Upstream eventReduction, Plasma 17beta-estradiol concentrations
Reduction, Plasma vitellogenin concentrations
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||Moderate|
|Aromatase inhibition leading to reproductive dysfunction||non-adjacent||High||Moderate|
|Inhibition of thyroid peroxidase leading to impaired fertility in fish||adjacent|
|Inhibition of 5α-reductase leading to impaired fertility in female fish||adjacent||High||High|
|Embryonic Activation of the AHR leading to Reproductive failure, via epigenetic down-regulation of GnRHR||non-adjacent||High||Moderate|
|fathead minnow||Pimephales promelas||High||NCBI|
|Fundulus heteroclitus||Fundulus heteroclitus||High||NCBI|
Life Stage Applicability
|Adult, reproductively mature||High|
Key Event Relationship Description
There is not a direct structural/functional relationship between reduced concentrations of 17ß-estradiol in plasma and reduced plasma VTG concentrations. The relationship is thought to be mediated through additional events of hepatic estrogen receptor activation, vitellogenin protein synthesis in the liver, and subsequent secretion of vitellogenin into the plasma.
Evidence Supporting this KER
The mechanisms through which 17ß-estradiol stimulates the transcription and translation of hepatic vitellogenin are well understood.
- In fish, see: Tyler et al. 1996; Tyler and Sumpter 1996; Arukwe and Goksøyr 2003; Teo et al. 1998
- In frogs: Chang et al. 1992; Wangh and Knowland 1975
- In reptiles: Ho et al. 1980
- Ho (1987)
- In birds: Deeley et al. 1975;
17ß-estradiol is not synthesized in significant amounts in the liver. Its synthesis originates in other tissues, principally the gonads. It is then transported to the liver and other tissues via circulation (Norris 2007; Payne and Hales 2004; Miller 1988; Nagahama et al. 1993).
- Under conditions of continuous flow through exposure to 17ß-trenbolone (a non-aromatizable androgen receptor agonist), plasma E2 concentrations were reduced in female fathead minnows after 2, 4, or 8 d of exposure to concentrations of 0.05 ug/L or greater. Plasma VTG concentrations were significantly reduced only after 4 or 8 d of exposure, and at 4 d, only at a concentration of 0.5 ug/L, not 0.05 ug/L (Ekman et al. 2011).
- In the same study by Ekman et al. (2011), once exposure ceased, plasma E2 concentrations returned to control levels within 48 h, while plasma VTG concentrations remained significantly depressed until d. 4, post-exposure.
- Ankley et al. (2003) detected reductions in both plasma E2 and plasma VTG in female fathead minnows following 21 d of continuous exposure to 17ß-trenbolone. At 21 d, plasma E2 concentrations were impacted at concentrations of 0.5 ug/L or greater, while plasma VTG was significantly reduced at 0.05 ug/L or greater.
- Villeneuve et al. (2016) observed significant reductions in both plasma E2 and plasma VTG in female fathead minnows exposed to 0.5 ug/L 17ß-trenbolone for 14 d.
- Jensen et al. (2006) observed significant reductions in both plasma E2 and plasma VTG following exposure to 0.03 ug/L 17alpha-trenbolone for 21 d.
- Following 21 d of continuous exposure to spironolactone, plasma E2 and plasma VTG were both significantly reduced in female fathead minnows. The lowest effect concentration for plasma E2 was 0.5 ug/L, while that for plasma VTG was 5 ug/L (LaLone et al. 2013).
- In female Fundulus heteroclitus exposed to 5alpha-dihydrotestosterone for 14 d, plasma E2 was significantly reduced following exposure to 10 ug/L, while plasma VTG was reduced at 100 ug/L (Rutherford et al. 2015).
- In two experiments in which female Fundulus heteroclitus were exposed to 17alpha-methyltestosterone, both plasma E2 and plasma VTG were significantly reduced. In both cases, plasma E2 was impacted at lower concentrations (0.25 ug/L in a 7 d study; 0.01 ug/L in a 14 d study) than plasma VTG (1 ug/L in the 7 d study; 0.1 ug/L in the 14 d study; Sharpe et al. 2004).
- In two experiments where plasma E2 and plasma VTG were measured in female fathead minnows (Pimephales promelas) in a time-course following continuous exposure the aromatase inhibitor fadrozole, both plasma VTG and plasma E2 were depressed (Villeneuve et. al. 2009; 2013). In both cases, following cessation of exposure, plasma E2 concentrations recovered to control levels before plasma VTG concentrations recovered (Villeneuve et al. 2009; 2013).
- Shroeder et al. (in preparation) reported effects on plasma E2 concentrations within 4 h of initiating exposure to 5 or 50 ug/L fadrozole. Plasma VTG concentrations did not decline until 24 h or later (Schroeder et al. 2009; Villeneuve et al. 2009; 2013).
- In female fathead minnows exposed to 300 ug/L prochloraz, plasma E2 concentrations were significantly reduced after 12 h of exposure, while plasma VTG concentrations were not significantly reduced until 24 h of exposure (Skolness et al. 2011).
