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AOP: 536

Title

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 reduced survival and population growth due to renal failure

Short name

A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help

ER agonism leads to reduced survival/population growth

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 v2.7

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

Authors

The names and affiliations of the individual(s)/organisation(s) that created/developed the AOP. More help

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

Camille Baettig (email point of contact)

Contributors

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

Camille Baettig

Coaches

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 November 01, 2024 21:05

Revision dates for related pages

Page	Revision Date/Time
Agonism, Estrogen receptor	June 24, 2024 13:35
Increase, Vitellogenin synthesis in liver	June 24, 2024 13:38
Increase, Plasma vitellogenin concentrations	June 24, 2024 13:39
Increase, Renal pathology due to VTG deposition	June 24, 2024 13:40
Increased Mortality	July 08, 2022 07:32
Decrease, Population growth rate	January 03, 2023 09:09
Agonism, Estrogen receptor leads to Increase, Vitellogenin synthesis in liver	June 24, 2024 13:04
Increase, Vitellogenin synthesis in liver leads to Increase, Plasma vitellogenin concentrations	June 24, 2024 13:13
Increase, Plasma vitellogenin concentrations leads to Increase, Renal pathology due to VTG deposition	June 24, 2024 13:23
Increase, Renal pathology due to VTG deposition leads to Increased Mortality	June 24, 2024 13:34
Increased Mortality leads to Decrease, Population growth rate	July 08, 2022 08:29

Abstract

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 adverse outcome pathway details the linkage between binding and activation of estrogen receptor as a nuclear transcription factor, primarily in oviparous male vertebrates, and a decrease in population growth. Estrogen receptors are ligand-dependent transcription factors that regulate gene transcription through estrogen response elements, allowing for the normal biological functions of estrogens (Klinge, 2001). However, various chemicals/classes of chemicals have been shown to act as ER agonists with the most potent being estradiol (E2) and ethinylestradiol (EE2) (Aarts et al., 2013). Numerous compounds including polycyclic aromatic hydrocarbons, chlorinated chemicals (e.g. PCBs), plasticizers (e.g. phthalates), and phenolic industrial chemicals (e.g., alkylphenols, parabens), and plant sterols also interact with ERα in vitro, with the potential to produce in vivo estrogenic effects (Ng et al., 2014; Pillon et al., 2005). A well characterized response to ER agonists involves hepatic production of vitellogenin (VTG; egg yolk precursor protein). Induction of vtg mRNA can result in elevated plasma VTG, particularly in oviparous male vertebrates, and can potentially cause downstream issues such as renal failure and morbidity. This AOP is relevant to both sexes, although more so to males as they do not produce VTG under normal conditions and have no mechanism for readily excreting the lipoprotein (Sumpter & Jobling, 1995). While many aspects of the biology underlying this AOP are largely conserved across oviparous vertebrates our, focus on KER between increased plasma VTG and increased renal pathology was on freshwater fish. Therefore, caution should be used in applying the whole of the AOP beyond freshwater fish species.

AOP Development Strategy

Context

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

The key events in this AOP are well defined in the literature, particularly the early events. While this AOP was initially entered into the wiki over ten years ago it was only entered as a set of place-holder pages for which a full weight of evidence assembly had not been conducted. Following studies conducted on estrogenic PFAS, described below, there was motivation to redevelop and update the AOP.

Houck et al. (2021) used an in vitro high throughput platform to screen and categorize more than 140 structurally diverse PFAS based on their pathway-specific bioactivities including estrogenic activity. Villeneuve et al. (2023) confirmed the estrogenic activity of four diols identified by Houck et al. (2021) in 4 day in vivo experiment that evaluated expression of ER responsive genes in male fathead minnows. This led to the motivation to further evaluate FC10-diol, which showed the strongest response, using both male and female fathead minnows in a 21-day study. This study design allowed for the measurement of nearly all the key events within this AOP and allowed for linking activation of the ER to impacts on survival and reproduction in fish.

Strategy

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

This AOP was developed based on data derived from literature searches conducted online in PubMed, Scopus, and Google Scholar. Specific literature searches were used to add evidence from other studies for each key event. The initial search terms for the key events included: “estrogen receptor agonism”, “vitellogenin expression”, “vitellogenin plasma”, and “renal pathology”. This AOP focuses on fish as most of the literature used was based on fish studies, however this AOP can probably be applied to other oviparous vertebrate species as well. No systematic review approach was applied.

