Key Event Title
|Level of Biological Organization|
Key Event Components
|androgen biosynthetic process||11-Keto-testosterone||decreased|
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP|
|PPARa Agonism Impairs Fish Reproduction||KeyEvent|
|11β-hydroxylase inhibition, male infertility in fish||KeyEvent|
|11βHSD inhibition, impaired spermatogenesis||KeyEvent|
|teleost fish||teleost fish||High||NCBI|
|Adult, reproductively mature||High|
Key Event Description
11-ketotestosterone (11KT) is the dominant androgen in teleost fish. It is synthesized from testosterone using the enzymes CYP11b1 and HSD11b (Yazawa et al., 2008; Swart et al., 2013).
Zebrafish studies also show that cyp17a1 and cyp11c1 knockouts have dramatically reduced levels of 11KT (Shu et al., 2020; Zhang et al., 2020)
Although mutations in the mettl3 gene usually cause embryonic lethality, one particular mutation in non-lethal and causes significantly reduced 11KT levels in zebrafish (Xia et al., 2018)
How It Is Measured or Detected
11KT production can be measured in an ex vivo steroidogenesis assay using the organism's gonad after it has been exposed to a compound.
The concentration of 11KT can be measured in a radioimmunoassay or enzyme-linked immunosorbent assay (ELISA).
Several papers show that in fish, 11KT is correlated with testosterone levels (Spanò et al., 2004; Maclatchy & Vanderkraak, 1995; Lorenzi et al., 2008).
Domain of Applicability
Taxanomic Applicability: Most understand of 11KT comes from studies involving teleost fish as it is their dominant androgen. Some studies have measured 11KT in sharks of the order carcharhiniformes, but there is less research in this area (Manire et al., 1999; Garnier et al. 1999; Mills et al. 2010). Many mammals possess the genes necessary to produce 11KT (NCBI), but 11KT may not be as relevant when it’s not the dominant androgen.
Sex Applicability: Males and females use the same biological processes to produce steroids. However, sexual dimorphism in 11KT production varies between species. In humans, plasma levels of 11KT do not differ between sexes (Imamichi et al., 2016). In Zebrafish, gonad levels of 11KT are approximately two magnitudes higher in males than females (Wang & Orban, 2007). Of the 30 other fish species sampled by Lokman et al. (2002), 11KT levels are typically dramatically lower in females than in males, but a few species of the order Perciformes show no sexual dimorphism.
Life Stage Applicability: 11KT can be measured in fish larvae however individuals must be pooled for sufficient sample size (Hattori et al., 2009). Lokman et al. (2002) measured plasma levels of 11-KT in several species of juvenile and adult fish. 11KT levels tend to be higher in males although some fish species don’t show sexual dimorphism. Levels of 11KT in juveniles are similar to levels in females regardless of if the species shows sexual dimorphism in 11KT levels. In males, 11KT increases for spawning and decreases afterwards (Kindler et al., 1989; Páll et al., 2002). Because of it’s involvement in reproduction, 11KT levels may not be meaningful in juveniles.
Evidence for Perturbation by Stressor
Beta-sitosterol causes a dose-depended reduction in 11KT in male goldfish (MacLatchy & Van Der Kraak 1995)
Bezafibrate reduces 11-KT in the plasma of adult male zebrafish (Velasco-Santamaría et al. 2011)
Gemfibrozil reduced 11KT in the plasma of adult male medaka (Lee et al. 2019)
Gemfibrozil expsoure caused reduced 11KT in the testes, plasma, and whole-body samples of adult male zebrafish (Fraz et al., 2018)
A review of androgen signaling in fish cites several studies showing DEHP decreased 11KT (Golshan et al., 2019)
Cypermethrin causes decreased 11KT in catfish (Singh & Singh, 2008)
Carbamazepine decreased 11KT in the testes, plasma, and whole-body samples of adult male zebrafish (Fraz et al., 2018)
Fraz, S. et al. (2018) “Gemfibrozil and carbamazepine decrease steroid production in zebrafish testes (Danio rerio)”, Aquatic Toxicology, Vol. 198, Elsevier, pp. 1-9. https://doi.org/10.1016/j.aquatox.2018.02.006
Golshan, M. & S.M.H. Alvai (2019) “Androgen signaling in male fishes: Examples of anti-androgenic chemicals that cause reproductive disorders”, Theriogenology, Vol. 139, Elsevier, pp. 58-71. https://doi.org/10.1016/j.theriogenology.2019.07.020
Hattori, R.S. et al. (2009) “Cortisol-induced masculinization: Does thermal stress affect gonadal fate in pejerrey, a teleost fish with temperature-dependent sex determination?”, PLoS ONE, Vol. 4(8), pp. 1-7. doi:10.1371/journal.pone.0006548
