Aop: 30

Title

A descriptive phrase which references both the Molecular Initiating Event and Adverse Outcome.It should take the form “MIE leading to AO”. For example, “Aromatase inhibition leading to reproductive dysfunction” where Aromatase inhibition is the MIE and reproductive dysfunction the AO. In cases where the MIE is unknown or undefined, the earliest known KE in the chain (i.e., furthest upstream) should be used in lieu of the MIE and it should be made clear that the stated event is a KE and not the MIE. More help

Estrogen receptor antagonism leading to reproductive dysfunction

Short name
A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help
Estrogen receptor antagonism leading to reproductive dysfunction

Graphical Representation

A graphical representation of the AOP.This graphic should list all KEs in sequence, including the MIE (if known) and AO, and the pair-wise relationships (links or KERs) between those KEs. More help
Click to download graphical representation template Explore AOP in a Third Party Tool
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Authors

The names and affiliations of the individual(s)/organisation(s) that created/developed the AOP. More help

Daniel L. Villeneuve, US EPA Mid-Continent Ecology Division (villeneuve.dan@epa.gov)

Point of Contact

The user responsible for managing the AOP entry in the AOP-KB and controlling write access to the page by defining the contributors as described in the next section.   More help
Dan Villeneuve   (email point of contact)

Contributors

Users with write access to the AOP page.  Entries in this field are controlled by the Point of Contact. More help
  • Dan Villeneuve

Status

Provides users with information concerning how actively the AOP page is being developed, what type of use or input the authors feel comfortable with given the current level of development, and whether it is part of the OECD AOP Development Workplan and has been reviewed and/or endorsed. OECD Status - Tracks the level of review/endorsement the AOP has been subjected to. OECD Project Number - Project number is designated and updated by the OECD. SAAOP Status - Status managed and updated by SAAOP curators. More help
Author status OECD status OECD project SAAOP status
Open for citation & comment EAGMST Under Review 1.12 Included in OECD Work Plan
This AOP was last modified on June 04, 2021 10:50

Revision dates for related pages

Page Revision Date/Time
Decrease, Population growth rate July 08, 2022 07:40
Antagonism, Estrogen receptor September 16, 2017 10:14
Reduction, Vitellogenin synthesis in liver May 27, 2021 01:10
Reduction, Plasma vitellogenin concentrations September 16, 2017 10:14
Reduction, Vitellogenin accumulation into oocytes and oocyte growth/development September 16, 2017 10:14
Reduction, Cumulative fecundity and spawning March 20, 2017 17:52
Antagonism, Estrogen receptor leads to Reduction, Vitellogenin synthesis in liver November 30, 2016 12:10
Reduction, Vitellogenin synthesis in liver leads to Reduction, Plasma vitellogenin concentrations March 20, 2017 12:58
Reduction, Plasma vitellogenin concentrations leads to Reduction, Vitellogenin accumulation into oocytes and oocyte growth/development March 20, 2017 13:21
Reduction, Vitellogenin accumulation into oocytes and oocyte growth/development leads to Reduction, Cumulative fecundity and spawning March 20, 2017 13:35
Reduction, Cumulative fecundity and spawning leads to Decrease, Population growth rate March 20, 2017 13:49

Abstract

A concise and informative summation of the AOP under development that can stand-alone from the AOP page. The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance. More help

This adverse outcome pathway details the linkage between antagonism of estrogen receptor in females and the adverse effect of reduced cumulative fecundity in repeat-spawning fish species. Cumulative fecundity is the most apical endpoint considered in the OECD 229 Fish Short Term Reproduction Assay. The OECD 229 assay serves as screening assay for endocrine disruption and associated reproductive impairment (OECD 2012a). Cumulative fecundity is one of several variables known to be of demographic significance in forecasting fish population trends. Therefore, this AOP has utility in supporting the application of measures of ER antagonism, or in silico predictions of the ability to antagonize ER as a means to identify chemicals with known potential to adversely affect fish populations.

