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Event: 1800

Key Event Title

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

Granulosa cell proliferation of gonadotropin-independent follicles, Reduced

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. More help
Reduced granulosa cell proliferation
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Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. More help
Level of Biological Organization
Cellular

Cell 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
Cell term
eukaryotic cell

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
ovarian follicle

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
AR antagonism leading to decreased fertility KeyEvent Cataia Ives (send email) Under development: Not open for comment. Do not cite

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
human Homo sapiens High NCBI
mouse Mus musculus High NCBI
rat Rattus norvegicus High NCBI
Monkey Monkey High NCBI
Pig Pig High NCBI
cow Bos taurus High NCBI

Life Stages

An indication of the the relevant life stage(s) for this KE. More help
Life stage Evidence
During development and at adulthood 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

Granulosa cell function

Granulosa cells of the ovary play an important structural and functional role during folliculogenesis. They form the ovarian follicle architecture and transmit molecular messages to the oocyte through gap junction channels, ensuring developmental competence(Kidder and Vanderhyden, 2010). Folliculogenesis can be roughly divided into two phases: gonadotropin-independent and gonadotropin-dependent by the requirement for the gonadotropin follicle-stimulating hormone (FSH) to grow(Hsueh et al., 2015). During the gonadotropin-independent growth phase, growth factors secreted by the follicle, e.g. growth differentiation factor-9 (GDF9) by the oocyte and anti-Müllerian hormone (AMH) by the granulosa cells control the necessary morphological changes of granulosa cells and their proliferation(Hsueh et al., 2015). The growth can be histologically observed as proliferation of the granulosa cells as the flat granulosa cells of primordial follicles become cuboidal and increase in numbers(Gougeon, 2010). The connection between granulosa cell numbers and follicle growth during gonadotropin-independent growth is well described (Gougeon and Chainy, 1987).

Reduced granulosa cell proliferation as Key Event

Genetically modified mouse models have demonstrated that granulosa cell proliferation is a prerequisite for normal follicle growth and fertility. For example, deletion of the oocyte-specific growth factor GDF9 that stimulates granulosa cells halt folliculogenesis at the primary follicle stage in mice: the granulosa cells fail to proliferate to generate secondary follicles, the oocytes degenerate, and the mice are sterile(Dong et al., 1996). Conversely, mice administered GDF9 have accelerated granulosa cell proliferation and higher numbers of primary and secondary follicles compared to non-treated ones(Vitt et al., 2000).

AMH is a growth factor secreted by granulosa cells during the gonadotropin-independent follicle growth stage, and it inhibits the activation of primordial follicles to keep the growing and dormant follicles in balance. In mice overexpressing AMH, follicle growth to antral stages is inhibited and the numbers of all developmental stages of follicles decline faster by age than in wildtype controls(Pankhurst et al., 2018). Exposure of human ovarian tissue to AMH in culture inhibits follicle growth(Carlsson et al., 2006).

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 vitro

Decreased granulosa cell proliferation can be measured in cell culture. There are commercially available human granulosa cell tumor lines, for instance KGN (#RCB1154) “Granulosa cell tumor”, available from the Riken cell Bank. This cell line is representative of undifferentiated granulosa cells at early stages of follicle development making it suitable to study interactions of primordial to early antral pathways independent from hormonal control from theca cells and hypothalamic-pituitary axis (Nishi et al., 2001).

Well-established assays to detect proliferation include methods to assess DNA synthesis (e.g. BrdU), cellular metabolism (e.g. MTT, XTT, ATP detection assays), and proliferation proteins (e.g. PCNA, Ki67, MCM-2)(Adan et al., 2016). The same methods can also be used in ovarian follicle or tissue culture.

In vivo

Granulosa cell proliferation manifests as increased numbers of granulosa cells within ovarian follicles(Gougeon and Chainy, 1987). Analysis of follicle growth is based on the numbers of granulosa cell layers which is also reflected in the diameter of the follicle(Gougeon and Chainy, 1987). Granulosa cell proliferation is inseparably connected to folliculogenesis, and therefore numbers of follicles in different developmental stages reflect the proliferation of granulosa cells. Granulosa cell proliferation can therefore be measured by counting follicles in different stages (primordial, primary, secondary) or by measuring the follicle diameters. Changes in the proliferation of granulosa cells during the early follicle growth phase would lead to altered proportions of follicles in different stages. For example, inhibition of granulosa cell proliferation can lead to reduced numbers of secondary follicles(Dong et al., 1996; Pankhurst et al., 2018). Therefore, studying ratios between follicles in different developmental stages can reveal changes in the proliferation of granulosa cells. Follicle counts are already suggested endpoints in the Extended One-Generation Reproductive Toxicity Study; EOGRTS (OECD 443)(2018).