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

Events:

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

KE	307	Increase, Vitellogenin synthesis in liver	Increase, Vitellogenin synthesis in liver
KE	220	Increase, Plasma vitellogenin concentrations	Increase, Plasma vitellogenin concentrations
KE	252	Increase, Renal pathology due to VTG deposition	Increase, Renal pathology due to VTG deposition
KE	351	Increased Mortality	Increased Mortality
KE	360	Decrease, Population growth rate	Decrease, Population growth rate

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

Title	Adjacency	Evidence	Quantitative Understanding

Agonism, Estrogen receptor leads to Increase, Vitellogenin synthesis in liver	adjacent	High	Low
Increase, Vitellogenin synthesis in liver leads to Increase, Plasma vitellogenin concentrations	adjacent	High	Moderate
Increase, Plasma vitellogenin concentrations leads to Increase, Renal pathology due to VTG deposition	adjacent	Moderate	Low
Increase, Renal pathology due to VTG deposition leads to Increased Mortality	adjacent	Moderate	Low
Increased Mortality leads to Decrease, Population growth rate	adjacent	Moderate	Moderate

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

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

Sex Applicability

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

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

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

Sex: Although this AOP is applicable to both sexes it is far more relevant for males. This is in part because females have an excretion pathway for vitellogenin - namely deposition into oocytes which are then released into the environment. Males lack that mechanism, and thus are more likely to accumulate protein that can cause kidney pathologies.

Life stages: This AOP is applicable to all life stages following the differentiation of the liver and kidney. Larvae prior to liver and kidney differentiation should not be included.

Taxonomic: The assumed taxonomic applicability domain of this AOP is oviparous vertebrates that synthesize yolk precursor proteins and have functional kidneys.

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

Overall, the confidence in the supporting data for essentiality of KEs within the AOP is moderate. There is direct evidence of ER agonism leading to an increase in vitellogenin mRNA expression that is supported in multiple review articles (e.g., Matozzo et al., 2008; Palmer & Selcer, 1996; Verderame & Scudiero, 2017). Similarly, there is direct evidence vtg mRNA synthesis precedes increases in plasma VTG. Korte et al. (2000) observed vtg mRNA increase in the liver of male fathead minnows within 4 hours followed by plasma VTG increase within 16 hours of treatment. There is indirect evidence that increased plasma VTG can lead to downstream KE, renal pathology, as well as resulting in downstream AOs, mortality and decrease in population growth rate. Studies have shown that when large quantities of VTG are circulating it can lead to hyalin material accumulation in the kidneys which can cause significant pathology (e.g., Folmar et al., 2001; Herman & Kincaid, 1988). Because the kidneys perform a suite of physiological roles that are critical for organismal homeostasis including waste excretion, osmoregulation, and fluid homeostasis (Preuss, 1993), damage to the renal system, including damage caused by circulating VTG, can lead to a loss of renal functions such as decreased glomerular filtration rate or impaired clearance of waste products which can lead to mortality (McKee & Wingert, 2015). As survival rate is an obvious determinant of population size there is indirect evidence linking increased mortality to decrease in population growth rate.

Evidence Assessment

Addressess the biological plausibility, empirical support, and quantitative understanding from each KER in an AOP. More help

The weight of evidence for each of the KERs comprising the AOP are ranked moderate to high. In particular the biological plausibility at the molecular and cellular level of the early key events is strong. The biological plausibility linking ER activation to increased vtg mRNA synthesis is high. Actions of endogenous and exogenous estrogens are mediated by the ER which is part of the nuclear receptor superfamily. Binding to the ligand-binding domain (LBD) of the ER initiates a series of molecular events culminating in the modulation of genes. Transcription of vtg is regulated by estrogens and their interaction on ERs and under high estrogen stimulation the fold increase of vtg transcripts increases by orders of magnitude (Brock & Shapiro, 1983). Additionally, there is high biological plausibility linking increased vtg mRNA synthesis to increased plasma VTG. The liver is the primary source of VTG synthesis and production and after it is synthesized it is secreted into the blood (Wallace, 1985). Vitellogenin transcription and translation results in protein production although there is a delay between expression of vtg and actual production/detection of VTG (e.g., Korte et al. 2000). Although a precise quantitative relationship describing all steps of vitellogenesis transcription/translation has not been described there are models and statistical relationships that define quantitative relationships between circulating E2 concentrations and circulating VTG concentrations have been developed (Ankley et al., 2008; Li et al., 2011; Murphy et al., 2009; Murphy et al., 2005).

