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Aop: 29

AOP Title

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Estrogen receptor agonism leading to reproductive dysfunction

Short name:

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Estrogen receptor agonism leading to reproductive dysfunction

Authors

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  • Professor Tom Hutchinson, School of Biological Sciences, Plymouth, UK [tom.hutchinson{at}plymouth.ac.uk]
  • Dan Villeneuve, US EPA Mid-Continent Ecology Division, Duluth, MN. [villeneuve.dan{at}epa.gov]

Point of Contact

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Tom Hutchinson

Contributors

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  • Tom Hutchinson

Status

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Author status OECD status OECD project SAAOP status
Under development: Not open for comment. Do not cite Under Development 1.29 Included in OECD Work Plan


This AOP was last modified on December 03, 2016 16:37

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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 trajectory March 20, 2017 17:53
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

Abstract

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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.


Background (optional)

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This optional section should be 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.

Instructions

To add background information, click Edit in the upper right hand menu on the AOP page. Under the “Background (optional)” field, a text editable form provides ability to edit the Background.  Clicking ‘Update AOP’ will update these fields.


Summary of the AOP

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Stressors

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Describes stressors known to trigger the MIE and provides evidence supporting that initiation. This will often be a list of prototypical compounds demonstrated to interact with the target molecule in the manner detailed in the MIE description to initiate a given pathway (e.g., 2,3,7,8-TCDD as a prototypical AhR agonist; 17α-ethynyl estradiol as a prototypical ER agonist). However, depending on the information available, this could also refer to chemical categories (i.e., groups of chemicals with defined structural features known to trigger the MIE). It can also include non-chemical stressors such as genetic or environmental factors. The evidence supporting the stressor will typically consist of a brief description and citation of literature showing that particular stressors can trigger the MIE.

Instructions

To add a stressor associated with an AOP, under “Summary of the AOP” click ‘Add Stressor’ will bring user to the “New Aop Stressor” page. In the Name field, user can search for stressor by name. Choosing a stressor from the resulting drop down populates the field. Selection of an Evidence level from the drop down menu and add any supporting evidence in the text box. Click ‘Add stressor’ to add the stressor to the AOP page.


Molecular Initiating Event

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Title Short name
Agonism, Estrogen receptor Agonism, Estrogen receptor

Key Events

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Title Short name
Reduction, Cumulative fecundity and spawning Reduction, Cumulative fecundity and spawning
Increase, Plasma vitellogenin concentrations Increase, Plasma vitellogenin concentrations
Increase, Vitellogenin synthesis in liver Increase, Vitellogenin synthesis in liver
Increase, Renal pathology due to VTG deposition Increase, Renal pathology due to VTG deposition

Adverse Outcome

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Title Short name
Decrease, Population trajectory Decrease, Population trajectory
Altered, Reproductive behaviour Altered, Reproductive behaviour
Altered, Larval development Altered, Larval development
Impaired development of, Reproductive organs Impaired development of, Reproductive organs

Relationships Between Two Key Events (Including MIEs and AOs)

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Network View

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Life Stage Applicability

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Life stage Evidence
Juvenile Strong
Embryo Strong

Taxonomic Applicability

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Term Scientific Term Evidence Link
fathead minnow Pimephales promelas Strong NCBI
Japanese quail Coturnix japonica Strong NCBI
northern leopard frog Rana pipiens Strong NCBI
medaka Oryzias latipes Strong NCBI
zebrafish Danio rerio Strong NCBI

Sex Applicability

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Sex Evidence
Male Strong

Graphical Representation

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Click to download graphical representation template

Overall Assessment of the AOP

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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

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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

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The essentiality of various of the KEs is influential in considering confidence in an overall hypothesised AOP for potential regulatory application being secondary only to biological plausibility of KERs (Meek et al., 2014; 2014a). The defining question for determining essentiality (included in Annex 1) relates to whether or not downstream KEs and/or the AO is prevented if an upstream event is experimentally blocked. It is assessed, generally, then, on the basis of direct experimental evidence of the absence/reduction of downstream KEs when an upstream KE is blocked or diminished (e.g., in null animal models or reversibility studies). Weight of evidence for essentiality of KEs would be considered high if there is direct evidence from specifically designed experimental studies illustrating essentiality for at least one of the important key events [e.g., stop/reversibility studies, antagonism, knock out models, etc.) moderate if there is indirect 25 evidence that experimentally induced change of an expected modulating factor attenuates or augments a key event (e.g., augmentation of proliferative response (KEupstream) leading to increase in tumour formation (KEdownstream or AO)) and weak if there is no or contradictory experimental evidence of the essentiality of any of the KEs (Annex 1).

Instructions

To edit the “Essentiality of the Key Events” section, on an AOP page, in the upper right hand menu, click ‘Edit.’ This brings you to a page entitled, “Editing AOP.” Scroll down to the “Essentiality of the Key Events” section, where a text entry box allows you to submit text. In the upper right hand menu, click ‘Update AOP’ to save your changes and return to the AOP page.  The new text should appear under the “Essentiality of the Key Events” section on the AOP page.


