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Event: 1882

Key Event Title

The KE title should describe a discrete biological change that can be measured. It should generally define the biological object or process being measured and whether it is increased, decreased, or otherwise definably altered relative to a control state. For example “enzyme activity, decreased”, “hormone concentration, increased”, or “growth rate, decreased”, where the specific enzyme or hormone being measured is defined. More help

Disrupted meiotic initiation of fetal oogonia of the ovary

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. The short name should be less than 80 characters in length. More help
Oocyte meiosis, disrupted

Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. Note, KEs should be defined within a particular level of biological organization. Only KERs should be used to transition from one level of organization to another. Selection of the level of biological organization defines which structured terms will be available to select when defining the Event Components (below). More help
Level of Biological Organization
Cellular

Cell term

Further information on Event Components and Biological Context may be viewed on the attached pdf.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable. More help

Organ term

Further information on Event Components and Biological Context may be viewed on the attached pdf.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable. More help
Organ term
ovary sex cord

Key Event Components

Further information on Event Components and Biological Context may be viewed on the attached pdf.Because one of the aims of the AOP-KB is to facilitate de facto construction of AOP networks through the use of shared KE and KER elements, authors are also asked to define their KEs using a set of structured ontology terms (Event Components). In the absence of structured terms, the same KE can readily be defined using a number of synonymous titles (read by a computer as character strings). In order to make these synonymous KEs more machine-readable, KEs should also be defined by one or more “event components” consisting of a biological process, object, and action with each term originating from one of 22 biological ontologies (Ives, et al., 2017; See List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signalling by that receptor).Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. More help

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE. Clicking on the name of the AOP will bring you to the individual page for that AOP. More help
AOP Name Role of event in AOP Point of Contact Author Status OECD Status
Inhibition of ALDH1A leading to reduced fertility, female KeyEvent Cataia Ives (send email) Under development: Not open for comment. Do not cite Under Development

Stressors

This is a structured field used to identify specific agents (generally chemicals) that can trigger the KE. Stressors identified in this field will be linked to the KE in a machine-readable manner, such that, for example, a stressor search would identify this as an event the stressor can trigger. NOTE: intermediate or downstream KEs in one AOP may function as MIEs in other AOPs, meaning that stressor information may be added to the KE description, even if it is a downstream KE in the pathway currently under development.Information concerning the stressors that may trigger an MIE can be defined using a combination of structured and unstructured (free-text) fields. For example, structured fields may be used to indicate specific chemicals for which there is evidence of an interaction relevant to this MIE. By linking the KE description to a structured chemical name, it will be increasingly possible to link the MIE to other sources of chemical data and information, enhancing searchability and inter-operability among different data-sources and knowledgebases. The free-text section “Evidence for perturbation of this MIE by stressor” can be used both to identify the supporting evidence for specific stressors triggering the MIE as well as to define broad chemical categories or other properties that classify the stressors able to trigger the MIE for which specific structured terms may not exist. More help

Taxonomic Applicability

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

Life Stages

The structured ontology terms for life-stage are more comprehensive than those for taxa, but may still require further description/development and explanation in the free text section. More help
Life stage Evidence
Foetal High
Development High

Sex Applicability

The authors must select from one of the following: Male, female, mixed, asexual, third gender, hermaphrodite, or unspecific. More help
Term Evidence
Female High

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. For example, the biological state being measured could be the activity of an enzyme, the expression of a gene or abundance of an mRNA transcript, the concentration of a hormone or protein, neuronal activity, heart rate, etc. The biological compartment may be a particular cell type, tissue, organ, fluid (e.g., plasma, cerebrospinal fluid), etc. The role in the biology could describe the reaction that an enzyme catalyses and the role of that reaction within a given metabolic pathway; the protein that a gene or mRNA transcript codes for and the function of that protein; the function of a hormone in a given target tissue, physiological function of an organ, etc. Careful attention should be taken to avoid reference to other KEs, KERs or AOPs. Only describe this KE as a single isolated measurable event/state. This will ensure that the KE is modular and can be used by other AOPs, thereby facilitating construction of AOP networks. More help

Oocyte meiosis

Oogonia, the female germ cells, are the precursors for the female oocytes. Primary oocytes are formed in the ovaries during fetal development when oogonia enter into prophase I of meiosis; meiotic entry initiates at around embryonic (E) day 13.5 in mice, E15.5 in rats, and gestational week 10-12 in humans. The entry into meiosis is driven by expression of the key genes Stra8, Meiosin and Rec8 and is followed by expression of meiotic proteins including SYCP3 and γH2AX (Baltus et al, 2006; Bowles et al, 2006; Ishiguro et al, 2020; Kojima et al, 2019; Koubova et al, 2014; Spiller et al, 2017). The crucial role for Stra8 in meiotic entry is conserved from mice to humans (Childs et al, 2011).

Disrupted meiotic entry as Key Event

The initiation of meiosis during fetal life is critical for maintenance of the oocytes throughout development and, eventually, for establishing the oocyte pool, or ‘oocyte reserve’ at birth. Without timely fetal entry into meiosis, the oogonia are depleted, as evidenced in Stra8-null mice (Baltus et al, 2006). The Stra8-null female mice are infertile and display abnormally small ovaries that are devoid of oocytes. For Stra8 to be expressed and, therefore, for meiosis to initiate, the oogonia require direct stimulation by atRA as evidenced in mice (Bowles et al, 2016; Bowles et al, 2006; Feng et al, 2021; Koubova et al, 2006; Spiller et al, 2017; Teletin et al, 2017), and humans (Childs et al, 2011; Le Bouffant et al, 2010).