Some uncertainties regarding the connection between increased VTG availability and the increase in renal pathology remain, resulting in our weight of evidence call as moderate. However, there is evidence that 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, numerous studies have documented further renal pathology such as hemorrhages in kidney tubules, hypertrophy of tubular epithelia, accumulated eosinophilic material in renal tissue, and edema in the interstitium between kidney tubules (e.g., Folmar et al., 2001; Hahlbeck et al., 2004; Länge et al., 2001; Mihaich et al., 2012; Palace et al., 2002; Zha et al., 2007). In fish exposed to estrogenic compounds there can be excessive production of VTG, which leads to renal failure, and increases mortality in fish (Herman & Kincaid, 1988). Generally, the molecular mass of proteins in glomerular filtrate are lower than albumin but when proteins like VTG are deposited in the kidneys they cannot be resorbed and the excess protein can lead to glomerular rupturing or hemorrhaging (Tojo & Kinugasa, 2012). Ultimately these pathologies can cause acute renal failure resulting in mortality. As survival rate is an obvious determinant of population size and is included in population modeling to calculate long-term persistence of the population (e.g., Miller et al., 2020) there is a moderate weight of evidence linking increased mortality to decrease in population growth rate. Numerous factors have the potential to lead to declining populations (e.g., increased mortality in the reproductive population, excessive mortality in larval population) however there is considerable evidence to support the idea that ER agonism can ultimately lead to decrease in the population growth. A notable example exposed fathead minnows to low concentrations of 17α-ethynylestradiol (EE2) in the Experimental Lakes Area, Canada. Vitellogenin mRNA and plasma was significantly elevated and, after the second season of EE2 additions to the lake, the fathead minnow population collapsed due to loss of the young-of-the-year (Kidd et al., 2007; Palace et al., 2002). Overall, there is considerable evidence to support the idea that ER agonism can ultimately lead to decrease in the population growth rate. Overall weight of evidence is moderate.

Uncertainties, inconsistencies, and data gaps

Uncertainties related to MIE: Some uncertainty remains regarding which ER subtype(s) regulates vitellogenin gene expression in the liver of fish. In general, the literature suggests a close interplay between several ER subtypes in the regulation of vitellogenesis. Consequently, at present, the AOP is generalized to impacts on all ER subtypes, even though it remains possible that impacts on a particular sub-type may drive the adverse response.
- Using selective agonists and antagonists for ERα and ERβ, it was concluded that ERβ was primarily responsible for inducing vitellogenin production in rainbow trout and that compounds exhibiting ERα selectivity would not be detected using a vitellogenin ELISA bioassay (Leaños-Castañeda & Van Der Kraak, 2007). However, a subsequent study conducted in tilapia concluded that agonistic and antagonistic characteristics of mammalian, isoform-specific ER agonists and antagonists, cannot be reliably extrapolated to piscine ERs (Davis et al., 2010).
- Based on RNA interference knock-down experiments Nelson and Habibi (Nelson & Habibi, 2010) proposed a model in which all ER subtypes are involved in E2-mediated vitellogenesis, with ERβ isoforms stimulating expression of both vitellogenin and ERα gene expression, and ERα helping to drive vitellogenesis, particularly as it becomes more abundant following sensitization.
Uncertainties related to cause of renal pathology: 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 even though hepatic vtg was elevated in fish exposed to the estrogen (Bailey et al., 2019; Rehberger et al., 2020).

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

Modulating Factor (MF)	Influence or Outcome	KER(s) involved

Quantitative Understanding

Optional field to provide quantitative weight of evidence descriptors. More help

Overall, the quantitative understanding for this AOP is low. Presently there is insufficient data to develop a quantitative AOP linking ER activation to mortality and decreased population growth rate. However, a 21-day reproductive study to estrogenic PFAS, FC10-diol, which allowed for the measurement of nearly all the key events within this AOP and allowed for linking activation of the ER to impacts on survival and reproduction in fish (Ankley et al. in prep).

Increase in vtg synthesis leading to increase in plasma VTG was scored as having a moderate quantitative understanding due to the well-defined relationship between gene expression and protein synthesis. However, because the delay between expression of vtg and production/detection of VTG is not well defined our understanding is still limited.

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

References

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

Aarts, J. M. M. J. G., Wang, S., Houtman, R., van Beuningen, R. M. G. J., Westerink, W. M. A., Van De Waart, B. J., Rietjens, I. M. C. M., & Bovee, T. F. H. (2013). Robust Array-Based Coregulator Binding Assay Predicting ERα-Agonist Potency and Generating Binding Profiles Reflecting Ligand Structure. Chemical Research in Toxicology, 26(3), 336-346. https://doi.org/10.1021/tx300463b

Ankley, G. T., Miller, D. H., Jensen, K. M., Villeneuve, D. L., & Martinović, D. (2008). Relationship of plasma sex steroid concentrations in female fathead minnows to reproductive success and population status. Aquatic Toxicology, 88(1), 69-74. https://doi.org/https://doi.org/10.1016/j.aquatox.2008.03.005

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

Brock, M. L., & Shapiro, D. (1983). Estrogen regulates the absolute rate of transcription of the Xenopus laevis vitellogenin genes. Journal of Biological Chemistry, 258(9), 5449-5455.

