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Relationship: 1386

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Reduction, Plasma 17beta-estradiol concentrations leads to Reduction, Plasma vitellogenin concentrations

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Reduction, Plasma 17beta-estradiol concentrations

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Reduction, Plasma vitellogenin concentrations

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name	Adjacency	Weight of Evidence	Quantitative Understanding	Point of Contact	Author Status	OECD Status
Androgen receptor agonism leading to reproductive dysfunction (in repeat-spawning fish)	non-adjacent	High	Moderate	Dan Villeneuve (send email)	Open for citation & comment	WPHA/WNT Endorsed
Aromatase inhibition leading to reproductive dysfunction	non-adjacent	High	Moderate	Dan Villeneuve (send email)	Open for citation & comment	WPHA/WNT Endorsed
Inhibition of thyroid peroxidase leading to impaired fertility in fish	adjacent	High	High	June-Woo Park (send email)	Open for comment. Do not cite	Under Development
Inhibition of 5α-reductase leading to impaired fecundity in female fish	adjacent	High	High	Young Jun Kim (send email)	Open for citation & comment	Under Development
Embryonic Activation of the AHR leading to Reproductive failure, via epigenetic down-regulation of GnRHR	non-adjacent	High	Moderate	Jon Doering (send email)	Under development: Not open for comment. Do not cite
Androgen receptor agonism leading to reproduction dysfunction （in zebrafish）	non-adjacent	High	High	Hongling Liu (send email)	Under development: Not open for comment. Do not cite

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER. More help

Term	Scientific Term	Evidence	Link
fathead minnow	Pimephales promelas	High	NCBI
Fundulus heteroclitus	Fundulus heteroclitus	High	NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help

Sex	Evidence
Female	High

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER. More help

Term	Evidence
Adult, reproductively mature	High

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

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 Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings. Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Updated 2017-03-17

Biological Plausibility

Addresses the biological rationale for a connection between KEupstream and KEdownstream. This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured. More help

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).

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

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

Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

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.

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references. More help

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

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.

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

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.

y=0.2855e^(365.55x) Response-response plot

Time-scale

Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

Known Feedforward/Feedback loops influencing this KER

Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

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.

References

List of the literature that was cited for this KER description. More help

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.