Aop: 334

Title

Each AOP should be given a descriptive title that takes the form “MIE leading to AO”. For example, “Aromatase inhibition [MIE] leading to reproductive dysfunction [AO]” or “Thyroperoxidase inhibition [MIE] leading to decreased cognitive function [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

Glucocorticoid Receptor Agonism Leading to Impaired Fin Regeneration

Short name
A short name should also be provided that succinctly summarises the information from the title. This name should not exceed 90 characters. More help
GR Agonism Leading to Impaired Fin Regeneration

Graphical Representation

A graphical summary of the AOP listing all the KEs in sequence, including the MIE (if known) and AO, and the pair-wise relationships (links or KERs) between those KEs should be provided. This is easily achieved using the standard box and arrow AOP diagram (see this page for example). The graphical summary is prepared and uploaded by the user (templates are available) and is often included as part of the proposal when AOP development projects are submitted to the OECD AOP Development Workplan. The graphical representation or AOP diagram provides a useful and concise overview of the KEs that are included in the AOP, and the sequence in which they are linked together. This can aid both the process of development, as well as review and use of the AOP (for more information please see page 19 of the Users' Handbook).If you already have a graphical representation of your AOP in electronic format, simple save it in a standard image format (e.g. jpeg, png) then click ‘Choose File’ under the “Graphical Representation” heading, which is part of the Summary of the AOP section, to select the file that you have just edited. Files must be in jpeg, jpg, gif, png, or bmp format. Click ‘Upload’ to upload the file. You should see the AOP page with the image displayed under the “Graphical Representation” heading. To remove a graphical representation file, click 'Remove' and then click 'OK.'  Your graphic should no longer be displayed on the AOP page. If you do not have a graphical representation of your AOP in electronic format, a template is available to assist you.  Under “Summary of the AOP”, under the “Graphical Representation” heading click on the link “Click to download template for graphical representation.” A Powerpoint template file should download via the default download mechanism for your browser. Click to open this file; it contains a Powerpoint template for an AOP diagram and instructions for editing and saving the diagram. Be sure to save the diagram as jpeg, jpg, gif, png, or bmp format. Once the diagram is edited to its final state, upload the image file as described above. More help

Authors

List the name and affiliation information of the individual(s)/organisation(s) that created/developed the AOP. In the context of the OECD AOP Development Workplan, this would typically be the individuals and organisation that submitted an AOP development proposal to the EAGMST. Significant contributors to the AOP should also be listed. A corresponding author with contact information may be provided here. This author does not need an account on the AOP-KB and can be distinct from the point of contact below. The list of authors will be included in any snapshot made from an AOP. More help

Alexander R. Cole, Oak Ridge Institute for Science and Education, U.S. Environmental Protection Agency, Great Lakes Ecology Divison, Duluth, MN

Point of Contact

Indicate the point of contact for the AOP-KB entry itself. This person is responsible for managing the AOP entry in the AOP-KB and controls write access to the page by defining the contributors as described below. Clicking on the name will allow any wiki user to correspond with the point of contact via the email address associated with their user profile in the AOP-KB. This person can be the same as the corresponding author listed in the authors section but isn’t required to be. In cases where the individuals are different, the corresponding author would be the appropriate person to contact for scientific issues whereas the point of contact would be the appropriate person to contact about technical issues with the AOP-KB entry itself. Corresponding authors and the point of contact are encouraged to monitor comments on their AOPs and develop or coordinate responses as appropriate.  More help
Alexander Cole   (email point of contact)

Contributors

List user names of all  authors contributing to or revising pages in the AOP-KB that are linked to the AOP description. This information is mainly used to control write access to the AOP page and is controlled by the Point of Contact.  More help
  • Alexander Cole
  • Dan Villeneuve

Status

The status section is used to provide AOP-KB users with information concerning how actively the AOP page is being developed, what type of use or input the authors feel comfortable with given the current level of development, and whether it is part of the OECD AOP Development Workplan and has been reviewed and/or endorsed. “Author Status” is an author defined field that is designated by selecting one of several options from a drop-down menu (Table 3). The “Author Status” field should be changed by the point of contact, as appropriate, as AOP development proceeds. See page 22 of the User Handbook for definitions of selection options. More help
Author status OECD status OECD project SAAOP status
Under development: Not open for comment. Do not cite
This AOP was last modified on July 27, 2020 12:54
The date the AOP was last modified is automatically tracked by the AOP-KB. The date modified field can be used to evaluate how actively the page is under development and how recently the version within the AOP-Wiki has been updated compared to any snapshots that were generated. More help