AOP Development Strategy

Context

Used to provide background information for AOP reviewers and users that is considered helpful in understanding the biology underlying the AOP and the motivation for its development.The background should NOT provide an overview of the AOP, its KEs or KERs, which are captured in more detail below. More help

Strategy

Provides a description of the approaches to the identification, screening and quality assessment of the data relevant to identification of the key events and key event relationships included in the AOP or AOP network.This information is important as a basis to support the objective/envisaged application of the AOP by the regulatory community and to facilitate the reuse of its components.  Suggested content includes a rationale for and description of the scope and focus of the data search and identification strategy/ies including the nature of preliminary scoping and/or expert input, the overall literature screening strategy and more focused literature surveys to identify additional information (including e.g., key search terms, databases and time period searched, any tools used). More help

Summary of the AOP

This section is for information that describes the overall AOP. The information described in section 1 is entered on the upper portion of an AOP page within the AOP-Wiki. This is where some background information may be provided, the structure of the AOP is described, and the KEs and KERs are listed. More help

Events:

Molecular Initiating Events (MIE)
An MIE is a specialised KE that represents the beginning (point of interaction between a prototypical stressor and the biological system) of an AOP. More help
Key Events (KE)
A measurable event within a specific biological level of organisation. More help
Adverse Outcomes (AO)
An AO is a specialized KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help
Type Event ID Title Short name
MIE 112 Antagonism, Estrogen receptor Antagonism, Estrogen receptor
KE 285 Reduction, Vitellogenin synthesis in liver Reduction, Vitellogenin synthesis in liver
KE 221 Reduction, Plasma vitellogenin concentrations Reduction, Plasma vitellogenin concentrations
KE 309 Reduction, Vitellogenin accumulation into oocytes and oocyte growth/development Reduction, Vitellogenin accumulation into oocytes and oocyte growth/development
KE 78 Reduction, Cumulative fecundity and spawning Reduction, Cumulative fecundity and spawning
AO 360 Decrease, Population growth rate Decrease, Population growth rate

Relationships Between Two Key Events (Including MIEs and AOs)

This table summarizes all of the KERs of the AOP and is populated in the AOP-Wiki as KERs are added to the AOP.Each table entry acts as a link to the individual KER description page. More help

Network View

This network graphic is automatically generated based on the information provided in the MIE(s), KEs, AO(s), KERs and Weight of Evidence (WoE) summary tables. The width of the edges representing the KERs is determined by its WoE confidence level, with thicker lines representing higher degrees of confidence. This network view also shows which KEs are shared with other AOPs. More help

Prototypical Stressors

A structured data field that can be used to identify one or more “prototypical” stressors that act through this AOP. Prototypical stressors are stressors for which responses at multiple key events have been well documented. More help

Life Stage Applicability

The life stage for which the AOP is known to be applicable. More help
Life stage Evidence
Adult, reproductively mature High

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available. More help
Term Scientific Term Evidence Link
zebra danio Danio rerio NCBI
fathead minnow Pimephales promelas NCBI
medaka Oryzias latipes NCBI

Sex Applicability

The sex for which the AOP is known to be applicable. More help
Sex Evidence
Female High