Domain of Applicability

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

Overview

Mechanisms controlling folliculogenesis are well conserved between mammalian species, including mice, farm animals and humans(Adhikari and Liu, 2009; McGee and Hsueh, 2000).

References

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

Adan, A., Kiraz, Y., and Baran, Y. (2016). Cell Proliferation and Cytotoxicity Assays. Current Pharmaceutical Biotechnology 17, 1213–1221. https://doi.org/10.2174/1389201017666160808160513.

Adhikari, D., and Liu, K. (2009). Molecular mechanisms underlying the activation of mammalian primordial follicles. Endocrine Reviews 30, 438–464. https://doi.org/10.1210/er.2008-0048.

Carlsson, I.B., Scott, J.E., Visser, J.A., Ritvos, O., Themmen, A.P.N., and Hovatta, O. (2006). Anti-Müllerian hormone inhibits initiation of growth of human primordial ovarian follicles in vitro. Human Reproduction 21, 2223–2227. https://doi.org/10.1093/humrep/del165.

Dong, J., Albertini, D.F., Nishimori, K., Kumar, T.R., Lu, N., and Matzuk, M.M. (1996). Growth differentiation factor-9 is required during early ovarian folliculogenesis. Nature 383, 531–535. https://doi.org/10.1038/383531a0.

Gougeon, A. (2010). Croissance folliculaire dans l’ovaire humain: de l’entrée en croissance du follicule primordial jusqu’à la maturation préovulatoire. Annales d’Endocrinologie 71, 132–143. https://doi.org/10.1016/j.ando.2010.02.021.

Gougeon, A., and Chainy, G.B.N. (1987). Morphometric studies of small follicles in ovaries of women at different ages. Journal of Reproduction and Fertility 81, 433–442. https://doi.org/10.1530/jrf.0.0810433.

Hsueh, A.J.W., Kawamura, K., Cheng, Y., and Fauser, B.C.J.M. (2015). Intraovarian control of early folliculogenesis. Endocrine Reviews 36, 1–24. https://doi.org/10.1210/er.2014-1020.

Kidder, G.M., and Vanderhyden, B.C. (2010). Bidirectional communication between oocytes and follicle cells: Ensuring oocyte developmental competence. Canadian Journal of Physiology and Pharmacology 88, 399–413. https://doi.org/10.1139/Y10-009.

McGee, E.A., and Hsueh, A.J.W. (2000). Initial and Cyclic Recruitment of Ovarian Follicles*. Endocrine Reviews 21, 200–214. https://doi.org/10.1210/edrv.21.2.0394.

Nishi, Y., Yanase, T., Mu, Y.-M., Oba, K., Ichino, I., Saito, M., Nomura, M., Mukasa, C., Okabe, T., Goto, K., et al. (2001). Establishment and Characterization of a Steroidogenic Human Granulosa-Like Tumor Cell Line, KGN, That Expresses Functional Follicle-Stimulating Hormone Receptor. Endocrinology 142, 437–445. https://doi.org/10.1210/endo.142.1.7862.

Pankhurst, M.W., Kelley, R.L., Sanders, R.L., Woodcock, S.R., Oorschot, D.E., and Batchelor, N.J. (2018). Anti-Müllerian hormone overexpression restricts preantral ovarian follicle survival. Journal of Endocrinology 237, 153–163. https://doi.org/10.1530/JOE-18-0005.

Vitt, U.A., McGee, E.A., Hayashi, M., and Hsueh, A.J.W. (2000). In vivo treatment with GDF-9 stimulates primordial and primary follicle progression and theca cell marker CYP17 in ovaries of immature rats. Endocrinology 141, 3814–3820. https://doi.org/10.1210/endo.141.10.7732.

(2018). Test No. 443: Extended One-Generation Reproductive Toxicity Study (OECD).