Revision dates for related pages

Page Revision Date/Time
Activation, Glucocorticoid Receptor July 07, 2020 12:19
Increase, Cripto-1 expression July 10, 2020 15:26
Inhibition, Activin signaling July 10, 2020 15:36
Inhibition, Fin regeneration July 10, 2020 13:05
Reduced, Swimming performance November 20, 2020 12:57
Decrease, Population trajectory September 26, 2017 11:33
Activation, Glucocorticoid Receptor leads to Increase, Cripto-1 expression July 10, 2020 15:28
Increase, Cripto-1 expression leads to Inhibition, Fin regeneration July 10, 2020 15:53
Increase, Cripto-1 expression leads to Inhibition, Activin signaling July 07, 2020 15:08
Inhibition, Activin signaling leads to Inhibition, Fin regeneration July 10, 2020 15:41
Inhibition, Fin regeneration leads to Reduced, Swimming performance July 10, 2020 15:45
Reduced, Swimming performance leads to Decrease, Population trajectory June 04, 2020 13:09
Beclomethasone dipropionate monohydrate July 07, 2020 15:19

Abstract

In the abstract section, authors should provide a concise and informative summation of the AOP under development that can stand-alone from the AOP page. Abstracts should typically be 200-400 words in length (similar to an abstract for a journal article). Suggested content for the abstract includes the following: The background/purpose for initiation of the AOP’s development (if there was a specific intent) A brief description of the MIE, AO, and/or major KEs that define the pathway A short summation of the overall WoE supporting the AOP and identification of major knowledge gaps (if any) If a brief statement about how the AOP may be applied (optional). The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance More help

This adverse outcome pathway specifies the relationship between activation of the glucocorticoid receptor in fish species and impaired fin regeneration. Glucocorticoid receptor agonists are used in a variety of over the counter and prescribed medications. Though beneficial in many ways, the adverse effects associated with the use of exposure to GR agonists have not been well documented as those for other endocrine modes of action such as estrogen receptor agonism or inhibition of steroid biosynthesis. More recently, GR activity has been detected in wastewaters and wastewater impacted surface waters (van der Linden et al., 2008). Unlike mammals, fish can regenerate damaged or amputated limbs (fins). Damage to fins is a common throughout a fish’s life cycle (Wehner & Weidinger, 2015), and impaired or delayed ability to regenerate fins following damage can plausibly reduce ecological fitness making affected fish less capable of obtaining food, avoiding predation, and/or migrating within their range. This AOP will help to understand the potential ecological significance of being exposed to environmental GR agonists.

Background (optional)

This optional subsection 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. Examples of potential uses of the optional background section are listed on pages 24-25 of the User Handbook. More help

Pending

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 stressor and the biological system) of an AOP. More help
Key Events (KE)
This table summarises all of the KEs of the AOP. This table is populated in the AOP-Wiki as KEs are added to the AOP. Each table entry acts as a link to the individual KE description page.  More help
Adverse Outcomes (AO)
An AO is a specialised KE that represents the end (an adverse outcome of regulatory significance) of an AOP.  More help
Sequence Type Event ID Title Short name
MIE 122 Activation, Glucocorticoid Receptor Activation, Glucocorticoid Receptor
KE 1759 Increase, Cripto-1 expression Increase, Cripto-1 expression
KE 1760 Inhibition, Activin signaling Inhibition, Activin signaling
KE 1761 Inhibition, Fin regeneration Inhibition, Fin regeneration
KE 1005 Reduced, Swimming performance Reduced, Swimming performance
AO 360 Decrease, Population trajectory Decrease, Population trajectory

Relationships Between Two Key Events (Including MIEs and AOs)

