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Event: 408

Key Event Title

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

reduction in ovarian granulosa cells, Aromatase (Cyp19a1)

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
reduction in ovarian granulosa cells, Aromatase (Cyp19a1)
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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
granulosa 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

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
Process Object Action
aromatase activity aromatase decreased
mRNA transcription aromatase decreased

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
Aromatase (Cyp19a1) reduction leading to reproductive toxicity MolecularInitiatingEvent Elise Grignard (send email) Open for citation & comment Under Review

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
rat Rattus norvegicus Moderate NCBI
human Homo sapiens High NCBI
zebra fish Danio rerio High NCBI

Life Stages

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

Sex Applicability

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

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

Biological state

Aromatase (Cyp19a1, estrogen synthetase, estrogen synthase) is an enzyme responsible for a key step in the biosynthesis of estrogens, in particular it is responsible for conversion of C-19 androgens into C-18 estrogens (E R Simpson et al., 1994), (Ryan, 1982). It is a member of the cytochrome P450 superfamily (Ryan, 1982). The aromatase gene uses multiple promoters in a tissue-specific manner, resulting in a tissue-specific regulation of aromatase activity (Evan R Simpson, 2004). The cAMP/PKA/CREB pathway is considered to be the primary signalling cascade through which the gonadal Cyp19 promoter is regulated (Stocco, 2008).

Biological compartments

Aromatase in the specialized cells of the ovary, hypothalamus, and placenta has a crucial role in reproduction for mammalian and other vertebrates by converting androgens to estrogens. This enzyme is also present in various other tissues, such as skin, fat, bone marrow, liver, adrenals, and testes (Ryan, 1982).

General role in biology

The ovarian aromatase produces systemic and locally acting estrogens for general reproductive functions. The systemic estrogen produced by ovarian aromatase modulates the central nervous system and pituitary functions for the ovarian cycle and in spontaneously ovulating mammals it triggers the release of the ovulatory surge of luteinizing hormone (Ryan, 1982), (Hillier, 1985). Because only a single gene (CYP19) encodes aromatase in humans, targeted disruption of this gene or inhibition of its product effectively eliminates estrogen biosynthesis (Evan R Simpson et al., 2002). Much attention has been given to the regulation of the aromatase gene and its implication in the development and progression of human estrogen-dependent diseases, including breast cancer, endometrial cancer, and endometriosis, see review (Bulun et al., 2005).

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

Aromatase levels can be assayed by standard methods for assessment of gene expression levels like: q-PCR or direct protein levels: Western blot or ELISA. The level of aromatase as well as other steroidogenic protein can be measured in vitro cultured ovarian cells. The methods for culturing ovarian cells can be found in the Database Service on Alternative Methods to animal experimentation (DB-ALM): Culture of Human Cumulus Granulosa Cells [1], Granulosa and Theca Cell Culture Systems [2].

However, in early life stage zebrafish embryos are not practical to measure tissue-specific expression. In those cases, whole body measurements can be used as an indicator of this key event.

Domain of Applicability

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

Aromatase (CYP19) orthologs are known to be present in most of the vertebrates [see review (E R Simpson et al., 1994)]. In humans, CYP19 transcript is extensively distributed in tissues including ovaries, placenta, adipose, and brain (E R Simpson et al., 1994). In rodents, aromatase is restricted to the gonads and the brain (Stocco, 2008).

References

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

Bulun, S. E., Lin, Z., Imir, G., Amin, S., Demura, M., Yilmaz, B., … Deb, S. (2005). Regulation of aromatase expression in estrogen-responsive breast and uterine disease: from bench to treatment. Pharmacological Reviews, 57(3), 359–83. doi:10.1124/pr.57.3.6

Hillier, S. G. (1985). Sex steroid metabolism and follicular development in the ovary. Oxford Reviews of Reproductive Biology, 7, 168–222.

Ryan, K. J. (1982). Biochemistry of aromatase: significance to female reproductive physiology. Cancer Research, 42(8 Suppl), 3342s–3344s.

Simpson, E. R. (2004). Aromatase: biologic relevance of tissue-specific expression. Seminars in Reproductive Medicine, 22(1), 11–23. doi:10.1055/s-2004-823023

Simpson, E. R., Clyne, C., Rubin, G., Boon, W. C., Robertson, K., Britt, K., … Jones, M. (2002). Aromatase--a brief overview. Annual Review of Physiology, 64, 93–127. doi:10.1146/annurev.physiol.64.081601.142703

Simpson, E. R., Mahendroo, M. S., Means, G. D., Kilgore, M. W., Hinshelwood, M. M., Graham-Lorence, S., … Michael, M. D. (1994). Aromatase cytochrome P450, the enzyme responsible for estrogen biosynthesis. Endocrine Reviews, 15(3), 342–55. doi:10.1210/edrv-15-3-342

Stocco, C. (2008). Aromatase expression in the ovary: hormonal and molecular regulation. Steroids, 73(5), 473–87. doi:10.1016/j.steroids.2008.01.017