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Key Event Title
Reduction, Testosterone synthesis by ovarian theca cells
|Level of Biological Organization|
Key Event Components
|testosterone biosynthetic process||testosterone||decreased|
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP||Point of Contact||Author Status||OECD Status|
|Androgen receptor agonism leading to reproductive dysfunction||KeyEvent||Dan Villeneuve (send email)||Open for citation & comment||WPHA/WNT Endorsed|
|Adult, reproductively mature||High|
Key Event Description
Testosterone is synthesized in ovarian theca cells through a series of enzyme catalyzed reactions that convert cholesterol to androgens (see KEGG reference pathway 00140 for details; www.genome.jp/kegg; (Payne and Hales 2004; Magoffin 2005; Young and McNeilly 2010). Binding of luteinizing hormone to luteinizing hormone receptors located on the surface of theca cell membranes leads to increased expression of steriodogenic cytochrome P450s, steroidogeneic acute regulatory protein, and consequent increases in androgen production (Payne and Hales 2004; Miller 1988; Miller and Strauss 1999).
How It Is Measured or Detected
Steroid production by isolated primary theca cells can be measured using radioimmunoassay or enzyme linked immunosorbent assay approaches (e.g., (Benninghoff and Thomas 2006; Campbell et al. 1998). However, the isolation and culture methods are not trivial. Similarly, development of immortalized theca cell lines has proven challenging (Havelock et al. 2004). Consequently, this key event is perhaps best evaluated by examining T production by intact ovarian tissue explants either exposed to chemicals in vitro (e.g., (Villeneuve et al. 2007; McMaster ME 1995) or in vivo (i.e., via ex vivo steroidogenesis assay; e.g., (Ankley et al. 2007)). Reductions in T production by ovarian tissue explants can indicate either direct inhibition of steriodogenic enzymes involved in T synthesis, or indirect impacts due to feedback along the hypothalamic-pituitary-gonadal axis (in cases where chemical exposures occur in vivo). However, because T synthesis in the theca cells is closely linked to estradiol (E2) synthesis by granulosa cells, reductions in T production by intact ovary tissue can also be due to increased aromatase activity and the resulting increased rate of converting T to E2.
Domain of Applicability
This key event is relevant to vertebrates and amphioxus, but not invertebrates.
- Cytochrome P45011a (Cyp11a), a rate limiting enzyme for the production of testosterone, is specific to vertebrates and amphioxus (Markov et al. 2009; Baker et al. 2011; Payne and Hales, 2004).
- Cyp11a does not occur in invertebrates, as a result, they do not synthesize testosterone, nor other steroid intermediates required for testosterone synthesis (Markov et al. 2009; Payne and Hales, 2004).
- Ankley GT, Jensen KM, Kahl MD, Makynen EA, Blake LS, Greene KJ, et al. 2007. Ketoconazole in the fathead minnow (Pimephales promelas): reproductive toxicity and biological compensation. Environ Toxicol Chem 26(6): 1214-1223.
- Baker ME. 2011. Origin and diversification of steroids: Co-evolution of enzymes and nuclear receptors. Mol Cell Endocrinol 334: 14-20.
- Benninghoff AD, Thomas P. 2006. Gonadotropin regulation of testosterone production by primary cultured theca and granulosa cells of Atlantic croaker: I. Novel role of CaMKs and interactions between calcium- and adenylyl cyclase-dependent pathways. General and comparative endocrinology 147(3): 276-287.
- Campbell BK, Baird DT, Webb R. 1998. Effects of dose of LH on androgen production and luteinization of ovine theca cells cultured in a serum-free system. Journal of reproduction and fertility 112(1): 69-77.
- Havelock JC, Rainey WE, Carr BR. 2004. Ovarian granulosa cell lines. Molecular and cellular endocrinology 228(1-2): 67-78.
- Magoffin DA. 2005. Ovarian theca cell. The international journal of biochemistry & cell biology 37(7): 1344-1349.
- Markov GV, Tavares R, Dauphin-Villemant C, Demeneix BA, Baker ME, Laudet V. Independent elaboration of steroid hormone signaling pathways in metazoans. Proc Natl Acad Sci U S A. 2009 Jul 21;106(29):11913-8. doi: 10.1073/pnas.0812138106.
- McMaster ME MK, Jardine JJ, Robinson RD, Van Der Kraak GJ. 1995. Protocol for measuring in vitro steroid production by fish gonadal tissue. Canadian Technical Report of Fisheries and Aquatic Sciences 1961 1961: 1-78.
- Miller WL, Strauss JF, 3rd. 1999. Molecular pathology and mechanism of action of the steroidogenic acute regulatory protein, StAR. The Journal of steroid biochemistry and molecular biology 69(1-6): 131-141.
- Miller WL. 1988. Molecular biology of steroid hormone synthesis. Endocrine reviews 9(3): 295-318.
- Payne AH, Hales DB. 2004. Overview of steroidogenic enzymes in the pathway from cholesterol to active steroid hormones. Endocrine reviews 25(6): 947-970
- Villeneuve DL, Ankley GT, Makynen EA, Blake LS, Greene KJ, Higley EB, et al. 2007. Comparison of fathead minnow ovary explant and H295R cell-based steroidogenesis assays for identifying endocrine-active chemicals. Ecotoxicol Environ Saf 68(1): 20-32.
- Young JM, McNeilly AS. 2010. Theca: the forgotten cell of the ovarian follicle. Reproduction 140(4): 489-504.