This table summarises 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.To add a key event relationship click on either Add relationship: events adjacent in sequence or Add relationship: events non-adjacent in sequence.For example, if the intended sequence of KEs for the AOP is [KE1 > KE2 > KE3 > KE4]; relationships between KE1 and KE2; KE2 and KE3; and KE3 and KE4 would be defined using the add relationship: events adjacent in sequence button.  Relationships between KE1 and KE3; KE2 and KE4; or KE1 and KE4, for example, should be created using the add relationship: events non-adjacent button. This helps to both organize the table with regard to which KERs define the main sequence of KEs and those that provide additional supporting evidence and aids computational analysis of AOP networks, where non-adjacent KERs can result in artifacts (see Villeneuve et al. 2018; DOI: 10.1002/etc.4124).After clicking either option, the user will be brought to a new page entitled ‘Add Relationship to AOP.’ To create a new relationship, select an upstream event and a downstream event from the drop down menus. The KER will automatically be designated as either adjacent or non-adjacent depending on the button selected. The fields “Evidence” and “Quantitative understanding” can be selected from the drop-down options at the time of creation of the relationship, or can be added later. See the Users Handbook, page 52 (Assess Evidence Supporting All KERs for guiding questions, etc.).  Click ‘Create [adjacent/non-adjacent] relationship.’  The new relationship should be listed on the AOP page under the heading “Relationships Between Two Key Events (Including MIEs and AOs)”. To edit a key event relationship, click ‘Edit’ next to the name of the relationship you wish to edit. The user will be directed to an Editing Relationship page where they can edit the Evidence, and Quantitative Understanding fields using the drop down menus. Once finished editing, click ‘Update [adjacent/non-adjacent] relationship’ to update these fields and return to the AOP page.To remove a key event relationship to an AOP page, under Summary of the AOP, next to “Relationships Between Two Key Events (Including MIEs and AOs)” click ‘Remove’ The relationship should no longer be listed on the AOP page under the heading “Relationships Between Two Key Events (Including MIEs and AOs)”. More help

Network View

The stressor field is a structured data field that can be used to annotate an AOP with standardised terms identifying stressors known to trigger the MIE/AOP. Most often these are chemical names selected from established chemical ontologies. 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. Although AOPs themselves are not chemical or stressor-specific, linking to stressor terms known to be relevant to different AOPs can aid users in searching for AOPs that may be relevant to a given stressor. More help

Stressors

The stressor field is a structured data field that can be used to annotate an AOP with standardised terms identifying stressors known to trigger the MIE/AOP. Most often these are chemical names selected from established chemical ontologies. 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. Although AOPs themselves are not chemical or stressor-specific, linking to stressor terms known to be relevant to different AOPs can aid users in searching for AOPs that may be relevant to a given stressor. More help
Name Evidence Term
Beclomethasone dipropionate monohydrate Moderate

Life Stage Applicability

Identify the life stage for which the KE is known to be applicable. More help
Life stage Evidence
larvae High
Adult, reproductively mature High
Juvenile High

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 in relation to this KE. More help
Term Scientific Term Evidence Link
teleost fish teleost fish High NCBI

Sex Applicability

The authors must select from one of the following: Male, female, mixed, asexual, third gender, hermaphrodite, or unspecific. More help
Sex Evidence
Mixed High

Overall Assessment of the AOP

This section addresses the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and WoE for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). The goal of the overall assessment is to provide a high level synthesis and overview of the relative confidence in the AOP and where the significant gaps or weaknesses are (if they exist). Users or readers can drill down into the finer details captured in the KE and KER descriptions, and/or associated summary tables, as appropriate to their needs.Assessment of the AOP is organised into a number of steps. Guidance on pages 59-62 of the User Handbook is available to facilitate assignment of categories of high, moderate, or low confidence for each consideration. While it is not necessary to repeat lengthy text that appears elsewhere in the AOP description (or related KE and KER descriptions), a brief explanation or rationale for the selection of high, moderate, or low confidence should be made. More help

    

Domain of Applicability

The relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context are defined in this section. Biological domain of applicability is informed by the “Description” and “Biological Domain of Applicability” sections of each KE and KER description (see sections 2G and 3E for details). In essence the taxa/life-stage/sex applicability is defined based on the groups of organisms for which the measurements represented by the KEs can feasibly be measured and the functional and regulatory relationships represented by the KERs are operative.The relevant biological domain of applicability of the AOP as a whole will nearly always be defined based on the most narrowly restricted of its KEs and KERs. For example, if most of the KEs apply to either sex, but one is relevant to females only, the biological domain of applicability of the AOP as a whole would be limited to females. While much of the detail defining the domain of applicability may be found in the individual KE and KER descriptions, the rationale for defining the relevant biological domain of applicability of the overall AOP should be briefly summarised on the AOP page. More help
Domain Evidence Reasoning

