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Relationship: 2481

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

Oocyte meiosis, disrupted leads to Ovarian follicle pool, reduced

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
Inhibition of ALDH1A (RALDH) leading to impaired fertility via disrupted meiotic initiation of fetal oogonia of the ovary adjacent Moderate Moderate Cataia Ives (send email) Under development: Not open for comment. Do not cite Under Development

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
human Homo sapiens High NCBI
mouse Mus musculus High NCBI
rat Rattus norvegicus High NCBI

Sex Applicability

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

Life Stage Applicability

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

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

The establishment of the primordial follicle pool is a multistep process that spans from early fetal life to reproductive maturity. This period of time varies greatly between species, lasting only a few weeks in mice and rats, but years in humans (Tingen et al, 2009). One important process is for the mitotic primordial germs cells to enter meiosis prior to cyst formation (Findlay et al, 2015; Tingen et al, 2009). Notably, in females there is a massive loss of oocytes between cyst formation and time of maturity, and the exact mechanisms behind this oocyte degradation is not well understood (Findlay et al, 2015; Sun et al, 2017).

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

It is well established that disruption to meiosis during oocyte development can lead to     sub-/infertility in females at reproductive age. There are numerous gene mutation in mice showing links between meiotic defects and fertility phenotypes, as well as associations to female fertility phenotypes in humans (Adelfalk et al, 2011).

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

Although the entry into meiosis is required for oocyte development, the relationship between meiotic entry and final oocyte reserve remains unclear. However, there are strong correlations between disrupted meiosis and infertility (or aneuploidy) in females (Handel & Schimenti, 2010). For instance, 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). Other examples include Fanca and Fancd2 genes that are involved in recombination. Mutations to these genes 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). Fzr1 is a regulator of mitotic cell division. When conditionally ablated from the germ cells, female mice display premature ovarian failure by 5 months of age and are subfertile; oocytes are lost in utero during early meiotic prophase I (Holt et al, 2014).

CYP51 (lanosterol 14 α-demethylase) is expressed by fetal oocytes and is involved in meiotic regulation (Mu et al, 2018).  Inhibition of CYP51 activity reduces the formation of primordial follicles (Zhang et al, 2009) by disrupting entry into diplotene stage (Mu et al, 2018). Importantly, retinoic acid induces nuclear translocation of CYP51 in oocytes at the onset of meiosis (Mu et al, 2018)

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

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

atRA is synthesized from vitamin A in a two-step enzymatic pathway. Vitamin A is required from the diet; hence, dietary changes to vitamin A can greatly affect the level of available atRA and thus modulate atRA-regulated responses.

Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help

The ovarian follicle pool (ovarian reserve) refers to the final number of primordial follicles in the mature ovary and is established through a series of events. In most mammals, it is determined during gestation or just after birth and relies on i) how many germ cells were established during embryogenesis, ii) their proliferation during migration and early ovary development, iii) death rate during oogenesis and iv) formation of primordial follicles at nest breakdown (Findlay et al, 2015). The last two stages, which includes nest formation and breakdown, is largely influenced by the mitotic-meiotic transition, in that oocytes that have failed to enter meiosis may contribute to the cysts population, but only high quality oocytes in meiotic prophase are spared during cyst breakdown (Findlay et al, 2015). Thus, there is a response-response relationship between meiotic entry and final follicle pool, albeit the quantitative relationship is not that well understood.

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

The time-scale for oocyte mitotic-meiotic transition and subsequent nest breakdown varies between species, but generally takes place from mid gestation to around the time of birth. In mice, meiosis and nest formation is initiated from around E13, whereas in humans it initiates at around GW12-14 (Childs et al, 2012; Findlay et al, 2015; Grive & Freiman, 2015; Pepling, 2006; Tingen et al, 2009). Nest breakdown starts just before birth in mice and completes around postnatal day 5 (Grive & Freiman, 2015; Pepling, 2006). In humans, nest breakdown takes place during second trimester (Grive & Freiman, 2015; Tingen et al, 2009)

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

Adelfalk C, Ahmed EA, Scherthan H (2011) Reproductive Phenotypes of Mouse Models Illuminate Human Infertility. J Reproduktionsmed Endokrinol 8: 376-383

Agamanolis DP, Greenstein JI (1979) Ataxia-telangiectasia. Report of a case with Lewy bodies and vascular abnormalities within cerebral tissue. J Neuropathol Exp Neurol 38: 475-489

Aguilar MJ, Kamoshita S, Landing BH, Boder E, Sedgwick RP (1968) Pathological observations in ataxia-telangiectasia. A report of five cases. J Neuropathol Exp Neurol 27: 659-676

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

Cheng NC, van de Vrugt HJ, van der Valk MA, Oostra AB, Krimpenfort P, de Vries Y, Joenje H, Berns A, Arwert F (2000) Mice with a targeted disruption of the Fanconi anemia homolog Fanca. Hum Mol Genet 9: 1805-1811

