AOP: 496

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

Androgen receptor agonism leading to reproduction dysfunction （in zebrafish）

Short name

A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help

Androgen receptor agonism leading to reproduction dysfunction

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 v2.5

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

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Authors

The names and affiliations of the individual(s)/organisation(s) that created/developed the AOP. More help

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

Arthur Author (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

xuan liu
Arthur Author

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

OECD Information Table

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OECD Project #	OECD Status	Reviewer's Reports	Journal-format Article	OECD iLibrary Published Version

This AOP was last modified on September 25, 2023 16:27

Revision dates for related pages

Page	Revision Date/Time
Agonism, Androgen receptor	March 20, 2017 17:44
Increase, Gonadotropins concentration in plasma	May 16, 2023 21:50
Reduction,Testosterone concentration in plasma	May 16, 2023 21:54
Reduction, Plasma 17beta-estradiol concentrations	September 26, 2017 11:30
Reduction, the ratio of 17beta-estradiol/11-Keto Testosterone in plasma	May 16, 2023 22:04
Reduction, Plasma vitellogenin concentrations	September 16, 2017 10:14
Reduction, Vitellogenin accumulation into oocytes and oocyte growth/development	September 16, 2017 10:14
Reduction, Cumulative fecundity and spawning	March 20, 2017 17:52
Decreased, Population trajectory	April 18, 2017 16:19
Increased, gene expression of AR	May 18, 2023 02:05
Agonism, Androgen receptor leads to Increased, gene expression of AR	May 22, 2023 21:36
Reduction,Testosterone concentration in plasma leads to Reduction, the ratio of E2/11-KT in plasma	May 22, 2023 21:45
Increased, gene expression of AR leads to Increase, Gonadotropins concentration in plasma	May 22, 2023 21:37
Reduction, Plasma 17beta-estradiol concentrations leads to Reduction, Plasma vitellogenin concentrations	October 18, 2018 11:02
Increase, Gonadotropins concentration in plasma leads to Reduction,Testosterone concentration in plasma	May 22, 2023 21:37
Agonism, Androgen receptor leads to Reduction, the ratio of E2/11-KT in plasma	May 22, 2023 22:19
Reduction,Testosterone concentration in plasma leads to Reduction, Plasma 17beta-estradiol concentrations	May 22, 2023 21:38
Reduction, Plasma 17beta-estradiol concentrations leads to Reduction, the ratio of E2/11-KT in plasma	May 22, 2023 21:39
Reduction, the ratio of E2/11-KT in plasma leads to Reduction, Plasma vitellogenin concentrations	May 22, 2023 21:40
Reduction, Plasma vitellogenin concentrations leads to Reduction, Vitellogenin accumulation into oocytes and oocyte growth/development	March 20, 2017 13:21
Reduction, Vitellogenin accumulation into oocytes and oocyte growth/development leads to Reduction, Cumulative fecundity and spawning	March 20, 2017 13:35
Reduction, Cumulative fecundity and spawning leads to Decreased, Population trajectory	May 22, 2023 21:44
17beta-Trenbolone	November 29, 2016 18:42

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 adverse outcome pathway is a further development and improvement for AOP 23 and details the linkage of androgen receptor agonism in female zebrafish with reproductive dysfunction and reductions of cumulative fecundity and spawning as adverse effect. Based on AOP 23, it also adds some new KEs for the pathway and quantitative understanding for key events through experiments data. This work found that there are some differences and similarities in KEs between zebrafish and Pimephales promelas induced by androgen receptor agonism. The impairments in zebrafish in vivo is connected with androgen receptor activities in vitro by agonism.

The 21-day exposure experiments to adult zebrafish revealed that female zebrafish showed strong dose-response relationships to the androgen receptor agonism (17beta-trenbolone) at the genetic, enzymatic, tissue, and individual levels than male zebrafish. The quantitative relationships from experiments and evidence analysis revealed stronger evidence of androgen agonism, ar gene expression, circulating E2 and VTG concentrations in plasma, and spawning, while weaker evidence and dose-effect results in GtH and T concentrations in plasma, and oocytes development. In addition, it was the ratio of E2/11-KT rather than E2/T that became an important KE to reveal the transformation of T to E2 when qualitative and quantitative relationship were considered, since T will be catalyzed by aromatase (CYP19A1A and CYP11C1) and transform into E2 or 11-KT.

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

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

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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	25	Agonism, Androgen receptor	Agonism, Androgen receptor
MIE	2143	Increased, gene expression of AR	Increased, gene expression of AR

KE	2137	Increase, Gonadotropins concentration in plasma	Increase, Gonadotropins concentration in plasma
KE	2138	Reduction,Testosterone concentration in plasma	Reduction,Testosterone concentration in plasma
KE	219	Reduction, Plasma 17beta-estradiol concentrations	Reduction, Plasma 17beta-estradiol concentrations
KE	2139	Reduction, the ratio of 17beta-estradiol/11-Keto Testosterone in plasma	Reduction, the ratio of E2/11-KT in plasma
KE	221	Reduction, Plasma vitellogenin concentrations	Reduction, Plasma vitellogenin concentrations
KE	309	Reduction, Vitellogenin accumulation into oocytes and oocyte growth/development	Reduction, Vitellogenin accumulation into oocytes and oocyte growth/development
KE	78	Reduction, Cumulative fecundity and spawning	Reduction, Cumulative fecundity and spawning

442

Decreased, Population trajectory

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

Agonism, Androgen receptor leads to Increased, gene expression of AR	adjacent	High	Moderate
Increased, gene expression of AR leads to Increase, Gonadotropins concentration in plasma	adjacent	Low	Low
Increase, Gonadotropins concentration in plasma leads to Reduction,Testosterone concentration in plasma	adjacent	Moderate	Low
Reduction,Testosterone concentration in plasma leads to Reduction, Plasma 17beta-estradiol concentrations	adjacent	High	Moderate
Reduction, Plasma 17beta-estradiol concentrations leads to Reduction, the ratio of E2/11-KT in plasma	adjacent	High	Moderate
Reduction, the ratio of E2/11-KT in plasma leads to Reduction, Plasma vitellogenin concentrations	adjacent	High	High
Reduction, Plasma vitellogenin concentrations leads to Reduction, Vitellogenin accumulation into oocytes and oocyte growth/development	adjacent	Moderate	Moderate
Reduction, Vitellogenin accumulation into oocytes and oocyte growth/development leads to Reduction, Cumulative fecundity and spawning	adjacent	High	Moderate
Reduction, Cumulative fecundity and spawning leads to Decreased, Population trajectory	adjacent	High	Moderate

Reduction,Testosterone concentration in plasma leads to Reduction, the ratio of E2/11-KT in plasma	non-adjacent	Moderate	Moderate
Reduction, Plasma 17beta-estradiol concentrations leads to Reduction, Plasma vitellogenin concentrations	non-adjacent	High	High
Agonism, Androgen receptor leads to Reduction, the ratio of E2/11-KT in plasma	non-adjacent	Moderate	Moderate

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
17beta-Trenbolone

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
zebrafish	Danio rerio	High	NCBI

Sex Applicability

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

Sex	Evidence
Female	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

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

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

References

List of the literature that was cited for this AOP. More help