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Relationship: 254

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Increase, Plasma vitellogenin concentrations leads to Increase, Renal pathology due to VTG deposition

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Increase, Plasma vitellogenin concentrations

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Increase, Renal pathology due to VTG deposition

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name	Adjacency	Weight of Evidence	Quantitative Understanding	Point of Contact	Author Status	OECD Status
Estrogen receptor agonism leading to reproductive dysfunction	adjacent	High		Undefined (send email)	Under Development: Contributions and Comments Welcome
Estrogen receptor agonism leading to reduced survival and population growth due to renal failure	adjacent	Moderate	Low	Camille Baettig (send email)	Under development: Not open for comment. Do not cite

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER. More help

Sex Applicability

An indication of the the relevant sex for this KER. More help

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER. More help

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings. Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Biological Plausibility

Addresses the biological rationale for a connection between KEupstream and KEdownstream. This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured. More help

Original text - unknown contribution

High level of biological plausibility in fish.

Added by C. Baettig on June 24, 2024

When large quantities of VTG are circulating hyalin material can accumulate in the kidneys which can cause significant pathology (Folmar et al., 2001; Herman & Kincaid, 1988; Palace et al., 2002). Additionally, eosinophilic material is known to accumulate in kidney tubules and has been proposed to be due to high circulating VTG (Hahlbeck et al., 2004). Similarly, cilia proliferation observed in renal tubules is assumed to be related to increased absorption of circulating vitellogenin (Zha et al., 2008).

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

Original text - unknown contribution

Laboratory in vivo aquatic exposures of fish (fathead minnow) to 17alpha-ethinylestradiol led to renal pathology within 16 weeks, concomitant with macroscopic evidence of osmoregulatory dysfunction and morbidity (Laenge et al., 2001).

Added by C. Baettig on June 24, 2024

Male summer flounder injected with 17β-estradiol (E2) had increased levels of circulating VTG. The accumulation of VTG resulted in obstruction or rupture of renal glomeruli (Folmar et al., 2001).
Male rare minnow exposed to 17α-ethinylestradiol (EE2) and 4-nonylphenol (NP) had significantly increased plasma VTG concentrations, as did females after EE2 exposure. This resulted in hemorrhages in male kidney tubules, hypertrophy of tubular epithelia, and accumulated eosinophilic material in renal tissue (Zha et al., 2007).
Elevated levels of VTG and kidney hypertrophy in juvenile three-spined sticklebacks was observed after exposure to E2 and EE2 (Hahlbeck et al., 2004).
Male fathead minnows experimentally exposed to EE2 within a whole lake experiment showed 9000-fold higher VTG concentrations than fish captured from the same lake prior to the EE2 additions. Edema in the interstitium between kidney tubules and eosinophilic deposits in the kidney tubule lumen were also observed in the EE2-exposed male fatheads (Palace et al., 2002).
After exposure to bisphenol A VTG levels increased in fathead minnows resulting in glomerular epithelial cell hyperplasia, hyaline droplets in glomeruli, glomerular mesangial membrane thickening, intravascular proteinaceous fluid, tubular dilation, and dilation of Bowman’s spaces (Mihaich et al., 2012).
Fathead minnow embryos exposed to EE2 exhibited increased whole body VTG levels and tubular degeneration and dilation and glomerulonephritis/glomerulosclerosis was observable after 16 weeks (Länge et al., 2001).
In male fathead minnows exposed to E2 and an estrogenic PFAS, FC-10 diol, for 21 days plasma VTG was significantly increased. Neuropathy in the kidneys of diol-exposed fish was observed, specifically tubule dilation, tubule protein, enlarged glomeruli, glomerular protein, and thickened basement membranes. Additionally, interstitial and intravascular proteinaceous fluid was significantly elevated (Ankley et al. in prep).

Uncertainties and Inconsistencies

Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

Original text - unknown contribution

None that the author of this entry is aware of.

Added by C. Baettig on June 24, 2024

Although the accumulation of hyalin material/lipoprotein within the kidneys has been confirmed to be partially caused by accumulated VTG, some of the accumulated proteins do not respond to VTG antibody (e.g., Folmar et al., 2001). Because male fish will also express other estrogen inducible proteins such as vitelline envelope and zona radiata some renal pathology could be caused by these related proteins rather than VTG (Johan Hyllner et al., 1994; Oppen‐Berntsen et al., 1994).

Proliferative kidney disease (PKD) in fish caused by the parasite Tetracapsuloides bryosalmonae results in significant kidney pathology. However, when PKD infection took place under simultaneous exposure to EE2, kidney pathology was less pronounced despite the fact that hepatic vtg was elevated in fish exposed to the estrogen (Bailey et al., 2019; Rehberger et al., 2020).

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references. More help

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

Published studies include 17beta-estradiol and 17alpha-ethinylestradiol as known modulators of this relationship in fish. Model fish species (eg fathead minnow) have been used to study this biological effect and while there are no quantitative extrapolation models published to date, empirical data suggests renal pathology occurs in juvenile or male fish when plasma VTG levels are >1000-fold above baseline for a period of several weeks.

