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Event: 1883

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

Reduced size of the ovarian follicle pool

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
Ovarian follicle pool, reduced

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
Organ

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
Fetal 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

Formation of the follicle pool (follicle assembly)

During fetal life, primordial germ cells migrate to the genital ridges where they arrange into germ cell nests and proceed through to meiosis prophase I (Pepling & Spradling, 2001). Assembly into individual follicles occurs via mechanisms that are not well known, but involves germ cell nest break down and a reduction in oocyte numbers via programmed cell death. Somatic pre-granulosa cells infiltrate between the oocytes, arrange around them in a single layer, and establish what is called the primordial follicles (Escobar et al, 2008; Gawriluk et al, 2011; Pepling & Spradling, 2001). The primordial follicles constitute the follicle pool - a limited stock of oocytes that are available for maturation and potential fertilization determining the length of a female’s reproductive life span (Grive & Freiman, 2015).

The timing of follicle assembly differs between mammalian species, but the processes involved seem to be relatively well conserved (Grive & Freiman, 2015). In humans, follicle assembly occurs during mid-gestation whereas in mice and rats it is initiated around the time of birth and continues until approximately six days post partum.

Reduced follicle pool as Key Event

An intact follicle pool is critical for female fertility. Any disruption to the formation of the final pool can have adverse consequences for reproductive capacity, leading to sub- or infertility. Loss of oocytes/follicles can occur during any of the abovementioned stages during the process of follicle assembly – oocyte nest breakdown, programmed cell death or somatic pre-granulosa cell intrusion. Follicle assembly and establishment of the functional follicle pool is also dependent on the stages occurring before this process, e.g. migration of primordial germ cells to the genital ridges, sex determination and meiosis.

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). ?

In animal studies, counting of follicles of different sizes is included in OECD guidelines: TG 416 (Two-Generation Reproductive Toxicity Study) and TG 443 (Extended One-Generation Reproductive Toxicity Study). It is a time-consuming and labor-intensive method and it is not recommended to compare values between studies (Tilly, 2003).

In humans, there is no direct way to count the follicle pool in vivo. Instead, surrogate markers are used. The most established biomarker for estimation of the follicle pool is anti-Müllerian hormone (AMH). It is readily measured in a blood sample and the levels are rather stable throughout the menstrual cycle (Broer et al, 2014).

The size of the pool can also be measured indirectly by mRNA and protein expression of meiotic markers, or by assessing overall ovary histology by histological assessments (Zhang et al, 2012).

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

Follicle assembly occur in females during fetal life (humans) or around and after birth (rodents). Many of the mechanisms involved are preserved between mice, rats and humans.

Evidence for Perturbation by Stressor

Diethylstilbestrol

Diethylstilbestrol (DES) exposure (0.2 an 20 µg/kg, s.c., 1, 3, 5, and 7 dpp, killed 8 dpp) reduced the number of primordial follicles in rats exposed postnatally (Rodríguez et al. 2010)

Bisphenol A

Bisphenol A (BPA) exposure during the postnatal period (20 mg/kg, s.c., 1, 3, 5, and 7 dpp, killen on 8 dpp) reduced the number of primordial follicles in rats exposed postnatally (Rodríguez et al. 2010). In mice exposed exposed to BPA during fetal life (0.5 and 50 µg/kg/day, oral, 11 dpc-birth, killed on 4 dpp) reduced number of primordial follicles were seen (Wang et al. 2014). Reduced number of primordial follicles was also seen in mice exposed during a shorter window of time during fetal life (0.08mg/kg, oral, 12.5-18.5 dpc, killed 15.5, 17.5 and 19.5 dpc and 3, 5 and 7 dpp (Zhang et al. 2012).

Genistein

Genistein exposure during postnatal life (50 mg/kg/day, s.c. 1-5 dpp, killed 4 dpp) reduced the number of primordial follicles (Jefferson et al. 2006).

Bis(2,4,6-trimethylphenyl)-lambda~2~-germane--selenium (1/1)

Diethylhexyl phthalate (DEHP) exposure during postnatal life (2.5, 5, 10 µg(g bw/day, i.p. 0-4 dpp, killed on 5 dpp) resulted in reduced number of primordial follicles (Mu et al. 2015).

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

Broer SL, Broekmans FJM, Laven JSE, Fauser BCJM (2014) Anti-Müllerian hormone: ovarian reserve testing and its potential clinical implications. Hum Reprod Update 20: 688-701

Escobar ML, Echeverría OM, Ortíz R, Vázquez-Nin GH (2008) Combined apoptosis and autophagy, the process that eliminates the oocytes of atretic follicles in immature rats. Apoptosis 13: 1253-1266

Gawriluk TR, Hale AN, Flaws JA, Dillon CP, Green DR, Rucker 3rd EB (2011) Autophagy is a cell survival program for female germ cells in the murine ovary. Reproduction 141: 759-765

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

Jefferson W, Newbold R, Padilla-Banks E, Pepling M (2006) Neonatal genistein treatment alters ovarian differentiation in the mouse: inhibition of oocyte nest breakdown and increased oocyte survival. Biol Reprod 74: 161-168

Mu X, Liao X, Chen X, Li Y, Wang M, Shen C, Zhang X, Wang Y, Liu X, He J (2015) DEHP exposure impairs mouse oocyte cyst breakdown and primordial follicle assembly through estrogen receptor-dependent and independent mechanisms. Journal of Hazardous Materials 298: 232-240

Pepling ME, Spradling AC (2001) Mouse ovarian germ cell cysts undergo programmed breakdown to form primordial follicles. Dev Biol 234: 339-351

Rodríguez HA, Santambrosio N, Santamaría CG, Muñoz-de-Toro M, Luque EH (2010) Neonatal exposure to bisphenol A reduces the pool of primordial follicles in the rat ovary. Reprod Toxicol 30: 550-557

Tilly JL (2003) Ovarian follicle counts--not as simple as 1, 2, 3. Reprod Biol Endocrinol 1: 11

Wang W, Hafner KS, Flaws JA (2014) In utero bisphenol A exposure disrupts germ cell nest breakdown and reduces fertility with age in the mouse. Toxicol Appl Pharmacol 276: 157-164

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