Taxa

High
  • Biological plausibility suggests that fin regeneration occurs throughout the teleost class (Fu et al., 2013; Wehner & Weidinger, 2015).
Sex High
  • Biological plausibility suggests that fin regeneration is not sex specific
  • Empirical evidence shows fin regeneration occurs in both sex (Sengupta et al., 2012; Garland et al., 2019).
Lifestage High
  • Biological plausibility suggests that fin regeneration is universal to a fish's life; excluding embryonic stage.
  • Empirical evidence shows fin regeneration can occur ineven during larval stage.

Essentiality of the Key Events

An important aspect of assessing an AOP is evaluating the essentiality of its KEs. 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.When assembling the support for essentiality of the KEs, authors should organise relevant data in a tabular format. The objective is to summarise briefly the nature and numbers of investigations in which the essentiality of KEs has been experimentally explored either directly or indirectly. See pages 50-51 in the User Handbook for further definitions and clarifications.  More help

Essentiallity has beeen determined in the evidence assesment.

Evidence Assessment

The biological plausibility, empirical support, and quantitative understanding from each KER in an AOP are assessed together.  Biological plausibility of each of the KERs in the AOP is the most influential consideration in assessing WoE or degree of confidence in an overall hypothesised AOP for potential regulatory application (Meek et al., 2014; 2014a). Empirical support entails consideration of experimental data in terms of the associations between KEs – namely dose-response concordance and temporal relationships between and across multiple KEs. It is examined most often in studies of dose-response/incidence and temporal relationships for stressors that impact the pathway. While less influential than biological plausibility of the KERs and essentiality of the KEs, empirical support can increase confidence in the relationships included in an AOP. For clarification on how to rate the given empirical support for a KER, as well as examples, see pages 53- 55 of the User Handbook.  More help
Key Event Evidence Reasoning
Relationship 2077: GR agonism -> Cripto-1 Expression Moderate
  • Empirical evidence for GR agonism leading to an increase in cripto-1 transcription is prevelant and has been replicated (Sengupta et al., 2012; Garland et al., 2019).
  • The biological pathway regarding GR regulation of Cripto-1 is currently lacking. 

Relationship 2078: Cripto-1 Expression -> Activin inhibition

Moderate
  • Empirical evidence has shown how the mechanism of cripto-1 inhibiting activin receptors occurs (Gray et al., 2003).
  • Biological plausibility suggests cripto-1 is capable of binding with the ALK-4 subunit of the Activin receptor (Gray et al., 2003).

Relationship 2079: Activin Inhibition -> Inibition Fin Regeneration

High
  • Currently there is no emprical evidence measuring activin signalling, or lack there of, during the fin regeneration process.
  • Biological plausibility suggests that activin signalling plays a strong and crucial roll in the fin regeneration process (Wehner & Weidinger, 2015). 

Relationship 2080: Inhibition Fin Regeneration -> Decreased Swim Performance

High
  • Empirical evidence has shown that different fish species with amputated fins have a significant decrease in swim performance (Fu et al., 2013).
  • Biological plausibility suggests that without a main source of locomotion, i.e. fins, locomotion itself will decrease (Fu et al., 2013).
Relationship 2081: Decreased Swim Performance -> Population Decrease High
  • Biological plausibility suggests that without the ability to swim, fish will lack the mobility needed for predator avoidance, obtaining food, or migration (Fu et al., 2013).

Relationship 2082: Cripto-1 Expression -> Inhibition Fin Regeneration

Moderate
  • Empircal evidence showing the relationship between an increase in cripto-1 expression and an inhibition of fin regeneration is prevalent and has been replicated. This indicates an essentiality for cripto-1 expression for inhibition of fin regeneration to occur (Sengupta et al., 2012; Garland et al., 2019).

