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Event: 1883

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Reduced size of the ovarian follicle pool

Short name

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Ovarian follicle pool, reduced

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Biological Context

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Level of Biological Organization
Organ

Organ term

The location/biological environment in which the event takes place.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. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Organ term
ovary sex cord

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling). 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 signaling 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. Further information on Event Components and Biological Context may be viewed on the attached pdf. 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	KeyEvent	Terje Svingen (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 KE.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

An indication of the the relevant life stage(s) for this KE. More help

Life stage	Evidence
Fetal	High

Sex Applicability

An indication of the the relevant sex for this KE. 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. 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

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.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). Do not provide detailed protocols. More help

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

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided). 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.

References

List of the literature that was cited for this KE description. 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