SNAPSHOT

AOP ID and Title:

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

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

Events

Molecular Initiating Events (MIE), Key Events (KE), Adverse Outcomes (AO)

Key Event Relationships

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].

Domain of Applicability

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).

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

Appendix 1

List of MIEs in this AOP

List of Key Events in the AOP

List of Adverse Outcomes in this AOP

Appendix 2

List of Key Event Relationships in the AOP