Overall Assessment of the AOP

Addressess the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and Weight of Evidence (WoE) for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). More help
  • Overall Assessment of the AOP
  • Concordance of dose-response relationships:
  • In a 42 d static renewal exposure to tamoxifen, significant, concentration dependent reduction in the number of clutches and cumulative fecundity were observed for zebrafish (Wester et al. 2003).
  • A concentration-dependent reduction in circulating vitellogenin concentrations was detected in female medaka exposed to tamoxifen for 21 d (Sun et al. 2007b). Vitellogenin reductions occurred at a lower concentration (i.e., ≥ 25 μg tamoxifen/L) than reductions in fecundity (i.e., 625 μg tamoxifen/L).
  • Temporal concordance among the key events and adverse effect: To date, there are no time-course studies that allow for robust evaluation of the temporal concordance of the entire AOP. However, the temporal concordance of some of the key event relationships has been established. Specifically, reductions in transcription of vitellogenin mRNAs have been shown to precede changes in circulating vitellogenin concentrations.
  • Consistency:
  • In zebrafish exposed to tamoxifen, reductions in the number of clutches and cumulative egg production were predicted to result in population reductions, although this was in conjunction with altered sex ratios as a concurrent effect in a partial life-cycle test (Wester et al. 2003).
  • In medaka co-exposed to 17β-estradiol (E2; 200 ng/L) and 10, 50, or 250 μg tamoxifen/L, exposure to 250 μg tamoxifen significantly reduced fecundity compared to both controls and fish exposed to E2 alone (Sun et al. 2009).
  • Fecundity was significantly reduced in medaka exposed to 625 μg tamoxifen/L (Sun et al. 2007b).
  • Increases in atretic oocytes and oviducts filled with degenerated eggs were observed in female zebrafish exposed to tamoxifen (Wester et al. 2003). Reduced vitellogenin immuno staining was observed in tamoxifen-exposed zebrafish, based on blind semi-quantitative scoring (van der Ven et al. 2007; Wester et al. 2003). The results are therefore consistent with the AOP.
  • In Japanese medaka co-exposed to E2 and tamoxifen for 21 d, both plasma vitellogenin and fecundity were reduced in a tamoxifen concentration-dependent manner (Sun et al. 2009). Although from a co-exposure, the results are broadly consistent with the AOP.
  • In Japanese medaka exposed to tamoxifen for 21 d, plasma vitellogenin in females was reduced in a concentration-dependent manner and cumulative fecundity was reduced at the maximum concentration tested (Sun et al. 2007b). The results are consistent with the AOP.
  • Dietary exposure to tamoxifen was also shown to reduce circulating vitellogenin concentrations in female medaka (Chikae et al. 2004). The results are consistent with the AOP.
  • In tilapia co-injected with E2 or o,p-DDT, tamoxifen inhibited the stimulatory effects of E2 and o,p-DDT on plasma vitellogenin (measured as alkaline labile phosphorous). Alkaline labile phosphorous was not reduced following injection with tamoxifen alone (Leanos-Castaneda et al. 2002). These results are neither entirely consistent nor inconsistent with the AOP.
  • Uncertainties, inconsistencies, and data gaps:
  • In a 42 d in vivo, flow through, exposures to tamoxifen citrate, no significant reductions in circulating vitellogenin or cumulative fecundity were detected (Williams et al. 2007). The results are therefore inconsistent with the AOP.
  • 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 AOP is generalized to impacts on all ER subtypes, even though it remains possible that impacts on a particular sub-type may drive the adverse response.
  • 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).
  • Expression of both ERα1 and ERβ1 were strongly correlated with plasma vitellogenin concentrations over the reproductive cycle of rainbow trout (Nagler et al. 2012).
  • 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).
  • There remains uncertainty as to whether there is a direct biological linkage, as opposed to correlation only, between impaired VTG uptake into oocytes and impaired spawning/reduced cumulative fecundity. Plausible biological connections have been hypothesized but have not yet been tested experimentally.

Domain of Applicability

Addressess the relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context. More help

Life Stage: This AOP applies to sexually mature animals. Sex: This AOP applies to females. Taxonomic Applicability: Based on the taxonomic applicability of the component key events, this AOP could potentially apply to most oviparous chordates.

Domain(s) of Applicability

  • Sex: The AOP applies to females only
  • Life stages: The relevant life stages for this AOP are reproductively mature adults. This AOP does not apply to adult stages that lack a sexually mature ovary, for example as a result of seasonal or environmentally-induced gonadal senescence (i.e., through control of temperature, photo-period, etc. in a laboratory setting).
  • Taxonomic: At present, the assumed taxonomic applicability domain of this AOP is class Osteichthyes. In all likelihood, the AOP will also prove applicable to all classes of fish (e.g., Agnatha and Chondrithyes as well). Additionally, all the key events described should be conserved among all oviparous vertebrates, suggesting that the AOP may also have relevance for amphibians, reptiles, and birds. However, species-specific differences in reproductive strategies/life histories, ADME (adsorption, distribution, metabolism, and elimination), compensatory reproductive endocrine responses may influence the outcomes, particularly from a quantitative standpoint.

Essentiality of the Key Events

The essentiality of KEs can only be assessed relative to the impact of manipulation of a given KE (e.g., experimentally blocking or exacerbating the event) on the downstream sequence of KEs defined for the AOP. Consequently, evidence supporting essentiality is assembled on the AOP page, rather than on the independent KE pages that are meant to stand-alone as modular units without reference to other KEs in the sequence. The nature of experimental evidence that is relevant to assessing essentiality relates to the impact on downstream KEs and the AO if upstream KEs are prevented or modified. This includes: Direct evidence: directly measured experimental support that blocking or preventing a KE prevents or impacts downstream KEs in the pathway in the expected fashion. Indirect evidence: evidence that modulation or attenuation in the magnitude of impact on a specific KE (increased effect or decreased effect) is associated with corresponding changes (increases or decreases) in the magnitude or frequency of one or more downstream KEs. More help