Childs AJ, Kinnell HL, He J, Anderson RA (2012) LIN28 is selectively expressed by primordial and pre-meiotic germ cells in the human fetal ovary. Stem Cells Dev 21: 2343-2349

Choi Y, Ballow DJ, Xin Y, Rajkovic A (2008) Lim homeobox gene, lhx8, is essential for mouse oocyte differentiation and survival. Biol Reprod 79: 442-449

D'Ignazio L, Michel M, Beyer M, Thompson K, Forabosco A, Schlessinger D, Pelosi E (2018) Lhx8 ablation leads to massive autophagy of mouse oocytes associated with DNA damage. Biol Reprod 98: 532-542

Dean A, van den Driesche S, Wang Y, McKinnell C, Macpherson S, Eddie SL, Kinnell HL, Hurtado-Gonzalez P, Chambers TJ, Stevenson K, Wolfinger E, Hrabalkova L, Calarrao A, Bayne RA, Hagen CP, Mitchell RT, Anderson RA, Sharpe RM (2016) Analgesic exposure in pregnant rats affects fetal germ cell development with inter-generational reproductive consequences. Sci Rep 6: 19789

Findlay JK, Hutt KJ, Hickey M, Anderson RA (2015) How Is the Number of Primordial Follicles in the Ovarian Reserve Established? Biol Reprod 93: 111

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

Handel MA, Schimenti JC (2010) Genetics of mammalian meiosis: regulation, dynamics and impact on fertility. Nat Rev Genet 11: 124-136

Holt JE, Pye V, Boon E, Stewart JL, García-Higuera I, Moreno S, Rodríguez R, Jones KT, McLaughlin EA (2014) The APC/C activator FZR1 is essential for meiotic prophase I in mice. Development 141: 1354-1365

Houghtaling S, Timmers C, Noll M, Finegold MJ, Jones SN, Meyn MS, Grompe M (2003) Epithelial cancer in Fanconi anemia complementation group D2 (Fancd2) knockout mice. Genes Dev 17: 2021-2035

Mu X, Wen J, Chen Q, Wang Z, Wang Y, Guo M, Yang Y, Xu J, Wei Z, Xia G, Yang M, Wang C (2018) Retinoic acid-induced CYP51 nuclear translocation promotes meiosis prophase I process and is correlated to the expression of REC8 and STAG3 in mice. Biol Open 7: bio035626

Pepling ME (2006) From primordial germ cell to primordial follicle: mammalian female germ cell development. Genesis 44: 622-632

Sun YC, Sun XF, Dyce PW, Shen W, Chen H (2017) The role of germ cell loss during primordial follicle assembly: a review of current advances. Int J Biol Sci 13: 449-457

Tingen C, Kim A, Woodruff TK (2009) The primordial pool of follicles and nest breakdown in mammalian ovaries. Mol Hum Reprod 15: 795-803

Wong JCY, Alon N, Mckerlie C, Huang JR, Meyn MS, Buchwald M (2003) Targeted disruption of exons 1 to 6 of the Fanconi Anemia group A gene leads to growth retardation, strain-specific microphthalmia, meiotic defects and primordial germ cell hypoplasia. Hum Mol Genet 12: 2063-2076

Xu Y, Ashley T, Brainerd EE, Bronson RT, Meyn MS, Baltimore D (1996) Targeted disruption of ATM leads to growth retardation, chromosomal fragmentation during meiosis, immune defects, and thymic lymphoma. Genes Dev 10: 2411-2422

Zhang H, Xu B, Xie H, Zhou B, Quyang H, Ning G, Li G, Zhang M (2009) Lanosterol metabolic product(s) is involved in primordial folliculogenesis and establishment of primordial follicle pool in mouse fetal ovary. Mol Reprod Dev 76: 514-521

Zhang HQ, Zhang XF, Zhang LJ, Chao HH, Pan B, Feng YM, Li L, Sun XF, Shen W (2012) Fetal exposure to bisphenol A affects the primordial follicle formation by inhibiting the meiotic progression of oocytes. Mol Biol Rep 39: 5651-5657

Zhang XF, Zhang T, Han Z, Liu JC, Liu YP, Ma JY, Li L, Shen W (2015) Transgenerational inheritance of ovarian development deficiency induced by maternal diethylhexyl phthalate exposure. Reprod Fertil Dev 27: 1213-1221

Zhou Q, Nie R, Li Y, Friel P, Mitchell D, Hess RA, Small C, Griswold MD (2008) Expression of Stimulated by Retinoic Acid Gene 8 (Stra8) in Spermatogenic Cells Induced by Retinoic Acid: An In Vivo Study in Vitamin A-Sufficient Postnatal Murine Testes. Biol Reprod 79: 35-42