Aop:29

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Status

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AOP Title

Estrogen receptor agonism leading to reproductive dysfunction
Short name: Estrogen receptor agonism leading to reproductive dysfunction

Authors

  • 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]

Status

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Under development: Do not distribute or cite.

OECD Project 1.29: A catalog of putative AOPs that will enhance the utility of US EPA Toxcast high throughput screening data for hazard identification

This AOP page was last modified on 12/11/2016.

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Abstract

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.

Summary of the AOP

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Molecular Initiating Event

Molecular Initiating Event Support for Essentiality
Estrogen receptor, Agonism Strong

Key Events

Event Support for Essentiality
Cumulative fecundity and spawning, Reduction Strong
Plasma vitellogenin concentrations, Increase Strong
Vitellogenin synthesis in liver, Increase Strong
Renal pathology due to VTG deposition, Increase Strong

Adverse Outcome

Adverse Outcome
Population trajectory, Decrease
Reproductive behaviour, Altered
Larval development, Altered
Reproductive organs, Impaired development of

Relationships Among Key Events and the Adverse Outcome

Event Description Triggers Weight of Evidence Quantitative Understanding
Estrogen receptor, Agonism Directly Leads to Reproductive organs, Impaired development of Strong
Renal pathology due to VTG deposition, Increase Directly Leads to Larval development, Altered Strong
Estrogen receptor, Agonism Directly Leads to Vitellogenin synthesis in liver, Increase Strong
Plasma vitellogenin concentrations, Increase Directly Leads to Renal pathology due to VTG deposition, Increase Strong
Estrogen receptor, Agonism Directly Leads to Reproductive behaviour, Altered Strong
Vitellogenin synthesis in liver, Increase Directly Leads to Plasma vitellogenin concentrations, Increase Strong

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Life Stage Applicability

Life Stage Evidence Links
Juvenile Strong
Embryo Strong

Taxonomic Applicability

Name Scientific Name Evidence Links
fathead minnow Pimephales promelas Strong NCBI
Japanese quail Coturnix coturnix Strong NCBI
northern leopard frog Rana pipiens Strong NCBI
medaka Oryzias latipes Strong NCBI
zebrafish Danio rerio Strong NCBI

Sex Applicability

Sex Evidence Links
Male Strong

Graphical Representation

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Overall Assessment of the AOP

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].

Weight of Evidence Summary

Summary Table
Provide an overall summary of the weight of evidence based on the evaluations of the individual linkages from the Key Event Relationship pages.

Essentiality of the Key Events

Molecular Initiating Event Summary, Key Event Summary
Provide an overall assessment of the essentiality for the key events in the AOP. Support calls for individual key events can be included in the molecular initiating event, key event, and adverse outcome tables above.

Quantitative Considerations

Summary Table
Provide an overall discussion of the quantitative information available for this AOP. Support calls for the individual relationships can be included in the Key Event Relationship table above.

Applicability of the AOP

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).

Considerations for Potential Applications of the AOP (optional)

References


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