Quantitative Understanding

Some proof of concept examples to address the WoE considerations for AOPs quantitatively have recently been developed, based on the rank ordering of the relevant Bradford Hill considerations (i.e., biological plausibility, essentiality and empirical support) (Becker et al., 2017; Becker et al, 2015; Collier et al., 2016). Suggested quantitation of the various elements is expert derived, without collective consideration currently of appropriate reporting templates or formal expert engagement. Though not essential, developers may wish to assign comparative quantitative values to the extent of the supporting data based on the three critical Bradford Hill considerations for AOPs, as a basis to contribute to collective experience.Specific attention is also given to how precisely and accurately one can potentially predict an impact on KEdownstream based on some measurement of KEupstream. This is captured in the form of quantitative understanding calls for each KER. See pages 55-56 of the User Handbook for a review of quantitative understanding for KER's. More help

Pending

Considerations for Potential Applications of the AOP (optional)

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.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 or 'Update and continue' to continue editing AOP text sections.  The new text should appear under the “Considerations for Potential Applications of the AOP” section on the AOP page. More help

By collecting surface water samples, a screening for pharmaceuticals, personal care products and other known glucocorticoid agonists could provide insight to the potential risks of the afformentioned. A better understanding of the quantitative AOP would be an advantageous tool for risk assessors.

References

List the bibliographic references to original papers, books or other documents used to support the AOP. More help

Ellis T, Hoyle I, Oidtmann B, Turnbull JF, Jacklin TE, Knowles TG. 2009. Further development of the “Fin Index” method for quantifying fin erosion in rainbow trout. Aquaculture 289: 283-288. doi:10.1016/j.aquaculture.2009.01.022

Fu C, Cao ZD, Fu SJ. 2013. The effects of caudal fin loss and regeneration on the swimming performance of three cyprinid fish species with different swimming capacities. The Journal of Experimental Biology 216:3164-3174. doi:10.1242/jeb.084244

Garland MA, Sengupta S, Mathew LK, Truong L, Jong ED, Piersma AH, Du JL, Tanguay RL. 2019. Glucocorticoid receptor-dependent induction of cripto-1 (one-eyed pinhead) inhibits zebrafish caudal fin regeneration. Toxicology Reports 6:529-537. https://doi.org/10.1016/j.toxrep.2019.05.013

Gray PC, Harrison CA, Vale W. 2003. Cripto forms a complex with activin and type II activin receptors and can block activin signaling. Proceedings of the National Academy of Sciences of the United States of America 100(9):5193-5198. www.pnas.org/cgi/doi/10.1073/pnas.0531290100

Kaneko H, 2016. Handbook of Hormones: Pages 295-297, e33B-2.

Jaźwińska A, Badakov R, Keating MT. 2007. Activin-βA Signaling is Required for Zebrafish Fin Regeneration. Current Biology 17:1390-1395. DOI 10.1016/j.cub.2007.07.019

Kang HY, Shyr CR. 2011. Activins and Cell Migration. Vitamins and Hormons 85: 129-48. doi: 10.1016/B978-0-12-385961-7.00007-X.

Poss KD, Shen J, Keating MT, Nechiporuk A. 2003. Tales of Regeneration in Zebrafish. Developmental Dynamics 226:202-210. DOI 10.1002/dvdy.10220

Sengupta S, Bisson WH, Mathew LK, Kolluri SK, Tanguay RL. 2012. Alternative glucocorticoid receptor ligand binding structures influence outcomes in an in vivo tissue regeneration model. Comparative Biochemistry and Physiology, Part C 156:121-129. doi:10.1016/j.cbpc.2012.05.003

van der Linden SC, Heringa MB, Man HY, Sonneveld Edwin, Puijker LM, Brouwer A, van der Burg B. 2008. Detection of Multiple Hormonal Activities in Wastewater Effluents and Surface Water, Using a Panel of Steroid Receptor CALUX Bioassays. Envionmental Science & Technology 42(15):5814-5820. https://doi.org/10.1021/es702897y

Voesenek CJ, Muijres FT, van Leeuwen JL. 2018. Biomechanics of Swimming in Developing Larval Fish. Journal of Experimental Biology 221:jeb149583. doi: 10.1242/jeb.149583.

Wehner D, Weidinger G. 2015. Signaling networks organizing regenerative growth of the zebrafish fin. Trends in Genetics 31 (6):336-343. http://dx.doi.org/10.1016/j.tig.2015.03.012