve

MODERATE: There is indirect evidence that chemicals that reduce the ovarian reserve also affect the ovarian cycle.

INDIRECT EVIDENCE

  • In mice and rats, a chemically induced reduced follicle pool results in irregular cycles in vivo (Mayer et al, 2004, Lohff et al, 2005, Lohff et al, 2006, Mayer et al, 2002, Flaws et al, 1994, Hooser et al, 1994, Hu et al, 2018, Hannon et al, 2014, Xu et al, 2010).
  • In humans, chemotherapy can affect ovarian reserve as well as the menstrual cycle (Jacobson et al, 2016; Meirow et al., 2010). Smoking, that reduces primordial follicles in mice (Tuttle et al, 2009) is also associated with irregular cycles in humans (El-Nemr et al, 1998; Sharara et al, 1994).

Contradictory evidence:

Several chemotherapy agents damage ovarian reserve and disrupt folliculogenesis. However, it has been shown that regular menses can resume upon treatment cessation (Jacobson et al, 2016). Therefore, in this case reduced ovarian reserve did not lead to permanent irregularities of ovarian cycle. In a systematic review and meta-analysis investigating the connection between the ovarian reserve and the length of the menstrual cycle, studies are mentioned where reduced ovarian reserve markers did not associate with irregular menstrual cycles (Younis et al, 2020). Several factors affect the impact of chemotherapy on ovarian health in humans, including the age at the treatment, size of ovarian reserve at treatment, and treatment regimen. However, late side effects of chemotherapy often include amenorrhea, premature ovarian insufficiency, and infertility.

KE405

Disrupted, ovarian cycle

MODERATE: There is indirect evidence that chemicals that affect the ovarian cycle also cause impaired fertility.

INDIRECT EVIDENCE

  • In mice and rats, a chemically induced cycle irregularity is associated with impaired fertility in vivo (Blystone et al., 2010, Takai et al., 2009, NTP, 2005)

 

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
Modulating Factor (MF) Influence or Outcome KER(s) involved
     

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

Currently disrupted retinoid signaling is not directly tested for in OECD TG studies; however, in, for example, the identification of endocrine disruptors, the R-modality is highlighted as a pathway that should be included. Hence, this AOP provides added support for inclusion of retinoid signaling-relevant assays to be included in testing or screening strategies.

This AOP can be used to identify chemicals that inhibit ALDH1A activity (e.g., through in vitro assays for retinoic acid biosynthesis) as potential reproductive toxicants, facilitating prioritization for further testing. It also provides a mechanistic basis for linking molecular-level perturbations to reproductive outcomes, supporting weight-of-evidence approaches in regulatory risk assessment and justifying restrictions on chemicals identified as disrupting this pathway.

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

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