This AOP is licensed under the 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.

AOP: 29


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 agonism 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 agonism leading to reproductive dysfunction
The current version of the Developer's Handbook will be automatically populated into the Handbook Version field when a new AOP page is created.Authors have the option to switch to a newer (but not older) Handbook version any time thereafter. More help
Handbook Version v1.0

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


The names and affiliations of the individual(s)/organisation(s) that created/developed the AOP. More help
  • Professor Tom Hutchinson, School of Biological Sciences, Plymouth, UK [tom.hutchinson{at}]
  • Dan Villeneuve, US EPA Mid-Continent Ecology Division, Duluth, MN. [villeneuve.dan{at}]

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
Allie Always   (email point of contact)


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


This field is used to identify coaches who supported the development of the AOP.Each coach selected must be a registered author. More help

OECD Information Table

Provides users with information concerning how actively the AOP page is being developed and whether it is part of the OECD Workplan and has been reviewed and/or endorsed. OECD Project: Assigned upon acceptance onto OECD workplan. This project ID is managed and updated (if needed) by the OECD. OECD Status: For AOPs included on the OECD workplan, ‘OECD status’ tracks the level of review/endorsement of the AOP . This designation is managed and updated by the OECD. Journal-format Article: The OECD is developing co-operation with Scientific Journals for the review and publication of AOPs, via the signature of a Memorandum of Understanding. When the scientific review of an AOP is conducted by these Journals, the journal review panel will review the content of the Wiki. In addition, the Journal may ask the AOP authors to develop a separate manuscript (i.e. Journal Format Article) using a format determined by the Journal for Journal publication. In that case, the journal review panel will be required to review both the Wiki content and the Journal Format Article. The Journal will publish the AOP reviewed through the Journal Format Article. OECD iLibrary published version: OECD iLibrary is the online library of the OECD. The version of the AOP that is published there has been endorsed by the OECD. The purpose of publication on iLibrary is to provide a stable version over time, i.e. the version which has been reviewed and revised based on the outcome of the review. AOPs are viewed as living documents and may continue to evolve on the AOP-Wiki after their OECD endorsement and publication.   More help
OECD Project # OECD Status Reviewer's Reports Journal-format Article OECD iLibrary Published Version
This AOP was last modified on May 26, 2024 20:39

Revision dates for related pages

Page Revision Date/Time
Agonism, Estrogen receptor September 16, 2017 10:14
Reduction, Cumulative fecundity and spawning March 20, 2017 17:52
Increase, Plasma vitellogenin concentrations September 16, 2017 10:14
Increase, Vitellogenin synthesis in liver September 16, 2017 10:14
Increase, Renal pathology due to VTG deposition September 16, 2017 10:14
Decrease, Population growth rate January 03, 2023 09:09
Altered, Reproductive behaviour December 03, 2016 16:33
Altered, Larval development December 03, 2016 16:33
Impaired development of, Reproductive organs December 03, 2016 16:33
Agonism, Estrogen receptor leads to Impaired development of, Reproductive organs December 03, 2016 16:37
Increase, Renal pathology due to VTG deposition leads to Altered, Larval development December 03, 2016 16:37
Agonism, Estrogen receptor leads to Increase, Vitellogenin synthesis in liver December 03, 2016 16:37
Increase, Plasma vitellogenin concentrations leads to Increase, Renal pathology due to VTG deposition November 29, 2016 20:01
Agonism, Estrogen receptor leads to Altered, Reproductive behaviour December 03, 2016 16:37
Increase, Vitellogenin synthesis in liver leads to Increase, Plasma vitellogenin concentrations December 03, 2016 16:37


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 AOP describes the linkages between agonism of the estrogen receptor (ER) and population relevant impacts on reproductive function in a range of oviparous vertebrates including amphibia, birds and fish. The information in this AOP for ER agonism does not apply to mammalian species and also not to invertebrates.

Amphibians are sensitive to ER agonists during the transformation from larval tadpole to juvenile frog as these include critical periods of metamorphic development and sex differentiation that may be particularly sensitive to endocrine disruption. Larvae exposed to ER agonists during mid-metamorphosis show developmental effects, a subsequent strong female-biased sex ratio which suggests that transient early life-stage exposure to ER agonists can produce effects on the reproductive organs that persist into the beginning of adult life-stages. Birds are also known to be vulnerable to ER agonists causing disruption of estrogen-regulated functions such as sexual differentiation and sexual behaviour. Model species such as the Japanese quail have been widely used as a model for studying various long-term effects after embryonic exposure to ER agonists. In terms of teleost fish, exposure to ER agonists leads to a suite of adverse outcomes depending upon whether exposures occur during or beyond the larval, juvenile and adult life-stages. For example, aquatic exposure to potent ER agonists during the larval and juvenile life-stages may leads to gonadal and renal pathology and skewed-sex ratios in adult fish (potentially 100% females). Larval, juvenile and adult male fish exposed to the same ER agonists display abnormal plasma or whole body levels of vitellogenin (VTG). Cumulative fecundity in adult populations is also adversely affected by ER agonists and this is an important endpoint in the OECD Test Guideline 229 Fish Short Term Reproduction Assay. In summary, this AOP has utility in supporting the application of test methods for detecting ER agonists, or in silico predictions of the ability of chemicals to act as ER agonists and cause impaired sexual development and reproductive dysfunction.