How It Is Measured or Detected

One of the primary considerations in evaluating AOPs is the relevance and reliability of the methods with which the KEs can be measured. The aim of this section of the KE description is not to provide detailed protocols, but rather to capture, in a sentence or two, per method, the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements. Methods that can be used to detect or measure the biological state represented in the KE should be briefly described and/or cited. These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA).Key considerations regarding scientific confidence in the measurement approach include whether the assay is fit for purpose, whether it provides a direct or indirect measure of the biological state in question, whether it is repeatable and reproducible, and the extent to which it is accepted in the scientific and/or regulatory community. Information can be obtained from the OECD Test Guidelines website and the EURL ECVAM Database Service on Alternative Methods to Animal Experimentation (DB-ALM). ?

There are no OECD-validated assays for measuring meiotic inhibition.

The expression of meiotic factors, such as STRA8, SYCP3, γH2AX, can be assessed at mRNA and/or protein levels and levels measured using primers/probes and antibodies that are commercially available.

Indirect measurements in animal models can be performed using the Stra8 promoter element driving expression of reporter protein GFP (Feng et al, 2021). This reporter assay can detect the presence (GFP) or absence (GFP negative) of Stra8 promoter activation in a semi-quantitative manner.

Domain of Applicability

This free text section should be used to elaborate on the scientific basis for the indicated domains of applicability and the WoE calls (if provided). While structured terms may be selected to define the taxonomic, life stage and sex applicability (see structured applicability terms, above) of the KE, the structured terms may not adequately reflect or capture the overall biological applicability domain (particularly with regard to taxa). Likewise, the structured terms do not provide an explanation or rationale for the selection. The free-text section on evidence for taxonomic, life stage, and sex applicability can be used to elaborate on why the specific structured terms were selected, and provide supporting references and background information.  More help

Fetal oocytes need to enter meiosis prophase I to maintain the oocyte population and establish the oocyte pool. This process in conserver between mice, rats and humans.

Evidence for Perturbation by Stressor

Acetaminophen

Paracetamol (acetaminophen) exposure (350 mg/kg bw/d between 13.5-21.5 dpc) delayed meiotic entry in rat fetal ovaries, seen with delayed Stra8 expression (Dean et al, 2016). In mice, paracetamol exposure (50 and 150 mg/kg bw/day, from 7 dpc-birth) did not affect Stra8 expression, yet oocyte numbers were decreased (Holm et al, 2016).

Indomethacin

Indomethacin exposure delays meiotic entry in rat fetal ovaries, seen with delayed Stra8 expression (Dean et al, 2016).

Bis(2-ethylhexyl) phthalate

Diethyl hexyl phthalate (DEHP) exposure at a dose of 40 mg kg-1 from E0.5 to E18.5, caused delayed meiosis of oocytes, evident by delayed Stra8 expression and meiotic progression determined by SYCP3 staining of chromosome spreads (Zhang et al, 2015). An in vitro model reported the same delay to meiosis when E12.5 ovaries were cultured in 10 µM and 100 µM concentrations of DEHP (Liu et al, 2017).

Bisphenol A

Bisphenol A (BPA) exposure may delay entry into meiotic prophase I in mice, potentially through reduced Stra8 expression (Zhang et al, 2012). This effect from BPA exposure was not seen in a second mouse study (Lawson et al, 2011), nor in human ovary explant cultures (Brieño-Enríquez et al, 2012). As such, it remains uncertain if BPA can prevent oocytes from entering meiosis.  

References

List of the literature that was cited for this KE description. Ideally, the list of references, should conform, to the extent possible, with the OECD Style Guide (https://www.oecd.org/about/publishing/OECD-Style-Guide-Third-Edition.pdf) (OECD, 2015). 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

Bowles J, Feng CW, Miles K, Ineson J, Spiller C, 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

Brieno-Enriquez MA, Reig-Viader R, Cabero L, Toran N, Martinez F, Roig I, Garcia Caldes M (2012) Gene expression is altered after bisphenol A exposure in human fetal oocytes in vitro. Mol Hum Reprod 18: 171-183

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

Dean A, van den Driesche S, Wang Y, McKinnell C, Macpherson S, Eddie SL, Kinnell H, 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

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

Holm JB, Mazaud-Guittot S, Danneskiold-Samsoe NB, Chalmey C, Jensen B, Norregard MM, Hansen CH, Styrishave B, Svingen T, Vinggaard AM, Koch HM, Bowles J, Koopman P, Jegou B, Kristiansen K, Kristensen DM (2016) Intrauterine Exposure to Paracetamol and Aniline Impairs Female Reproductive Development by Reducing Follicle Reserves and Fertility. Toxicol Sci 150: 178-189

Ishiguro KI, Matsuura K, Tani N, Takeda N, Usuki S, Yamane M, Sugimoto M, Fujimura S, Hosokawa M, Chuma S, Ko MSH, Araki K, Niwa H (2020) MEIOSIN Directs the Switch from Mitosis to Meiosis in Mammalian Germ Cells. Dev Cell 52: 429-445 e410

Kojima ML, de Rooij DG, Page DC (2019) Amplification of a broad transcriptional program by a common factor triggers the meiotic cell cycle in mice. Elife 8

Koubova J, Hu YC, Bhattacharyya T, Soh YQ, 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

Lawson C, Gieske M, Murdoch B, Ye P, Li Y, Hassold T, Hunt PA (2011) Gene expression in the fetal mouse ovary is altered by exposure to low doses of bisphenol A. Biol Reprod 84: 79-86

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

Liu JC, Lai FN, Li L, Sun XF, Cheng SF, Ge W, Wang YF, Li L, Zhang XF, De Felici M, Dyce PW, Shen W (2017) Di (2-ethylhexyl) phthalate exposure impairs meiotic progression and DNA damage repair in fetal mouse oocytes in vitro. Cell Death Dis 8: e2966

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

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