Key Event Title
|Level of Biological Organization|
Key Event Components
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP|
Key Event Description
Biological state: expression of aromatase
Biological compartments: ovarian granulosa cells
General role in biology: enzyme converting the androgens to estrogens
Aromatase in the specialized cells of the ovary, hypothalamus, and placenta clearly serves crucial role in reproduction for mammalian and other vertebrates by converting the androgens to estrogens. This emzyme is also present in many diverse tissues, such as skin, fat, bone marrow, liver, adrenal, and testes, where its biological role in such sites is less understood (Ryan, 1982).
The ovarian aromatase produces systemic and locally acting estrogens for general reproductive functions. The systemic estrogen produced by ovarian aromatase modulates central nervous system and pituitary functions for the ovarian cycle and in spontaneously ovulating mammals triggers the release of the ovulatory surge of luteinizing hormone (Ryan, 1982),(Hillier, 1985). Much attention has been given to the regulation of the aromatase gene and its implication in the development and progression of human diseases. Alterations in aromatase expression have been implicated in the development and progression of human estrogen-dependent disease, including breast cancer, endometrial cancer, and endometriosis [see review (Bulun et al., 2005)]. Aromatase expression is regulated by follicle-stimulating hormone (FSH), through multiple signaling pathways including cyclic adenosine monophosphate (cAMP)-dependent regulatory events (Stocco, 2008).
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.
Domain of Applicability
Aromatase (CYP19) orthologs are known to be present among most of the vertebrates [see review (Simpson et al., 1994)] In humans, CYP19 transcript is extensively distributed in tissues including ovaries, placenta, adipose, and brain (Simpson et al., 1994) In rodents, aromatase is restricted to the gonads and the brain (Stocco, 2008). Much attention has been given to the regulation of the aromatase gene and its implication in the development and progression of human diseases. Alterations in aromatase expression have been implicated in the development and progression of human estrogen-dependent disease, including breast cancer, endometrial cancer, and endometriosis [see review (Bulun et al., 2005)].
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., 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