Upstream eventAgonism, Androgen receptor
Reduction, Vitellogenin synthesis in liver
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Androgen receptor agonism leading to reproductive dysfunction (in repeat-spawning fish)||non-adjacent||High||Low|
|fathead minnow||Pimephales promelas||High||NCBI|
|Danio rerio||Danio rerio||Moderate||NCBI|
|Fundulus heteroclitus||Fundulus heteroclitus||High||NCBI|
Life Stage Applicability
|Adult, reproductively mature||High|
Key Event Relationship Description
At present, a direct structural/functional linkage between androgen receptor agonism and reduced plasma vitellogenin concentrations is not known. Consequently, the relationship is supported primarily via 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. E2 is known to be a major regulator of hepatic vitellogenin production (Tyler et al. 1996; Tyler and Sumpter 1996; Arukwe and GoksØyr 2003).
Direct support for the effect of AR agonists on plasma vitellogenin (VTG) concentrations:
- Ekman et al. (2011) reported significant reductions in plasma VTG in female fathead minnows exposed to 0.5 ng 17beta-trenbolone/L for 4 or 8 d, or to 0.05 ng/L for 8 d.
- Ankley et al. (2010) showed significant reductions in plasma VTG in four independent experiments in which female fathead minnows were exposed to 17beta-trenbolone for 14 d and a fifth experiment where they were exposed for 21 d.
- Seki et al. (2006) showed significant reductions in plasma VTG in three different species of female fish (Oryzias latipes, Danio rerio, Pimephales promelas) following 21 d of exposure to 17beta-trenbolone.
- Villeneuve et al. (2016) reported significant reductions in plasma VTG following 22 d of exposure to 0.5 ng 17beta-trenbolone/L.
- Jensen et al. (2006) observed significant reductions in plasma VTG in female fathead minnows following exposure to 17alpha-trenbolone for 21 d.
- LaLone et al. (2013) reported significant reductions in plasma VTG in female fathead minnows exposed to 5 ug/L or higher concentrations of spironolactone.
- Rutherford et al. (2015) reported significant reductions in plasma VTG in female Fundulus heteroclitus after 14 d of exposure to 100 ug 5alpha-dihydrotestosterone/L as well as after exposure to 1 ug methyltestosterone/L.
- Sharpe et al. (2004), detected significant reductions in plasma VTG in female Fundulus heteroclitus exposed to 0.25 ug/L methyltestosterone for 7 d or 0.01 ug/L for 14 d.
Uncertainties and Inconsistencies
Quantitative Understanding of the Linkage
- Li et al. (2011) describe a computational model of the female fathead minnow (Pimephales promelas) hypothalamic-pituitary-gonadal axis that can be used to simulate impacts on plasma T, plasma E2, and plasma vitellogenin concentrations following exposure to 17ß-trenbolone. However, to date, that model has not been robustly tested to determine applicability to other species, or other types of AR agonists.
- At present, the scope of data for associating AR-activation potency with decreased plasma VTG 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 reproductively mature, adult, oviparous vertebrates.
- Androgen receptor orthologs are primarily limited to vertebrates (Baker 1997; Thornton 2001; Eick and Thornton 2011; Markov and Laudet 2011).
- Oviparous vertebrates synthesize yolk precursor proteins that are transported in the circulation for uptake by developing oocytes. Many invertebrates also synthesize vitellogenins that are taken up into developing oocytes via active transport mechanisms. However, invertebrate vitellogenins are transported in hemolymph or via other transport mechanisms rather than plasma.
- Ankley GT, Jensen KM, Kahl MD, Durhan EJ, Makynen EA, Cavallin JE, Martinović D, Wehmas LC, Mueller ND, Villeneuve DL. Use of chemical mixtures to differentiate mechanisms of endocrine action in a small fish model. Aquat Toxicol. 2010 Sep 1;99(3):389-96. doi: 10.1016/j.aquatox.2010.05.020.