Davis, L., Katsu, Y., Iguchi, T., Lerner, D., Hirano, T., & Grau, E. (2010). Transcriptional activity and biological effects of mammalian estrogen receptor ligands on three hepatic estrogen receptors in Mozambique tilapia. The Journal of steroid biochemistry and molecular biology, 122(4), 272-278.

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.

Houck, K. A., Patlewicz, G., Richard, A. M., Williams, A. J., Shobair, M. A., Smeltz, M., Clifton, M. S., Wetmore, B., Medvedev, A., & Makarov, S. (2021). Bioactivity profiling of per- and polyfluoroalkyl substances (PFAS) identifies potential toxicity pathways related to molecular structure. Toxicology, 457, 152789. https://doi.org/https://doi.org/10.1016/j.tox.2021.152789

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.

Kidd, K. A., Blanchfield, P. J., Mills, K. H., Palace, V. P., Evans, R. E., Lazorchak, J. M., & Flick, R. W. (2007). Collapse of a fish population after exposure to a synthetic estrogen. Proceedings of the National Academy of Sciences, 104(21), 8897-8901. https://doi.org/doi:10.1073/pnas.0609568104

Klinge, C. M. (2001). Estrogen receptor interaction with estrogen response elements. Nucleic Acids Res, 29(14), 2905-2919. https://doi.org/10.1093/nar/29.14.2905

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.

Leaños-Castañeda, O., & Van Der Kraak, G. (2007). Functional characterization of estrogen receptor subtypes, ERα and ERβ, mediating vitellogenin production in the liver of rainbow trout. Toxicology and applied pharmacology, 224(2), 116-125.

Li, Z., Kroll, K. J., Jensen, K. M., Villeneuve, D. L., Ankley, G. T., Brian, J. V., Sepúlveda, M. S., Orlando, E. F., Lazorchak, J. M., Kostich, M., Armstrong, B., Denslow, N. D., & Watanabe, K. H. (2011). A computational model of the hypothalamic - pituitary - gonadal axis in female fathead minnows (Pimephales promelas) exposed to 17α-ethynylestradiol and 17β-trenbolone. BMC Systems Biology, 5(1), 63. https://doi.org/10.1186/1752-0509-5-63

Matozzo, V., Gagné, F., Marin, M. G., Ricciardi, F., & Blaise, C. (2008). Vitellogenin as a biomarker of exposure to estrogenic compounds in aquatic invertebrates: A review. Environment International, 34(4), 531-545. https://doi.org/https://doi.org/10.1016/j.envint.2007.09.008

McKee, R. A., & Wingert, R. A. (2015). Zebrafish Renal Pathology: Emerging Models of Acute Kidney Injury. Current Pathobiology Reports, 3(2), 171-181. https://doi.org/10.1007/s40139-015-0082-2

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.

Murphy, C. A., Rose, K. A., Rahman, M. S., & Thomas, P. (2009). Testing and applying a fish vitellogenesis model to evaluate laboratory and field biomarkers of endocrine disruption in Atlantic croaker (Micropogonias undulatus) exposed to hypoxia. Environmental toxicology and chemistry, 28(6), 1288-1303. https://doi.org/https://doi.org/10.1897/08-304.1

Murphy, C. A., Rose, K. A., & Thomas, P. (2005). Modeling vitellogenesis in female fish exposed to environmental stressors: predicting the effects of endocrine disturbance due to exposure to a PCB mixture and cadmium. Reproductive Toxicology, 19(3), 395-409. https://doi.org/https://doi.org/10.1016/j.reprotox.2004.09.006

Nelson, E. R., & Habibi, H. R. (2010). Functional Significance of Nuclear Estrogen Receptor Subtypes in the Liver of Goldfish. Endocrinology, 151(4), 1668-1676. https://doi.org/10.1210/en.2009-1447

Ng, H. W., Perkins, R., Tong, W., & Hong, H. (2014). Versatility or Promiscuity: The Estrogen Receptors, Control of Ligand Selectivity and an Update on Subtype Selective Ligands. International Journal of Environmental Research and Public Health, 11(9), 8709-8742. https://www.mdpi.com/1660-4601/11/9/8709

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.

Palmer, B. D., & Selcer, K. W. (1996). Vitellogenin as a biomarker for xenobiotic estrogens: a review. Environmental Toxicology and Risk Assessment: Biomarkers and Risk Assessment: Fifth Volume, 3-22.

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