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

Time-scale

Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

Known Feedforward/Feedback loops influencing this KER

Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

Original text - unknown contribution

Publish studies specifically relate to fish, although it is plausible that the same response may occur in the aquatic life-stages of amphibians.

Added by C. Baettig on June 24, 2024

Taxonomic applicability: Oviparous vertebrates that synthesize yolk precursor proteins and have functional kidneys.

Life stage: This KER is applicable to all life stages following the differentiation of the liver and kidney.

Sex: This KER is applicable to both sexes.

References

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

Herman, R.L., Kincaid, H.L. (1988) Pathological effects of orally administered 17beta-estradiol to rainbow trout. Aquaculture 72:165–172

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 estrogen 17 alpha-ethinylestradiol on the life-cycle of the fathead minnow (Pimephales promelas). Environ Toxicol Chem 20:1216-1227

Bailey, C., von Siebenthal, E. W., Rehberger, K., & Segner, H. (2019). Transcriptomic analysis of the impacts of ethinylestradiol (EE2) and its consequences for proliferative kidney disease outcome in rainbow trout (Oncorhynchus mykiss). Comparative Biochemistry and Physiology Part C: Toxicology & Pharmacology, 222, 31-48. https://doi.org/https://doi.org/10.1016/j.cbpc.2019.04.009
Folmar, L. C., Gardner, G. R., Schreibman, M. P., Magliulo-Cepriano, L., Mills, L. J., Zaroogian, G., Gutjahr-Gobell, R., Haebler, R., Horowitz, D. B., & Denslow, N. D. (2001). Vitellogenin-induced pathology in male summer flounder (Paralichthys dentatus). Aquatic Toxicology, 51(4), 431-441.
Hahlbeck, E., Katsiadaki, I., Mayer, I., Adolfsson-Erici, M., James, J., & Bengtsson, B.-E. (2004). The juvenile three-spined stickleback (Gasterosteus aculeatus L.) as a model organism for endocrine disruption II—kidney hypertrophy, vitellogenin and spiggin induction. Aquatic Toxicology, 70(4), 311-326.
Herman, R. L., & Kincaid, H. L. (1988). Pathological effects of orally administered estradiol to rainbow trout. Aquaculture, 72(1-2), 165-172.
Johan Hyllner, S., Silvers, C., & Haux, C. (1994). Formation of the vitelline envelope precedes the active uptake of vitellogenin during oocyte development in the rainbow trout, Oncorhynchus mykiss. Molecular Reproduction and Development, 39(2), 166-175.
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 estrogen 17α‐ethinylestradiol on the life‐cycle of the fathead minnow (Pimephales promelas). Environmental Toxicology and Chemistry: An International Journal, 20(6), 1216-1227.
Mihaich, E., Rhodes, J., Wolf, J., van der Hoeven, N., Dietrich, D., Hall, A. T., Caspers, N., Ortego, L., Staples, C., & Dimond, S. (2012). Adult fathead minnow, Pimephales promelas, partial life‐cycle reproductive and gonadal histopathology study with bisphenol A. Environmental toxicology and chemistry, 31(11), 2525-2535.
Oppen‐Berntsen, D., Olsen, S., Rong, C., Taranger, G., Swanson, P., & Walther, B. (1994). Plasma levels of eggshell zr‐proteins, estradiol‐17β, and gonadotropins during an annual reproductive cycle of Atlantic salmon (Salmo salar). Journal of Experimental Zoology, 268(1), 59-70.
Palace, V. P., Evans, R. E., Wautier, K., Baron, C., Vandenbyllardt, L., Vandersteen, W., & Kidd, K. (2002). Induction of vitellogenin and histological effects in wild fathead minnows from a lake experimentally treated with the synthetic estrogen, ethynylestradiol. Water Quality Research Journal, 37(3), 637-650.
Rehberger, K., Wernicke von Siebenthal, E., Bailey, C., Bregy, P., Fasel, M., Herzog, E. L., Neumann, S., Schmidt-Posthaus, H., & Segner, H. (2020). Long-term exposure to low 17α-ethinylestradiol (EE2) concentrations disrupts both the reproductive and the immune system of juvenile rainbow trout, Oncorhynchus mykiss. Environment International, 142, 105836. https://doi.org/https://doi.org/10.1016/j.envint.2020.105836
Zha, J., Sun, L., Zhou, Y., Spear, P. A., Ma, M., & Wang, Z. (2008). Assessment of 17α-ethinylestradiol effects and underlying mechanisms in a continuous, multigeneration exposure of the Chinese rare minnow (Gobiocypris rarus). Toxicology and applied pharmacology, 226(3), 298-308.
Zha, J., Wang, Z., Wang, N., & Ingersoll, C. (2007). Histological alternation and vitellogenin induction in adult rare minnow (Gobiocypris rarus) after exposure to ethynylestradiol and nonylphenol. Chemosphere, 66(3), 488-495.