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AOP: 349

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

Inhibition of 11β-hydroxylase leading to decresed population trajectory

Short name
A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help
11β-hydroxylase inhibition, infertility in fish
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 v2.0

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

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

Park Chang-Beom, Korea Institute of Toxicology JRC-APT (Joint Research Center for Alternative and Predictive Toxicology)

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
Allie Always   (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
  • Young Jun Kim
  • Chang-Beom Park
  • Allie Always

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
  • Dan Villeneuve

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
1.93 Under Development
This AOP was last modified on May 26, 2024 20:39

Revision dates for related pages

Page Revision Date/Time
11β-hydroxylase inhibition July 13, 2020 04:28
Decreased, plasma 11-ketotestosterone level May 24, 2022 13:51
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 growth rate January 03, 2023 09:09
impaired, Fertility September 14, 2023 12:10
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 growth rate 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

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 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).

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

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.       

Acknowledgements: This research was supported by the National Research Council of Science & Technology(NST) grant by the Korea government (MSIP) (No. CAP-17-01-KIST Europe)  

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

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 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 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
11β-hydroxylase inhibition leads to Cortisol and 11β-(OH) testosterone decreased adjacent High Moderate
Cortisol and 11β-(OH) testosterone decreased leads to Decreased, 11KT adjacent High Moderate
Cortisol and 11β-(OH) testosterone decreased leads to Decreased plasma Cortisol level adjacent High Moderate
Decreased, 11KT leads to Decreased spermatogenesis adjacent Moderate Moderate
Decreased plasma Cortisol level leads to decreased oocyte maturation adjacent Moderate Moderate
Decreased spermatogenesis leads to impaired, Fertility adjacent High High
decreased oocyte maturation leads to impaired, Fertility adjacent High High
impaired, Fertility leads to Decrease, Population growth rate adjacent High High

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
Name
Metyrapone
Lysodren, Mitotan, Mitotane
Etomidate
Ketoconazole
Osilodrostat(LCI699)

Life Stage Applicability

The life stage for which the AOP 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. More help
Term Scientific Term Evidence Link
fish fish Moderate NCBI

Sex Applicability

The sex for which the AOP is known to be applicable. More help
Sex Evidence
Mixed High

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

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

Addressess the relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context. More help

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

Evidence Assessment

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

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

Quantitative Understanding

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

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

  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 of the literature that was cited for this 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