- Arukwe A, Goksøyr A. 2003. Eggshell and egg yolk proteins in fish: hepatic proteins for the next generation: oogenetic, population, and evolutionary implications of endocrine disruption. Comparative Hepatology 2(4): 1-21.
- Baker ME. 1997. Steroid receptor phylogeny and vertebrate origins. Molecular and cellular endocrinology 135(2): 101-107.
- 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.
- Jensen KM, Makynen EA, Kahl MD, Ankley GT. Effects of the feedlot contaminant 17alpha-trenbolone on reproductive endocrinology of the fathead minnow. Environ Sci Technol. 2006 May 1;40(9):3112-7.
- Jolly C, Katsiadaki I, Le Belle N, Mayer I, Dufour S. 2006. Development of a stickleback kidney cell culture assay for the screening of androgenic and anti-androgenic endocrine disrupters. Aquatic toxicology 79(2): 158-166.
- LaLone CA, Villeneuve DL, Cavallin JE, Kahl MD, Durhan EJ, Makynen EA, Jensen KM, Stevens KE, Severson MN, Blanksma CA, Flynn KM, Hartig PC, Woodard JS, Berninger JP, Norberg-King TJ, Johnson RD, Ankley GT. Cross-species sensitivity to a novel androgen receptor agonist of potential environmental concern, spironolactone. Environ Toxicol Chem. 2013 Nov;32(11):2528-41. doi: 10.1002/etc.2330.
- Li Z, Kroll KJ, Jensen KM, Villeneuve DL, Ankley GT, Brian JV, Sepúlveda MS, Orlando EF, Lazorchak JM, Kostich M, Armstrong B, Denslow ND, Watanabe KH. A computational model of the hypothalamic: pituitary: gonadal axis in female fathead minnows (Pimephales promelas) exposed to 17α-ethynylestradiol and 17β-trenbolone. BMC Syst Biol. 2011 May 5;5:63. doi: 10.1186/1752-0509-5-63.
- 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.
- 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.
- Rutherford R, Lister A, Hewitt LM, MacLatchy D. Effects of model aromatizable (17α-methyltestosterone) and non-aromatizable (5α-dihydrotestosterone) androgens on the adult mummichog (Fundulus heteroclitus) in a short-term reproductive endocrine bioassay. Comp Biochem Physiol C Toxicol Pharmacol. 2015 Apr;170:8-18. doi: 10.1016/j.cbpc.2015.01.004.
- Seki M, Fujishima S, Nozaka T, Maeda M, Kobayashi K. Comparison of response to 17 beta-estradiol and 17 beta-trenbolone among three small fish species. Environ Toxicol Chem. 2006 Oct;25(10):2742-52.
- Sharpe RL, MacLatchy DL, Courtenay SC, Van Der Kraak GJ. Effects of a model androgen (methyl testosterone) and a model anti-androgen (cyproterone acetate) on reproductive endocrine endpoints in a short-term adult mummichog (Fundulus heteroclitus) bioassay. Aquat Toxicol. 2004 Apr 28;67(3):203-15.
- 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.
- Tyler C, Sumpter J. 1996. Oocyte growth and development in teleosts. Reviews in Fish Biology and Fisheries 6: 287-318.
- Tyler C, van der Eerden B, Jobling S, Panter G, Sumpter J. 1996. Measurement of vitellogenin, a biomarker for exposure to oestrogenic chemicals, in a wide variety of cyprinid fish. Journal of Comparative Physiology and Biology 166: 418-426.
- Villeneuve DL, Jensen KM, Cavallin JE, Durhan EJ, Garcia-Reyero N, Kahl MD, Leino RL, Makynen EA, Wehmas LC, Perkins EJ, Ankley GT. Effects of the antimicrobial contaminant triclocarban, and co-exposure with the androgen 17β-trenbolone, on reproductive function and ovarian transcriptome of the fathead minnow (Pimephales promelas). Environ Toxicol Chem. 2017 Jan;36(1):231-242. doi: 10.1002/etc.3531.