Evidence Assessment

Addressess the biological plausibility, empirical support, and quantitative understanding from each KER in an AOP. More help

The weight of evidence for each of the KERs comprising the AOP are ranked moderate to strong. Biological plausibility at the molecular and cellular level of the early key events is very strong. Some uncertainties regarding the mechanistic details of the connection between reduced vtg availability and uptake limit the strength of evidence to some degree. However, there are considerable evidence to support the idea that ER antagonism can ultimately lead to reproductive failure. Overall weight of evidence is moderate.

Known Modulating Factors

Modulating factors (MFs) may alter the shape of the response-response function that describes the quantitative relationship between two KES, thus having an impact on the progression of the pathway or the severity of the AO.The evidence supporting the influence of various modulating factors is assembled within the individual KERs. More help

Quantitative Understanding

Optional field to provide quantitative weight of evidence descriptors.  More help

A quantitative relationship between ER antagonism (the MIE) and reductions in vitellogenin transcription and translation have not been well established. However, a correlative relationship between plasma vitellogenin concentrations and cumulative fecundity has been reported (Miller et al. 2007) and applied for quantitative modeling (Ankley et al.

Considerations for Potential Applications of the AOP (optional)

Addressess potential applications of an AOP to support regulatory decision-making.This may include, for example, possible utility for test guideline development or refinement, development of integrated testing and assessment approaches, development of (Q)SARs / or chemical profilers to facilitate the grouping of chemicals for subsequent read-across, screening level hazard assessments or even risk assessment. More help

References

List of the literature that was cited for this AOP. More help
  • OECD. 2012a. Test no. 229: Fish short term reproduction assay. Paris, France:Organization for Economic Cooperation and Development.
  • Wester P, van den Brandhof E, Vos J, van der Ven L. 2003. Identification of endocrine disruptive effects in the aquatic environment - a partial life cycle assay in zebrafish. (RIVM Report). Bilthoven, the Netherlands:Joint Dutch Environment Ministry
  • Sun L, Zha J, Spear PA, Wang Z. 2007b. Tamoxifen effects on the early life stages and reproduction of japanese medaka (oryzias latipes). Environmental toxicology and pharmacology 24:23-29.
  • Sun L, Zha J, Wang Z. 2009. Effects of binary mixtures of estrogen and antiestrogens on japanese medaka (oryzias latipes). Aquatic toxicology 93:83-89.
  • Williams TD, Caunter JE, Lillicrap AD, Hutchinson TH, Gillings EG, Duffell S. 2007. Evaluation of the reproductive effects of tamoxifen citrate in partial and full life-cycle studies using fathead minnows (pimephales promelas). Environmental toxicology and chemistry / SETAC 26:695-707.
  • van der Ven LT, van den Brandhof EJ, Vos JH, Wester PW. 2007. Effects of the estrogen agonist 17beta-estradiol and antagonist tamoxifen in a partial life-cycle assay with zebrafish (danio rerio). Environmental toxicology and chemistry / SETAC 26:92-99.
  • Chikae M, Ikeda R, Hasan Q, Morita Y, Tamiya E. 2004. Effects of tamoxifen, 17alpha-ethynylestradiol, flutamide, and methyltestosterone on plasma vitellogenin levels of male and female japanese medaka (oryzias latipes). Environmental toxicology and pharmacology 17:29-33.
  • 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.
  • 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.
  • 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.
  • Nagler JJ, Cavileer TD, Verducci JS, Schultz IR, Hook SE, Hayton WL. 2012. Estrogen receptor mrna expression patterns in the liver and ovary of female rainbow trout over a complete reproductive cycle. General and comparative endocrinology 178:556-561.
  • Nelson ER, Habibi HR. 2010. Functional significance of nuclear estrogen receptor subtypes in the liver of goldfish. Endocrinology 151:1668-1676.
  • Miller DH, Jensen KM, Villeneuve DL, Kahl MD, Makynen EA, Durhan EJ, Ankley GT. 2007. Linkage of biochemical responses to population-level effects: a case study with vitellogenin in the fathead minnow (Pimephales promelas). Environ. Toxicol. Chem. 26: 521-527.