This Key Event Relationship is licensed under the Creative Commons BY-SA license. This license allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use. If you remix, adapt, or build upon the material, you must license the modified material under identical terms.
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
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER).
More help
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 | Evgeniia Kazymova (send email) | Open for citation & comment | WPHA/WNT Endorsed |
| Aromatase inhibition leading to reproductive dysfunction | non-adjacent | High | Moderate | Cataia Ives (send email) | Open for citation & comment | WPHA/WNT Endorsed |
| Inhibition of thyroid peroxidase leading to impaired fertility in fish | adjacent | High | High | Cataia Ives (send email) | Open for comment. Do not cite | Under Development |
| Inhibition of 5α-reductase leading to impaired fecundity in female fish | adjacent | High | High | Cataia Ives (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 | Arthur Author (send email) | Under development: Not open for comment. Do not cite | |
| Androgen receptor agonism leading to reproduction dysfunction （in zebrafish） | non-adjacent | High | High | 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
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 |
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.
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
| ID | Experimental Design | Species | Upstream Observation | Downstream Observation | Citation (first author, year) | Notes |
|---|
Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP.
More help
| Title | First Author | Biological Plausibility |
Dose Concordance |
Temporal Concordance |
Incidence Concordance |
|---|
Biological Plausibility
Dose Concordance Evidence
Temporal Concordance Evidence
Incidence Concordance Evidence
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.
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
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.
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
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.