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Relationship: 252

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, Vitellogenin synthesis in liver

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

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
Aromatase inhibition leading to reproductive dysfunction adjacent High Moderate Cataia Ives (send email) Open for citation & comment WPHA/WNT Endorsed
Androgen receptor agonism leading to reproductive dysfunction (in repeat-spawning fish) adjacent High Moderate Evgeniia Kazymova (send email) Open for citation & comment WPHA/WNT Endorsed
Prolyl hydroxylase inhibition leading to reproductive dysfunction via increased HIF1 heterodimer formation adjacent High Moderate Allie Always (send email) Under Development: Contributions and Comments Welcome
Unknown MIE leading to reproductive dysfunction via increased HIF-1alpha transcription adjacent Evgeniia Kazymova (send email) Under Development: Contributions and Comments Welcome
Embryonic Activation of the AHR leading to Reproductive failure, via epigenetic down-regulation of GnRHR adjacent High Moderate Arthur Author (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 Moderate 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 Not Specified

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

See Plausibility below.

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

Vitellogenin synthesis in fish is localized in the liver and is well documented to be regulated by estrogens via interaction with estrogen receptors (Tyler et al. 1996; Tyler and Sumpter 1996; Arukwe and Goksøyr 2003). The vitellogenin gene contains estrogen repsonsive elements in its promoter region and site directed mutagenesis has shown these to be essential for estrogen-dependent expression of vitellogenin (Chang et al. 1992; Teo et al. 1998). Liver is not regarded as a major site of E2 synthesis (Norris 2007), therefore the majority of E2 in liver comes from the circulation.

  • Estrogen regulates expression of the vitellogenin gene in the amphibian Xenopus laevis (Skipper and Hamilton, 1977).

 

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

Based on the limited set of studies available to date, there are no known inconsistencies.

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

Key enzymes needed to synthesize 17β-estradiol first appear in the common ancestor of amphioxus and vertebrates (Baker 2011). However, non-oviparous vertebrates do not require vitellogenin. Consequently, this KER is applicable to oviparous vertebrates.

References

List of the literature that was cited for this KER description. More help
  • Ankley GT, Bencic D, Cavallin JE, Jensen KM, Kahl MD, Makynen EA, et al. 2009b. Dynamic nature of alterations in the endocrine system of fathead minnows exposed to the fungicide prochloraz. Toxicol Sci 112(2): 344-353.
  • Ankley GT, Bencic DC, Cavallin JE, Jensen KM, Kahl MD, Makynen EA, et al. 2009a. Dynamic nature of alterations in the endocrine system of fathead minnows exposed to the fungicide prochloraz. Toxicological sciences : an official journal of the Society of Toxicology 112(2): 344-353.
  • Ankley GT, Miller DH, Jensen KM, Villeneuve DL, Martinovic D. 2008. Relationship of plasma sex steroid concentrations in female fathead minnows to reproductive success and population status. Aquatic toxicology 88(1): 69-74.
  • 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.
  • 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\
  • Ekman DR, Villeneuve DL, Teng Q, Ralston-Hooper KJ, Martinovic-Weigelt D, Kahl MD, et al. 2011. Use of gene expression, biochemical and metabolite profiles to enhance exposure and effects assessment of the model androgen 17beta-trenbolone in fish. Environmental toxicology and chemistry / SETAC 30(2): 319-329.
  • Iguchi T, Irie F, Urushitani H, Tooi O, Kawashima Y, Roberts M, et al. 2006. Availability of in vitro vitellogenin assay for screening of estrogenic and anti-estrogenic activities of environmental chemicals. Environ Sci 13(3): 161-183.
  • Li Z, Kroll KJ, Jensen KM, Villeneuve DL, Ankley GT, Brian JV, et al. 2011a. A computational model of the hypothalamic: pituitary: gonadal axis in female fathead minnows (Pimephales promelas) exposed to 17alpha-ethynylestradiol and 17beta-trenbolone. BMC systems biology 5: 63.
  • Murphy CA, Rose KA, Rahman MS, Thomas P. 2009. Testing and applying a fish vitellogenesis model to evaluate laboratory and field biomarkers of endocrine disruption in Atlantic croaker (Micropogonias undulatus) exposed to hypoxia. Environmental toxicology and chemistry / SETAC 28(6): 1288-1303.
  • Murphy CA, Rose KA, Thomas P. 2005. Modeling vitellogenesis in female fish exposed to environmental stressors: predicting the effects of endocrine disturbance due to exposure to a PCB mixture and cadmium. Reproductive toxicology 19(3): 395-409.
  • Navas JM, Segner H. 2006. Vitellogenin synthesis in primary cultures of fish liver cells as endpoint for in vitro screening of the (anti)estrogenic activity of chemical substances. Aquat Toxicol 80(1): 1-22.
  • Norris DO. 2007. Vertebrate Endocrinology. Fourth ed. New York: Academic Press.
  • Schultz IR, Orner G, Merdink JL, Skillman A. 2001. Dose-response relationships and pharmacokinetics of vitellogenin in rainbow trout after intravascular administration of 17alpha-ethynylestradiol. Aquatic toxicology 51(3): 305-318.
  • Skipper JK, Hamilton TH. 1977. Regulation by estrogen of the vitellogenin gene. Proc Natl Acad Sci USA 74:2384-2388.
  • Skolness SY, Durhan EJ, Garcia-Reyero N, Jensen KM, Kahl MD, Makynen EA, et al. 2011. Effects of a short-term exposure to the fungicide prochloraz on endocrine function and gene expression in female fathead minnows (Pimephales promelas). Aquat Toxicol 103(3-4): 170-178.
  • Sun L, Wen L, Shao X, Qian H, Jin Y, Liu W, et al. 2010. Screening of chemicals with anti-estrogenic activity using in vitro and in vivo vitellogenin induction responses in zebrafish (Danio rerio). Chemosphere 78(7): 793-799.
  • 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 Endocrinol. 1998 Nov 25;146(1-2):103-20. PubMed PMID: 10022768.
  • 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, Breen M, Bencic DC, Cavallin JE, Jensen KM, Makynen EA, et al. 2013. Developing Predictive Approaches to Characterize Adaptive Responses of the Reproductive Endocrine Axis to Aromatase Inhibition: I. Data Generation in a Small Fish Model. Toxicological sciences : an official journal of the Society of Toxicology.
  • Villeneuve DL, Mueller ND, Martinovic D, Makynen EA, Kahl MD, Jensen KM, et al. 2009. Direct effects, compensation, and recovery in female fathead minnows exposed to a model aromatase inhibitor. Environ Health Perspect 117(4): 624-631.