Aop: 348

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-Hydroxysteroid Dehydrogenase leading to decreased population trajectory

Short name
A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help
11βHSD inhibition, decreased population trajectory

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
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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
Young Jun Kim   (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

Status

Provides 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. OECD Status - Tracks the level of review/endorsement the AOP has been subjected to. OECD Project Number - Project number is designated and updated by the OECD. SAAOP Status - Status managed and updated by SAAOP curators. More help
Author status OECD status OECD project SAAOP status
Under development: Not open for comment. Do not cite Under Development 1.93 Included in OECD Work Plan
This AOP was last modified on March 15, 2022 14:36

Revision dates for related pages

Page Revision Date/Time
Inhibition of 11β-HSD July 13, 2020 09:23
Decreased, plasma 11-ketotestosterone level May 24, 2022 13:51
Impaired, Spermatogenesis May 16, 2022 02:14
Decrease, Population growth rate July 08, 2022 07:40
impaired, Fertility December 02, 2016 09:21
Inhibition of 11β-HSD leads to Decreased, 11KT July 13, 2020 09:31
Decreased, 11KT leads to Impaired, Spermatogenesis April 19, 2021 13:32
Impaired, Spermatogenesis leads to impaired, Fertility April 19, 2021 13:02
impaired, Fertility leads to Decrease, Population growth rate March 26, 2021 15:24
N-(5-Hydroxytricyclo[3.3.1.13,7]dec-2-yl)-α,α-dimethyl-4-[5-(trifluoromethyl)-2-pyridinyl]-1-piperazineacetamide July 05, 2020 11:13
Carbenoxolone March 30, 2020 15:25
Glycyrrhizin July 13, 2020 10:41
PF915275 July 13, 2020 10:42

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 11βHSD to reproductive toxicity in fish. This AOP describes impaired spermatogenesis that may result from the inhibition of 11βHSD. Chemical inhibition of 11βHSD, the molecular-initiating event (MIE), results in decreased 11-KT and cortisone synthesis. The reduction of 11-KT induces the cumulative cortisol by enzymatic conversion insufficiency of cortisone, which leads to decreased spermatogonial proliferation. Impaired fertility is a significant endpoint for evaluation of reproductive toxicity caused by endocrine disruption. It can be used as an endpoint for endocrine disruptor screening. Therefore, this AOP would be useful to identify chemicals with known potential to affect male fish fertility.

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

In fish spermatogenesis,11-KT is the main androgen in teleosts, where it has functions in spermatogenesis and their main action of 11-beta dehydrogenase(11βHSD Type 2)  is generally regarded as the induction of sperm maturation. it has also its role is to protect these tissues from an excess of cortisol. Stress conditions or inhibition of 11bHSD dehydrogenase activities result in a cortisol excess in the Leydig cells. A surplus of glucocorticoids causes delayed genomic repression of 11KT production through GR or a rapid nongenomic decrease in 11 KT production. The rapid depression has been hypothesized to occur via the putative plasma membrane corticosteroid receptor11βHSD2 is unidirectional with NAD+ as a cofactor. It is expressed not only in mineralocorticoid sensitive tissues such as testis.11βHSD has enzyme activities, metabolizing cortisol to cortisone, and 11 beta -hydroxytestosterone to 11-ketotestosterone (11-KT) which is the main androgen functions spermatogenesis. Especially, spermatogenesis can induce by 11-ketotestosterone(11-KT), a significant androgen in teleost. However, excess circulating cortisol, which is produced by 11β-hydroxylase and decline of 11KT by 11βHSD inhibition, leads to inhibition of the DNA replication in spermatogonial mitosis, gonadal function, and spermatogonial proliferation in male fish.

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 1799 Inhibition of 11β-HSD Inhibition of 11β-HSD
KE 1756 Decreased, plasma 11-ketotestosterone level Decreased, 11KT
KE 1758 Impaired, Spermatogenesis Impaired, Spermatogenesis
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

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
Life stage Evidence
Adult, reproductively mature Moderate

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 High NCBI

Sex Applicability

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

11KT has functions in spermatogenesis and their main action of 11βHSD Type 2 is generally regarded as the induction of sperm maturation thus,This AOP will start with reviews about inhibitors of 11βHSD2 as MIE. Stressors for inhibiton were found in table and 11βHSD1 inhibitors were also denoted in previous studies (Jana Vitku et al 2016) . We will further find KERs with Androgen antagonisms and their impact on male fish.