Imamichi, Y. et al. (2016) “11-Ketotestosterone is a major androgen produced in human gonads”, The Journal of Clinical Endocrinology & Metabolism, Vol. 101(10), Oxford Academic, pp. 3582-3591. https://doi.org/10.1210/jc.2016-2311
Kindler, P. M. et al. (1989) “Serum 11-ketotestosterone and testosterone concentrations associated with reproduction in male bluegill (Lepomis macrochirus: Centrarchidae)”, General and Comparative Endocrinology, Vol. 75(3), Elsevier, pp. 446-453. https://doi.org/10.1016/0016-6480(89)90180-9
Lee, G. et al. (2019) “Effects of gemfibrozil on sex hormones and reproduction related performances of Oryzias latipes following long-term (155 d) and short-term (21 d) exposure”, Ecotoxicology and Environmental Safety, Vol. 173, Elsevier, pp. 174-181. https://doi.org/10.1016/j.ecoenv.2019.02.015
Lokman, P.M. et al. (2002) “11-Oxygenated androgens in female teleosts: prevalence, abundance, and life history implications”, General and Comparative Endocrinology, Vol. 129, Academic Press, pp. 1-12. doi: 10.1016/s0016-6480(02)00562-2
Lorenzi, V. et al. (2008) “Diurnal patterns and sex differences in cortisol, 11-ketotestosterone, testosterone, and 17β-estradiol in the bluebanded goby (Lythrypnus dalli)”, General and Comparative Endocrinology, Vol. 155(2)., Elsevier, pp. 438-446. https://doi.org/10.1016/j.ygcen.2007.07.010
MacLatchy, D.L. and G.J. Vanderkraak (1995) “The phytoestrogen β-sitosterol alters the reproductive endocrine status of goldfish”, Toxicology and Applied Pharmacology, Vol. 134(2), Elsevier, pp. 305-312. https://doi.org/10.1006/taap.1995.1196
Manire, C.A., L.E. Rasmussen & T.S. Gross (1999) “Serum steroid hormones including 11-ketotestosterone, 11-ketoandrostenedione, and dihydroprogesterone in juvenile and adult bonnethead sharks, Sphyrna tiburo”, Journal of Experimental Zoology, Vol. 284(5), Wiley-Blackwell, pp. 595-603. DOI: 10.1002/(sici)1097-010x(19991001)284:5<595::aid-jez15>3.0.co
Páll, M. K., I. Mayer and B. Borg (2002) “Androgen and behavior in the male three-spined stickleback, Gasterosteus aculeatus I. – Changes in 11-ketotestosterone levels during nesting cycle”, Hormones and Behavior, Vol. 41(4), Elsevier, pp. 377-383. https://doi.org/10.1006/hbeh.2002.1777
Shu, T. et al. (2020) “Zebrafish cyp17a1 knockout reveals that androgen-mediated signaling is important for male brain sex differentiation”, General and Comparative Endocrinology, Vol. 295. doi:10.1016/j.ygcen.2020.113490
Singh, P.B. & V. Singh (2008) “Cypermethrin induced histological changes in gonadotrophic cells, liver, gonads, plasma levels of estradiol-17beta and 11-ketotestosterone, and sperm motility in Heteropneustes fossilis (Bloch)”, Chemosphere, Vol. 72(3), Elsevier, pp. 422-431. DOI: 10.1016/j.chemosphere.2008.02.026
Spanó, L. et al. (2004) “Effects of atrazine on sex steroid dynamics, plasma vitellogenin concentration and gonad development in adult goldfish (Carassius auratus)”, Aquatic Toxicology, Vol. 66(4), Elsevier, pp. 369-379. https://doi.org/10.1016/j.aquatox.2003.10.009
Swart, A.C. et al. (2013) “11β-hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5α-reductase yielding 11β-hydroxy-5α-androstanedione”, The Journal of Steroid Biochemistry and Molecular Biology, Vol 138, Elsevier, pp. 132-142. https://doi.org/10.1016/j.jsbmb.2013.04.010
Velasco-Santamaría, Y.M. et al. (2011) “Bezafibrate, a lipid-lowering pharmaceutical, as a potential endocrine disruptor in male zebrafish (Danio rerio)”, Aquatic Toxicology, Vol. 105, Elsevier, pp. 107-118. doi:10.1016/j.aquatox.2011.05.018
Wang, X.G. and L. Orban (2007) “Anti-Müllerian hormone and 11β-hydroxylase show reciprocal expression to that of aromatase in the transforming gonad of zebrafish males”, Developmental Dynamics, Vol 236(5), Wiley-Liss, pp. 1329-1338. https://doi.org/10.1002/dvdy.21129
Xia, H. et al. (2018) “Mettl3 mutation disrupts gamete maturation and reduced fertility in zebrafish”, Genetics, Vol. 208(2), Genetics Society of America, pp. 729-743. DOI: 10.1534/genetics.117.300574
Yazawa, T. (2008) “Cyp11b1 is induced in the murine gonad by luteinizing hormone/human chorionic gonadotropin and involved in the production of 11-ketotestosterone, a major fish androgen: Conservation and evolution of the androgen metabolic pathway”, Endocrinology, Vol. 149(4), Oxford Academy, pp. 1786-1792. https://doi.org/10.1210/en.2007-1015
Zheng, Q. et al. (2020) “Loss of cyp11c1 causes delayed spermatogenesis due to the absence of 11-ketotestosterone", Journal of Endocrinology, Vol. 244(3), Bioscientifica, pp. 487-499. https://doi.org/10.1530/JOE-19-0438