Upstream eventAgonism, Androgen receptor
Reduction, 17beta-estradiol synthesis by ovarian granulosa cells
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Androgen receptor agonism leading to reproductive dysfunction||non-adjacent||Moderate||Low|
|fathead minnow||Pimephales promelas||Moderate||NCBI|
|Fundulus heteroclitus||Fundulus heteroclitus||Moderate||NCBI|
Life Stage Applicability
|Adult, reproductively mature||Moderate|
Key Event Relationship Description
At present, a direct structural/functional link between androgen receptor agonism and reduced estradiol synthesis by ovarian granulosa cells is not known. The linkage is thought to operate indirectly via endocrine feedback along the hypothalamic-pituitary-gonadal axis and subsequent effects on the regulation of enzymes involved in ovarian steroidogenesis. This relationship is primarily supported by association/correlation.
Evidence Supporting this KER
Synthesis of the steroidogenic enzymes that catalyze the formation of testosterone from cholesterol as a precursor as well as 17ß-estradiol (E2) from testosterone is stimulated by gonadotropins whose synthesis and secretion are in turn regulated by gonadotropin releasing hormone (GnRH) released from the hypothalamus (Payne and Hales 2004; Norris 2007; Miller 1988). Strong AR agonists are thought to exert negative feedback along the hypothalamic-pituitary-gonadal axis, leading to decreased stimulation of the steroidogenic pathway and subsequent declines in E2 production.
Direct support for the effect of AR agonists on estrogen production by ovary tissue:
- Ekman et al. (2011) reported reductions in ex vivo E2 production by ovary tissue collected from fathead minnows exposed to 17ß-trenbolone in vivo. However, among four exposure durations assessed (1, 2, 4, 8 d), E2 production was only reduced following 2 d of exposure.
- Glinka et al. (2015) reported reductions in E2 production in female Fundulus heteroclitus following 21 d of exposure to 0.5 or 5.0 ug 5alpha-dihydrotestosterone.
- Rutherford et al. (2015) demonstrate reduced E2 production in Fundulus heteroclitus following exposure to 100 ug 5alpha-dihydrotestosterone (a non-aromatizable androgen) or 0.1 and 1.0 ug methyltestosterone (an aromatizable androgen) for 14 d,
- Sharpe et al. (2004) reported reductions in E2 production in female Fundulus heteroclitus following exposure to 0.25 or 1.0 ug methyltestosterone/L for 7d, and in females exposed to 0.001, 0.01, or 0.1 ug methyltestosterone/L for 14 d.
Uncertainties and Inconsistencies
The work of Ekman et al. (2011) demonstrates the effects can be transient due to complex compensatory behaviors.
Quantitative Understanding of the Linkage
- At present, the scope of data for associating AR-activation potency with decreased E2 production is not sufficient to describe a quantitative response-response relationship.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
This KER is potentially applicable to sexually mature, female, vertebrates.
- Androgen receptor orthologs are primarily limited to vertebrates (Baker 1997; Thornton 2001; Eick and Thornton 2011; Markov and Laudet 2011).
- Key enzymes needed to synthesize 17β-estradiol first appear in the common ancestor of amphioxus and vertebrates (Markov et al. 2009; Baker 2011).
- Baker ME. 1997. Steroid receptor phylogeny and vertebrate origins. Molecular and cellular endocrinology 135(2): 101-107.
- Baker ME. 2011. Origin and diversification of steroids: Co-evolution of enzymes and nuclear receptors. Mol Cell Endocrinol 334: 14-20.
- Eick GN, Thornton JW. 2011. Evolution of steroid receptors from an estrogen-sensitive ancestral receptor. Molecular and cellular endocrinology 334(1-2): 31-38.
- Ekman DR, Villeneuve DL, Teng Q, Ralston-Hooper KJ, Martinović-Weigelt D, Kahl MD, Jensen KM, Durhan EJ, Makynen EA, Ankley GT, Collette TW. Use of gene expression, biochemical and metabolite profiles to enhance exposure and effects assessment of the model androgen 17β-trenbolone in fish. Environ Toxicol Chem. 2011 Feb;30(2):319-29. doi: 10.1002/etc.406.
- Markov GV, Laudet V. 2011. Origin and evolution of the ligand-binding ability of nuclear receptors. Molecular and cellular endocrinology 334(1-2): 21-30.
- 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.
- Miller WL. 1988. Molecular biology of steroid hormone synthesis. Endocrine reviews 9(3): 295-318.
- Norris DO. 2007. Vertebrate Endocrinology. Fourth ed. New York: Academic Press.
- Payne AH, Hales DB. 2004. Overview of steroidogenic enzymes in the pathway from cholesterol to active steroid hormones. Endocrine reviews 25(6): 947-970.
- Thornton JW. 2001. Evolution of vertebrate steroid receptors from an ancestral estrogen receptor by ligand exploitation and serial genome expansions. Proceedings of the National Academy of Sciences of the United States of America 98(10): 5671-5676.