Weight of Evidence Summary

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This involves evaluation of the Overall AOP based on Relative Level of Confidence in the KERs, Essentiality of the KEs and Degree of Quantitative Understanding based on Annexes 1 and 2. Annex 1 (“Guidance for assessing relative level of confidence in the Overall AOP”) guides consideration of the weight of evidence or degree of confidence in the predictive relationship between pairs of KEs based on KER descriptions and support for essentiality of KEs. It is designed to facilitate assignment of categories of high, moderate or low against specific considerations for each a series of defined element based on current experience in assessing MOAs/AOPs. In addition to increasing consistency through delineation of defining questions for the elements and the nature of evidence associated with assignment to each of the categories, importantly, the objective of completion of Annex 1 is to transparently delineate the rationales for the assignment based on the specified considerations. While it is not necessary to repeat lengthy text which appears in earlier parts of the document, the entries for the rationales should explicitly express the reasoning for assignment to the categories, based on the considerations for high, moderate or low weight of evidence included in the columns for each of the relevant elements. 24 While the elements can be addressed separately for each of the KERs, the essentiality of the KEs within the AOP is considered collectively since their interdependence is often illustrated through prevention or augmentation of an earlier or later key event. Where it is not possible to experimentally assess the essentiality of the KEs within the AOP (i.e., there is no experimental model to prevent or augment the key events in the pathway), this should be noted. Identified limitations of the database to address the biological plausibility of the KERs, the essentiality of the KEs and empirical support for the KERs are influential in assigning the categories for degree of confidence (i.e., high, moderate or low). Consideration of the confidence in the overall AOP is based, then, on the extent of available experimental data on the essentiality of KEs and the collective consideration of the qualitative weight of evidence for each of the KERs, in the context of their interdependence leading to adverse effect in the overall AOP. Assessment of the overall AOP is summarized in the Network View, which represents the degree of confidence in the weight of evidence both for the rank ordered elements of essentiality of the key events and biological plausibility and empirical support for the interrelationships between KEs. The AOP-Wiki provides such a network graphic based on the information provided in the MIE, KE, AO, and KER tables. The Key Event Essentiality calls are used to determine the size of each key event node with larger sizes representing higher confidence for essentiality. The Weight of Evidence summary in the KER table is used to determine the width of the lines connecting the key events with thicker lines representing higher confidence.

Instructions

To edit the “Weight of Evidence Summary” section, on an AOP page, in the upper right hand menu, click ‘Edit.’ This brings you to a page entitled, “Editing AOP.” Scroll down to the “Weight of Evidence Summary”  section, where a text entry box allows you to submit text. In the upper right hand menu, click ‘Update AOP’ to save your changes and return to the AOP page.  The new text should appear under the “Weight of Evidence Summary” section on the AOP page.


Quantitative Considerations

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The extent of quantitative understanding of the various KERs in the overall hypothesised AOP is also critical in consideration of potential regulatory application. For some applications (e.g. doseresponse analysis in in depth risk assessment), quantitative characterisation of downstream KERs may be essential while for others, quantitative understanding of upstream KERs may be important (e.g., QSAR modelling for category formation for testing). Because evidence that contributes to quantitative understanding of the KER is generally not mutually exclusive with the empirical support for the KER, evidence that contributes to quantitative understanding should generally be considered as part of the evaluation of the weight of evidence supporting the KER (see Annex 1, footnote b). General guidance on the degree of quantitative understanding that would be characterised as weak, moderate, or strong is provided in Annex 2.

Instructions

To edit the “Quantitative Considerations” section, on an AOP page, in the upper right hand menu, click ‘Edit.’ This brings you to a page entitled, “Editing AOP.” Scroll down to the “Quantitative Considerations” section, where a text entry box allows you to submit text. In the upper right hand menu, click ‘Update AOP’ to save your changes and return to the AOP page.  The new text should appear under the “Quantitative Considerations” section on the AOP page.


Considerations for Potential Applications of the AOP (optional)

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At their discretion, the developer may include in this section discussion of the 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. While it is challenging to foresee all potential regulatory application of AOPs and any application will ultimately lie within the purview of regulatory agencies, potential applications may be apparent as the AOP is being developed, particularly if it was initiated with a particular application in mind. This optional section is intended to provide the developer with an opportunity to suggest potential regulatory applications and describe his or her rationale. Detailing such considerations can aid the process of transforming narrative descriptions of AOPs into practical tools. In this context, it is necessarily beneficial to involve members of the regulatory risk assessment community on the development and assessment team. The Network view which is generated based on assessment of weight of evidence/degree of confidence in the hypothesized AOP taking into account the elements described in Section 7 provides a useful summary of relevant information as a basis to consider appropriate application in a regulatory context. Consideration of application needs then, to take into consideration the following rank ordered qualitative elements: Confidence in biological plausibility for each of the KERs Confidence in essentiality of the KEs Empirical support for each of the KERs and overall AOP The extent of weight of evidence/confidence in both these qualitative elements and that of the quantitative understanding for each of the KERs (e.g., is the MIE known, is quantitative understanding restricted to early or late key events) is also critical in determining appropriate application. For example, if the confidence and quantitative understanding of each KER in a hypothesised AOP are low and or low/moderate and the evidence for essentiality of KEs weak (Section 7), it might be considered as appropriate only for applications with less potential for impact (e.g., prioritisation, category formation for testing) versus those that have immediate implications potentially for risk management (e.g., in depth assessment). If confidence in quantitative understanding of late key events is high, this might be sufficient for an in depth assessment. The analysis supporting the Network view is also essential in identifying critical data gaps based on envisaged regulatory application.

Instructions

To edit the “Considerations for Potential Applications of the AOP” section, on an AOP page, in the upper right hand menu, click ‘Edit.’ This brings you to a page entitled, “Editing AOP.” Scroll down to the “Considerations for Potential Applications of the AOP” section, where a text entry box allows you to submit text. In the upper right hand menu, click ‘Update AOP’ to save your changes and return to the AOP page.  The new text should appear under the “Considerations for Potential Applications of the AOP” section on the AOP page.


References

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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