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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

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

Agnes Aggy (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
Agnes Aggy

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
Inhibition of 11β-HSD	July 13, 2020 09:23
Decreased, plasma 11-ketotestosterone level	May 24, 2022 13:51
Impaired, Spermatogenesis	April 10, 2024 17:41
Decrease, Population growth rate	January 03, 2023 09:09
impaired, Fertility	September 14, 2023 12:10
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	August 15, 2022 02:44
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

KE	1756	Decreased, plasma 11-ketotestosterone level	Decreased, 11KT
KE	1758	Impaired, Spermatogenesis	Impaired, Spermatogenesis
KE	406	impaired, Fertility	impaired, Fertility

360

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

Inhibition of 11β-HSD leads to Decreased, 11KT	adjacent	High	Moderate
Decreased, 11KT leads to Impaired, Spermatogenesis	adjacent	High	Moderate
Impaired, Spermatogenesis 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
N-(5-Hydroxytricyclo[3.3.1.13,7]dec-2-yl)-α,α-dimethyl-4-[5-(trifluoromethyl)-2-pyridinyl]-1-piperazineacetamide
Carbenoxolone
Glycyrrhizin
PF915275

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
Building the AOP frame	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
Diethyldithiocarbamate (DEDTC)	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
Tributyltin	HEK 293 cells	1.95
Dibutyltin	HEK 293 cells	5.03
Dibutyltin	Human microsomes	8.9
4-t-Octylphenol	HEK 293 cells	30
4-t-Octylphenol	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
Dicyclohexyl phtalate	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
Perfluorooctyl sulphonate	Rat microsomes	0.29
Perfluorooctanoic acid	Human microsomes	24.41
Perfluorooctanoic acid	Rat microsomes	3.8
Perfluorohexanesulfonate	Human microsomes	18.97
Perfluorohexanesulfonate	Rat microsomes	62.87
2-Bis(p-hydroxyphenyl)-1,1,1-trichloroethane	Human microsomes	55.57
2-Bis(p-hydroxyphenyl)-1,1,1-trichloroethane	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

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

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

Roles of 11β-Hydroxysteroid Dehydrogenase in Fish Spermatogenesis. Endocrinology 147(11):5139–5146
Hormonal induction of all stages of spermatogenesis in vitro in the male Japanese eel (Anguilla japonica). Proc Natl Acad Sci USA 88:5774–5778
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
Steroid profiles during spawning in male common carp. Gen Comp Endocrinol 80:223–231
11 β-Hydroxysteroid dehydrogenase complementary deoxyribonucleic acid in rainbow trout: cloning, sites of expression, and seasonal changes in gonads. Endocrinology 144:2534–2545
11 β –Hydroxysteroid dehydrogenase is a predominant reductase in intact Leydig cells. J Endocrinol 159:233–238
Large-scale transcriptome sequencing reveals novel expression patterns for key sex-related genes in a sex-changing fish. Biology of Sex Differences 6:26
Sex Steroids and Their Involvement in the Cortisol-Induced Inhibition of Pubertal Development in Male Common Carp, BIOLOGY OF REPRODUCTION 67, 465–472
Natural sex change in fish Current Topics in Developmental Biology, Volume 134
Absence of 11-keto reduction of cortisone and 11-ketotestosterone in the model organism zebrafish Journal of Endocrinology 232,323–335
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.