AOP Development Strategy


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


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


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 111 Agonism, Estrogen receptor Agonism, Estrogen receptor
KE 78 Reduction, Cumulative fecundity and spawning Reduction, Cumulative fecundity and spawning
KE 220 Increase, Plasma vitellogenin concentrations Increase, Plasma vitellogenin concentrations
KE 307 Increase, Vitellogenin synthesis in liver Increase, Vitellogenin synthesis in liver
KE 252 Increase, Renal pathology due to VTG deposition Increase, Renal pathology due to VTG deposition
AO 360 Decrease, Population growth rate Decrease, Population growth rate
AO 363 Altered, Reproductive behaviour Altered, Reproductive behaviour
AO 339 Altered, Larval development Altered, Larval development
AO 364 Impaired development of, Reproductive organs Impaired development of, Reproductive organs

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
Juvenile High
Embryo 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
fathead minnow Pimephales promelas High NCBI
Japanese quail Coturnix japonica High NCBI
northern leopard frog Rana pipiens High NCBI
medaka Oryzias latipes High NCBI
zebrafish Danio rerio High NCBI

Sex Applicability

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

In terms of the criteria associated with Key Events in this AOP, the following observations have been made as shown in parentheses []:

1. concordance of dose-response relationships?; [There is strong dose-response relationship concordance over a wide range of experimental studies using ER agonists in well-defined animals models, including amphibians, birds and fish];

2. temporal concordance among the key events and adverse effect?; [There is strong temporal concordance from partial and full life-cycle studies using ER agonists in well-defined animals models];

3. strength, consistency, and specificity of association of adverse effect and initiating event?; [In fish, there is a strong and consistent association between ER agonist exposure, disruption of sexual development and reproductive dysfunction. The same is true for amphibians and birds although the published studies are less numerous.];

4. biological plausibility, coherence, and consistency of the experimental evidence?; [For the oviparous species frequently studied to date, there is a high level of biological plausibility, coherence, and consistency across the published experimental evidence];

5. alternative mechanisms that logically present themselves and the extent to which they may distract from the postulated AOP?; [Other mechanisms of relevance to estrogen-mediated sexual development include the disruption of the steroidogenic pathways (eg see the AOP for aromatase inhibition in fish) and this alterative AOP should be considered alongside ER agonism in the context of elevated plasma VTG levels, disrupted sexual development of reproductive dysfunction. The possibility of other AOPs arisign should be kept in mind through critical analysis of the updated pree-reviewed literature];

6. uncertainties, inconsistencies and data gaps?; [An important aspect of uncertainty is quantifying the degree to which disrupted sexual development leads to a population-relevant impact via reproductive dysfunction. Experimental and validated population modelling is a key need to address this data gap and uncertainty. In the author's view, there are no major scientific inconsistencies with regard to the ER agonism AOP and associated Key Events].

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 Applicability, Taxonomic Applicability, Sex Applicability In terms of the taxonomic domains of applicability, exposure to ER agonists is capable of disrupting sexual development and causing reproductive dysfunction in oviparous species suchas amphibians, birds and fish (see examples of peer-revised literature cited below).

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

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

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


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

Dang, Z., Traas, T., Vermeire, T. (2011) Evaluation of the fish short term reproduction assay for detecting endocrine disrupters. Chemosphere 85: 1592-1603

Halldin, K., Axelsson, J., Brunström, B., (2005) Effects of endocrine modulators on sexual differentiation and reproductive function in male Japanese quail. Brain Research Bulletin 65: 211-218

Hogan, N.S., Duarte, P., Wade, M.G., Lean, D.R.S., Trudeau, V.L. (2008) Estrogenic exposure affects metamorphosis and alters sex ratios in the northern leopard frog (Rana pipiens): Identifying critically vulnerable periods of development. General and Comparative Endocrinology 156: 515-523

Hutchinson T.H. (2002) Impacts of endocrine disrupters on fish development: opportunities for adapting OECD Test Guideline 210. Environmental Sciences 9: 439-450

Länge R., Hutchinson T.H., Croudace C.P., Siegmund F., Schweinfurth H., Hampe P., Panter G.H., Sumpter J.P. (2001) Effects of the synthetic oestrogen 17-ethinylestradiol over the life-cycle of the fathead minnow. Environmental Toxicology and Chemistry 20: 1216–1227

Leino, R.L., Jensen,K.M., Ankley, G.T. (2005) Gonadal histology and characteristic histopathology associated with endocrine disruption in the adult fathead minnow (Pimephales promelas). Environmental Toxicology and Pharmacology 19: 85-98

Ottinger, M.N., Carro, T., Bohannon, M., Baltos,L., Marcell, A.M., McKernan, M., Dean, K.M., Lavoie, E., Abdelnabi, M. (2013) Assessing effects of environmental chemicals on neuroendocrine systems: Potential mechanisms and functional outcomes. General and Comparative Endocrinology 190: 194-202