Aop: 349

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

Inhibition of 11β-hydroxylase leading to decresed trajectory in fish

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
11β-hydroxylase inhibition, infertility in fish

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

Young Jun KimEnvironmental Safety Group, Korea Institute of Science and Technology (KIST) Europe Forschungsgesellschaft mbH, 66123 Saarbruecken, Germany

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
Allie Always   (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
  • Young Jun Kim
  • Allie Always

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 April 05, 2021 18:16
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
11β-hydroxylase inhibition July 13, 2020 04:28
Decreased, plasma 11-ketotestosterone level February 09, 2021 08:33
Decreased spermatogenesis February 09, 2021 08:36
Cortisol and 11β-(OH) testosterone decreased February 09, 2021 08:25
Decreased plasma Cortisol level February 09, 2021 08:27
decreased oocyte maturation February 09, 2021 08:32
Decrease, Population trajectory September 26, 2017 11:33
impaired, Fertility December 02, 2016 09:21
11β-hydroxylase inhibition leads to Cortisol and 11β-(OH) testosterone decreased February 09, 2021 08:40
Cortisol and 11β-(OH) testosterone decreased leads to Decreased, 11KT February 09, 2021 08:41
Cortisol and 11β-(OH) testosterone decreased leads to Decreased plasma Cortisol level February 09, 2021 08:40
Decreased, 11KT leads to Decreased spermatogenesis July 21, 2020 09:54
Decreased plasma Cortisol level leads to decreased oocyte maturation February 09, 2021 09:00
Decreased spermatogenesis leads to impaired, Fertility July 13, 2020 04:42
decreased oocyte maturation leads to impaired, Fertility March 26, 2021 15:32
impaired, Fertility leads to Decrease, Population trajectory March 26, 2021 15:24
Metyrapone July 12, 2020 10:26
Lysodren, Mitotan, Mitotane July 12, 2020 10:27
Etomidate July 12, 2020 10:27
Ketoconazole May 02, 2017 11:08
Osilodrostat(LCI699) July 12, 2020 10:30

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 AOP links inhibition of 11β-hydroxylase to reproductive toxicity in fish. The present AOP suggests the inhibition of 11β-hydroxylase mediated adverse outcome (AO) in fishes. In teleost, cyp11c1 encodes 11β-hydroxylase, one of the critical enzymes mediating testosterone conversion to 11β-(OH) testosterone, critical for biosynthesis of 11-KT and 11-deoxycortisol to cortisol in the differentiating gonads of both sexes at the juvenile stage. Qifeng Zhang et al, 2020 showed that the 11β-hydroxylase knockout male fish showed delayed and prolonged juvenile ovary-to-testis transition and displayed defective spermatogenesis at the adult stage, significantly reduced 11-KT and cortisol levels. Male zebrafish are infertile, have smaller testis, possess very little spermatozoa volume, and exhibit defective secondary sexual characteristics (Tang H et al.2018).

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

11β-hydroxylase is prominently expressed in the Leydig cells of the testis in teleost. Ribas L, et al, 2017 reported that elevated cortisol, primary glucocorticoid, during the stress response might play a role in teleost's masculinization. Cortisol has also been cross talked to be involved in reproduction and sex differentiation at a proper level for the success of spawning, oocyte maturation, and the survival of progeny in teleosts. In females, the 11β-hydroxylase knockout females showed less spawned eggs and the eggs were defective in germinal vesicle breakdown. Stress conditions or inhibition of 11β-hydroxylase activities finally decreased 11KT and cortisol in the Leydig and Sertoli cells. Taken together, the inhibitors of 11β-hydroxylase (i.e metyrapone, lysodren, eomidate and ketoconazole etc.) could result in decreased 11-KT and cortisol, subsequently, leading to impairment of spermatogenesis and oocyte maturation and ovulation.         

