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Key Event Title
reduction in ovarian granulosa cells, Aromatase (Cyp19a1)
|Level of Biological Organization|
Key Event Components
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP||Point of Contact||Author Status||OECD Status|
|Aromatase (Cyp19a1) reduction leading to reproductive toxicity||MolecularInitiatingEvent||Allie Always (send email)||Open for citation & comment||EAGMST Under Review|
Key Event Description
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).
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
Methods that have been previously reviewed and approved by a recognized authority should be included in the Overview section above. All other methods, including those well established in the published literature, should be described here. Consider the following criteria when describing each method: 1. Is the assay fit for purpose? 2. Is the assay directly or indirectly (i.e. a surrogate) related to a key event relevant to the final adverse effect in question? 3. Is the assay repeatable? 4. Is the assay reproducible?
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 , Granulosa and Theca Cell Culture Systems .
Domain of Applicability
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).
Evidence for Perturbation by Stressor
Overview for Molecular Initiating Event
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