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Relationship: 129

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

Antagonism, Estrogen receptor leads to Reduction, Vitellogenin synthesis in liver

Upstream event

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

Antagonism, Estrogen receptor

Downstream event

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

Reduction, Vitellogenin synthesis in liver

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
Estrogen receptor antagonism leading to reproductive dysfunction	adjacent	High	Low	Evgeniia Kazymova (send email)	Open for citation & comment	EAGMST Under Review

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

Life Stage Applicability

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

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

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

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 (Arukwe and Goksøyr 2003; Nelson and Habibi 2010; Tyler and Sumpter 1996; Tyler et al. 1996). During vitellogenic periods of the reproductive cycle, antagonism of the ER would be expected to reduce vitellogenin transcription and translation.

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

Eleven ER antagonists were shown to reduce in vitro E2-induced vitellogenin production by rainbow trout hepatocytes in a concentration-dependent manner (Petersen and Tollefsen 2012).
A review by Navas and Segner (Navas and Segner 2006) reports inhibition of E2-induced vitellogenin induction in primary fish liver cells to be useful for detecting anti-estrogens.
Methyl-piperidino-pyrazole (MPP), a synthetic mammalian ERα antagonist shown to antagonize activation of the tilapia ER, also reduced the ability of estradiol to stimulate vitellogenin production in tilapia injected with the compound in vivo (Davis et al. 2010).
A synthetic musk shown to act as a both a human and rainbow trout ERα antagonist inhibited E2-induced vitellogenin production in rainbow trout injected with the same compound (Simmons et al. 2010).
Tamoxifen inhibited vitellogenin induction in roach (Rutilus rutilus) liver explants exposed in vitro (Gerbron et al. 2010).
Hydroxytamoxifen inhibited vitellogenin induction in brown trout primary hepatocytes and rainbow trout and zebrafish liver cell lines (Christianson-Heiska and Isomaa 2008).
Nafoxidine and CI-628 inhibit estrogen-induced vitellogenin synthesis in roosters (Gschwendt 1975).

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

Some uncertainty remains regarding which ER subtype(s) regulates vitellogenin gene expression in the liver of fish. In general, the literature suggests a close interplay between several ER subtypes in the regulation of vitellogenesis. Consequently, at present, the key event relationship is generalized to impacts on all ER subtypes, even though it remains possible that impacts on a particular sub-type may drive the effect on vitellogenin transcription and translation.

Griffin et al. reported that morpholino knock-downs of either esr1 (ERα) or esr2b (ERβb) prevented estradiol-mediated induction of vitellogenin expression in zebrafish (Griffin et al. 2013).
Using selective agonists agonists and antagonists for ERα and ERβ, it was concluded that ERβ was primarily responsible for inducing vitellogenin production in rainbow trout and that compounds exhibiting ERα selectivity would not be detected using a vitellogenin bioassay (Leanos-Castaneda and Van Der Kraak 2007). However, a subsequent study conducted in tilapia concluded that agonistic and antagonistic characteristics of mammalian, isoform-specific ER agonists and antagonists, cannot be reliably extrapolated to piscine ERs (Davis et al. 2010).
Based on RNA interference knock-down experiments Nelson and Habibi proposed a model in which all ER subtypes are involved in E2-mediated vitellogenesis, with ERβ isoforms stimulating expression of both vitellogenin and ERα gene expression, and ERα helping to drive vitellogenesis, particularly as it becomes more abundant following sensitization (Nelson and Habibi 2010).

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

At present, we are not aware of any studies that have defined the quantitative relationship between measures of ER antagonism and the magnitude or severity of impaired vitellogenin transcription or translation in liver.

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

References

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

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 2:1-21.
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.
Petersen K, Tollefsen KE. 2012. Combined effects of oestrogen receptor antagonists on in vitro vitellogenesis. Aquatic toxicology 112-113:46-53.
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. Aquatic toxicology 80:1-22.
Davis LK, Katsu Y, Iguchi T, Lerner DT, Hirano T, Grau EG. 2010. Transcriptional activity and biological effects of mammalian estrogen receptor ligands on three hepatic estrogen receptors in mozambique tilapia. The Journal of steroid biochemistry and molecular biology 122:272-278.
Simmons DB, Marlatt VL, Trudeau VL, Sherry JP, Metcalfe CD. 2010. Interaction of galaxolide(r) with the human and trout estrogen receptor-alpha. The Science of the total environment 408:6158-6164.
Gerbron M, Geraudie P, Rotchell J, Minier C. 2010. A new in vitro screening bioassay for the ecotoxicological evaluation of the estrogenic responses of environmental chemicals using roach (rutilus rutilus) liver explant culture. Environmental toxicology 25:510-516.
Christianson-Heiska I, Isomaa B. 2008. The use of primary hepatocytes from brown trout (salmo trutta lacustris) and the fish cell lines rth-149 and zf-l for in vitro screening of (anti)estrogenic activity of wood extractives. Toxicology in vitro : an international journal published in association with BIBRA 22:589-597.
Gschwendt M. 1975. The effect of antiestrogens on egg yolk protein synthesis and estrogen-binding to chromatin in the rooster liver. Biochimica et biophysica acta 399:395-402.
Griffin LB, January KE, Ho KW, Cotter KA, Callard GV. 2013. Morpholino mediated knockdown of eralpha, erbetaa and erbetab mrnas in zebrafish (danio rerio) embryos reveals differential regulation of estrogen-inducible genes. Endocrinology.
Leanos-Castaneda O, Van Der Kraak G. 2007. Functional characterization of estrogen receptor subtypes, eralpha and erbeta, mediating vitellogenin production in the liver of rainbow trout. Toxicology and applied pharmacology 224:116-125.
Davis LK, Katsu Y, Iguchi T, Lerner DT, Hirano T, Grau EG. 2010. Transcriptional activity and biological effects of mammalian estrogen receptor ligands on three hepatic estrogen receptors in mozambique tilapia. The Journal of steroid biochemistry and molecular biology 122:272-278.
Nelson ER, Habibi HR. 2010. Functional significance of nuclear estrogen receptor subtypes in the liver of goldfish. Endocrinology 151:1668-1676.