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 1796 11β-hydroxylase inhibition 11β-hydroxylase inhibition
KE 1835 Cortisol and 11β-(OH) testosterone decreased Cortisol and 11β-(OH) testosterone decreased
KE 1756 Decreased, plasma 11-ketotestosterone level Decreased, 11KT
KE 1836 Decreased plasma Cortisol level Decreased plasma Cortisol level
KE 1798 Decreased spermatogenesis Decreased spermatogenesis
KE 1837 decreased oocyte maturation decreased oocyte maturation
KE 406 impaired, Fertility impaired, Fertility
AO 360 Decrease, Population trajectory Decrease, Population trajectory

Relationships Between Two Key Events (Including MIEs and AOs)

TESTINGThis 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 AOP-Wiki automatically generates a network view of the AOP. This network graphic is based on the information provided in the MIE, KEs, AO, KERs and 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

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
Metyrapone High
Lysodren, Mitotan, Mitotane High
Etomidate High
Ketoconazole High
Osilodrostat(LCI699) Moderate

Life Stage Applicability

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

To do

Expected duration

Building the AOP frame

Development of KEs

3 month

Production of experimental data for in vitro/in vivo

18 month

Overall assessment of the AOP

Biological domain of applicability

3 month

Essentiality of all KEs

3 month

Evidence supporting all KERs

5 month

Quantitative WoE considerations

5 month

Quantitative understanding for each KER

6 month

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

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

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

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

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

  This AOP is designed to estimate changes in the trajectory of fishes by potential inhibitors. Decreased trajectory applicable to both sex in the fish which is a potential endpoint for endocrine disruptions by inhibition of 11β-hydroxylase. The proposed endpoint will provide a useful high throughput risk assessment screening tool for possible chemicals. Consequently, this AOP can be applied to the prediction of VMG-eco and relevant to EDTA caused by the inhibition of 11β-hydroxylase

References

List the bibliographic references to original papers, books or other documents used to support the AOP. More help
  1. Zebrafish cyp11c1 Knockout Reveals the Roles of 11-ketotestosterone and Cortisol in Sexual Development and Reproduction. Endocrinology 2020 Jun 1;161(6):bqaa048.
  2. Appropriate rearing density in domesticated zebrafish to avoid masculinization: links with the stress response, J Exp Biol. 2017;220(Pt 6):1056-1064
  3. Loss of Cyp11c1 Causes Delayed Spermatogenesis Due to the Absence of 11-ketotestosterone. J Endocrinol 2020 Mar;244(3):487-499.
  4. The Onset of Spermatogenesis in Fish. Ciba Found Symp 1994;182:255-67; discussion 267-70.
  5. Impaired Spermatogenesis in the Japanese Eel, Anguilla Japonica: Possibility of the Existence of Factors That Regulate Entry of Germ Cells Into Meiosis.  Dev Growth Differ 1997 Dec;39(6):685-91
  6. Zebrafish 20β-Hydroxysteroid Dehydrogenase Type 2 Is Important for Glucocorticoid Catabolism in Stress Response PLOS 2013 8 (1) e54851
  7. A newly cyp11c1-GFP transgenic zebrafish model to study corticosteroidogenesis and its perturbation by endocrine active substances at early developmental stages. Conference paper
  8. Large-scale transcriptome sequencing reveals novel expression patterns for key sex-related genes in a sex-changing fish. Biol Sex Differ. 2015; 6: 26.
  9. A Critical Role of Follicle-Stimulating Hormone (Fsh) in Mediating the Effect of Clotrimazole on Testicular Steroidogenesis in Adult Zebrafish. Toxicology 2012 Aug 16;298(1-3):30
  10. Maternal stress and fish reproduction: The role of cortisol revisited Fish and Fisheries November 2018, Nov, 19(6) Pages 1016-1030
  11. Effects of steroid hormones on in vitro oocyte maturation in white sturgeon (Acipenser transmontanus)Fish Physiology and Biochemistry, 2000 volume 23, pages317–325
  12. Some aspects of oocyte maturation in catfish Journal of Steroid Biochemistry Volume 11, Issue 1, Part 3, July 1979, Pages 701-707      
  13. The in vitro metabolism of cortisol by ovarian follicles of rainbow trout (Oncorhynchus mykiss): comparison with ovulated oocytes and pre-hatch embryos  Reproduction, Pages 713–722 Volume 144: Issue 6