To do

Expected duration

Building the AOP frame

Development of KEs

6 month

Production of experimental data using inhibitors

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

Domain(s) of Applicability

Chemical: This AOP applies to inhibitors of 11KT (Androgen antagonists). Compounds which can bind the 11βHSD as follows

Inhibitors of 11bHSD2 Testing system IC50(μM)
(1E,4E)-1,5-Bis(3-methylthiophen-2-yl)penta-1,4-dien-3-one Human microsomes 19.58
Abietic acid HEK 293 cells 12
Zearalenone HEK 293 cells 107
Fusidic acid  HEK 293 cells 134
Euphane-3b,20-dihydroxy-24-ene HEK 293 cells  8.18
Kansuinone HEK 293 cells  2.63
Euphol HEK 293 cells  0.4
Kansenone HEK 293 cells  0.11
(24R)-Eupha-8,25-diene-3b,24-diol HEK 293 cells  1.69
(20R,23E)-Eupha-8,23-diene-3b,25-diol HEK 293 cells  0.67
Carbenoxolone CHO cells 0.02
Endosulfan HEK 293 cells 61
BPA HEK 293 cells 50
Disulfiram HEK 293 cells 0.13
Thiram HEK 293 cells 0.13
Diethyldithiocarbamate (DEDTC) HEK 293 cells 1.7
HEK 293 cells 6.3
Pyrrolidine dithiocarbamate (PDTC) HEK 293 cells 6.3
Maneb HEK 293 cells 0.75
Zineb HEK 293 cells 1.42
Diphenyltin HEK 293 cells 2.89
Human microsomes 3.3
HEK 293 cells  3.19
Triphenyltin HEK 293 cells  0.99
Human microsomes 16.5
HEK 293 cells 1.9
Tributyltin HEK 293 cells 1.52
HEK 293 cells 1.95
Dibutyltin HEK 293 cells 5.03
Human microsomes 8.9
4-t-Octylphenol HEK 293 cells 30
Human microsomes 20.3
4-Nonylphenol HEK 293 cells 79
4-n-Octylphenol Human microsomes 23.5
4-n-Nonylphenol Human microsomes 26.2
Dicyclohexyl phtalate Human microsomes 46.5
Rat microsomes 32.64
Dipropyl phthalate Rat microsomes 85.59
Di-n-butyl phthlate Rat microsomes 13.69
Mono(2-ethylhexyl)phthalate Rat microsomes 121.8
Mono(2-ethylhexyl)phthalate Human microsomes 110.8
Perfluorooctyl sulphonate Human microsomes 0.05
Rat microsomes 0.29
Perfluorooctanoic acid Human microsomes 24.41
Rat microsomes 3.8
Perfluorohexanesulfonate Human microsomes 18.97
Rat microsomes 62.87
2-Bis(p-hydroxyphenyl)-1,1,1-trichloroethane Human microsomes 55.57
Rat microsomes 12.96
Source: Journal of Steroid Biochemistry & Molecular Biology 2016 Jan;155(Pt B):207-16

Sex: The AOP applies to males only.

Life stages: The relevant life stages for this AOP are reproductively mature spermatogenesis. 

Taxonomic: At present, the assumed taxonomic applicability domain of this AOP is iteroparous teleost fish species.

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
  • Many studies showed that the essentiality of the proposed sequence of key events in teleost.
  • The essentiality of the proposed negative regulation of 11βHSD is supported by experimental work that evaluated the ability of inhibition to reduce 11KT production in vitro and in vivo

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

A decrease in 11keto levels leads afterward to adverse changes in spermatogenesis. Therefore, it seems that 11βHSD  could be a target for EDs and this could be one of the possible mechanisms of endocrine disruption in the testis that leads to impaired spermatogenesis. Consequently, this AOP can be applied to the prediction of VMG-eco and relevant to EDTA caused by the inhibition of 11β-HSD. 

References

List of the literature that was cited for this AOP. More help
  1. Roles of 11β-Hydroxysteroid Dehydrogenase in Fish Spermatogenesis. Endocrinology 147(11):5139–5146
  2. Hormonal induction of all stages of spermatogenesis in vitro in the male Japanese eel (Anguilla japonica). Proc Natl Acad Sci USA 88:5774–5778
  3. 17α,20 β Dihydroxy-4-pregnen-3-one: plasma levels during sexual maturation and in vitro production by the testes of amago salmon (Oncorhynchus rhodurus) and rainbow trout (Salmo gairdneri). Gen Comp Endocrinol 51:106–11
  4. Steroid profiles during spawning in male common carp. Gen Comp Endocrinol 80:223–231
  5. 11 β-Hydroxysteroid dehydrogenase complementary deoxyribonucleic acid in rainbow trout: cloning, sites of expression, and seasonal changes in gonads. Endocrinology 144:2534–2545
  6. 11 β –Hydroxysteroid dehydrogenase is a predominant reductase in intact Leydig cells. J Endocrinol 159:233–238
  7. Large-scale transcriptome sequencing reveals novel expression patterns for key sex-related genes in a sex-changing fish.  Biology of Sex Differences 6:26
  8. Sex Steroids and Their Involvement in the Cortisol-Induced Inhibition of Pubertal Development in Male Common Carp, BIOLOGY OF REPRODUCTION 67, 465–472
  9. Natural sex change in fish Current Topics in Developmental Biology, Volume 134
  10. Absence of 11-keto reduction of cortisone and 11-ketotestosterone in the model organism zebrafish Journal of Endocrinology 232,323–335
  11. Endocrine disruptors and other inhibitors of 11b-hydroxysteroid dehydrogenase 1 and 2: Tissue-specific consequences of enzyme inhibition.Journal of Steroid Biochemistry & Molecular Biology 155(Pt B):207-16.