- Ankley et al. (2009) reported significant reductions in plasma E2 in female fathead minnows following 24 h of exposure to 30 ug/L prochloraz. In the same study, plasma VTG concentrations did not significantly decline until 48 h of exposure, and then only at 300 ug/L prochloraz.
- In a 21 d exposure to prochloraz, plasma E2 was significantly reduced in females exposed to 300 ug prochloraz/L, while plasma VTG was significantly reduced in females exposed to 100 ug/L (Ankley et al. 2005).
Uncertainties and Inconsistencies
- In several studies, significant decreases in plasma vitellogenin are detected at lower concentrations than those that result in significant decreases in plasma E2. However, detection of differences in plasma VTG is ofen enhanced by the greater dynamic range in the concentrations of the protein that occur in plasma, compared to the dynamic range of steroid hormone concentrations.
Quantitative Understanding of the Linkage
- A computational model developed by Cheng et al. (2016) is capable of simulating altered plasma VTG concentrations associated with changes in plasma E2 concentrations in female fathead minnows. This model has been used to generate a quantitative response-response relationship that can predict steady state plasma VTG concentrations for a given steady state plasma E2 concentration (Conolly et al. 2017).
- The model and response-response relationship were developed based on data from exposures to the model aromatase inhibitor fadrozole. The validity of the model-based predictions/relationships for other stressors and species has not yet been established.
- Li et al. (2011) also developed a physiologically-based computational model of the adult female fathead minnow (Pimephales promelas) hypothalamic-pituitary-gonadal axis. Conceptually, this model could also be applied to derive a quantitative response-response relationship between plasma E2 and plasma VTG concentrations. The Li et al. model was calibrated based on data from exposures to 17alpha-ethynylestradiol and 17ß-trenbolone. Neither its validity for other stressors or speices, nor its agreement with the Cheng et al. (2016) model have been examined in detail.
Under long term, steady state exposure conditions, the following equation can be used to estimate the µM concentration of plasma vitellogenin (downstream event) from the µM concentration of plasma 17ß-estradiol.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
This key event relationship likely applies to oviparous vertebrates only.
- Key enzymes needed to synthesize 17β-estradiol first appear in the common ancestor of amphioxus and vertebrates (Baker 2011).
- Vitellogenesis is common to a range of egg-laying vertebrates and invertebrates. However, in the case of invertebrates, vitellogenins are transported via hemolymph rather than plasma and vitellogenesis is regulated by invertebrate hormones, not estradiol.
- Ankley GT, Jensen KM, Makynen EA, Kahl MD, Korte JJ, Hornung MW, Henry TR, Denny JS, Leino RL, Wilson VS, Cardon MC, Hartig PC, Gray LE. Effects of the androgenic growth promoter 17-beta-trenbolone on fecundity and reproductive endocrinology of the fathead minnow. Environ Toxicol Chem. 2003 Jun;22(6):1350-60.
- 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. 2011. Origin and diversification of steroids: co-evolution of enzymes and nuclear receptors. Molecular and cellular endocrinology 334(1-2): 14-20.
- Chang TC, Nardulli AM, Lew D, and Shapiro, DJ. 1992. The role of estrogen response elements in expression of the Xenopus laevis vitellogenin B1 gene. Molecular Endocrinology 6:3, 346-354\
- Chang TC, Nardulli AM, Lew D, Shapiro DJ. The role of estrogen response elements in expression of the Xenopus laevis vitellogenin B1 gene. Mol Endocrinol. 1992 Mar;6(3):346-54.
- Cheng WY, Zhang Q, Schroeder A, Villeneuve DL, Ankley GT, Conolly R. Computational Modeling of Plasma Vitellogenin Alterations in Response to Aromatase Inhibition in Fathead Minnows. Toxicol Sci. 2016 Nov;154(1):78-89.
- Deeley RG, Mullinix DP, Wetekam W, Kronenberg HM, Meyers M, Eldridge JD, Goldberger RF. Vitellogenin synthesis in the avian liver. Vitellogenin is the precursor of the egg yolk phosphoproteins. J Biol Chem. 1975 Dec 10;250(23):9060-6.
- 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.
- Ho DM, L'Italien J, Callard IP. 1980. Studies on reptilian yolk:Chrysemys. Comp. Biochem. Physiol. 65B: 139-144.
- Ho SM. Endocrinology of vitellogenesis. In Norris DO, Jones RE Eds, Hormones and reproduction in fishes, amphibians, and reptiles, Plenum, New York, (1987), pp. 146-169.
- 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.
- 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.
- Miller WL. 1988. Molecular biology of steroid hormone synthesis. Endocrine reviews 9(3): 295-318.
- Nagahama Y, Yoshikumi M, Yamashita M, Sakai N, Tanaka M. 1993. Molecular endocrinology of oocyte growth and maturation in fish. Fish Physiology and Biochemistry 11: 3-14.
- 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.
- 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.
- Teo BY, Tan NS, Lim EH, Lam TJ, Ding JL. A novel piscine vitellogenin gene: structural and functional analyses of estrogen-inducible promoter. Mol Cell
- 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.
- Wangh LJ, Knowland J. 1975. Synthesis of vitellogenin in cultures of male and female frog liver regulated by estradiol treatment in vitro. Proc. Nat. Acad. Sci. 72: 3172-3175.