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This AOP is licensed under the BY-SA license. This license allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use. If you remix, adapt, or build upon the material, you must license the modified material under identical terms.

AOP: 23

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 reproductive dysfunction (in repeat-spawning fish)

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 reproductive 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 v1.0

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

Dan Villeneuve, US EPA Mid-Continent Ecology Division (villeneuve.dan@epa.gov)

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
Evgeniia Kazymova   (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
  • Dan Villeneuve
  • Evgeniia Kazymova

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

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
1.12 WPHA/WNT Endorsed
This AOP was last modified on May 26, 2024 20:39

Revision dates for related pages

Page Revision Date/Time
Decrease, Population growth rate January 03, 2023 09:09
Agonism, Androgen receptor March 20, 2017 17:44
Reduction, Testosterone synthesis by ovarian theca cells September 16, 2017 10:14
Reduction, 17beta-estradiol synthesis by ovarian granulosa cells September 16, 2017 10:14
Reduction, Plasma 17beta-estradiol concentrations September 26, 2017 11:30
Reduction, Vitellogenin synthesis in liver May 27, 2021 01:10
Reduction, Cumulative fecundity and spawning March 20, 2017 17:52
Reduction, Plasma vitellogenin concentrations September 16, 2017 10:14
Reduction, Vitellogenin accumulation into oocytes and oocyte growth/development September 16, 2017 10:14
Reduction, Gonadotropins, circulating concentrations May 09, 2018 14:05
Agonism, Androgen receptor leads to Reduction, Gonadotropins, circulating concentrations March 20, 2017 11:15
Reduction, Gonadotropins, circulating concentrations leads to Reduction, Testosterone synthesis by ovarian theca cells March 20, 2017 11:24
Reduction, Testosterone synthesis by ovarian theca cells leads to Reduction, 17beta-estradiol synthesis by ovarian granulosa cells March 20, 2017 11:37
Reduction, 17beta-estradiol synthesis by ovarian granulosa cells leads to Reduction, Plasma 17beta-estradiol concentrations March 20, 2017 12:05
Reduction, Plasma 17beta-estradiol concentrations leads to Reduction, Vitellogenin synthesis in liver March 20, 2017 12:28
Reduction, Vitellogenin synthesis in liver leads to Reduction, Plasma vitellogenin concentrations March 20, 2017 12:58
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 Decrease, Population growth rate March 20, 2017 13:49
Agonism, Androgen receptor leads to Reduction, Testosterone synthesis by ovarian theca cells March 20, 2017 15:55
Agonism, Androgen receptor leads to Reduction, 17beta-estradiol synthesis by ovarian granulosa cells March 20, 2017 15:56
Agonism, Androgen receptor leads to Reduction, Vitellogenin synthesis in liver March 20, 2017 15:59
Reduction, Plasma 17beta-estradiol concentrations leads to Reduction, Plasma vitellogenin concentrations October 18, 2018 11:02
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 details the linkage between binding and activation of androgen receptor as a nuclear transcription factor in females and reproductive dysfunction as evidenced through reductions cumulative fecundity and spawning in repeat-spawning fish species.  Androgen receptor mediated activities are one of the major activities of concern to endocrine disruptor screening programs worldwide.  Cumulative fecundity is the most apical endpoint considered in the OECD 229 Fish Short Term Reproduction Assay. The OECD 229 assay serves as screening assay for endocrine disruption and associated reproductive impairment (OECD 2012). Cumulative fecundity is one of several variables known to be of demographic significance in forecasting fish population trends. Therefore, this AOP has utility in supporting the application of measures of androgen receptor binding and activation as a nuclear transcription factor as a means to identify chemicals with known potential to adversely affect fish populations. At present this AOP is largely supported by evidence conducted with small laboratory model fish species such as Pimephales promelas, Oryzias latipes, and Fundulus heteroclitus. While many aspects of the biology underlying this AOP are largely conserved across vertebrates, particularly oviparous vertebrates, the relevance of this AOP to vertebrate classes other than fish as well as to fish species employing different reproductive strategies has not been established at this time. Thus, caution should be used in applying this AOP beyond a fairly narrow range of fish species with life cycles similar to that of the three species noted above.

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

No additional background

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 25 Agonism, Androgen receptor Agonism, Androgen receptor
KE 129 Reduction, Gonadotropins, circulating concentrations Reduction, Gonadotropins, circulating concentrations
KE 274 Reduction, Testosterone synthesis by ovarian theca cells Reduction, Testosterone synthesis by ovarian theca cells
KE 3 Reduction, 17beta-estradiol synthesis by ovarian granulosa cells Reduction, 17beta-estradiol synthesis by ovarian granulosa cells
KE 219 Reduction, Plasma 17beta-estradiol concentrations Reduction, Plasma 17beta-estradiol concentrations
KE 285 Reduction, Vitellogenin synthesis in liver Reduction, Vitellogenin synthesis in liver
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
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
Agonism, Androgen receptor leads to Reduction, Gonadotropins, circulating concentrations adjacent Low Low
Reduction, Gonadotropins, circulating concentrations leads to Reduction, Testosterone synthesis by ovarian theca cells adjacent High Low
Reduction, Testosterone synthesis by ovarian theca cells leads to Reduction, 17beta-estradiol synthesis by ovarian granulosa cells adjacent High Low
Reduction, 17beta-estradiol synthesis by ovarian granulosa cells leads to Reduction, Plasma 17beta-estradiol concentrations adjacent High Low
Reduction, Plasma 17beta-estradiol concentrations leads to Reduction, Vitellogenin synthesis in liver adjacent High Moderate
Reduction, Vitellogenin synthesis in liver leads to Reduction, Plasma vitellogenin concentrations adjacent High Moderate
Reduction, Plasma vitellogenin concentrations leads to Reduction, Vitellogenin accumulation into oocytes and oocyte growth/development adjacent Moderate Low
Reduction, Vitellogenin accumulation into oocytes and oocyte growth/development leads to Reduction, Cumulative fecundity and spawning adjacent Moderate Moderate
Reduction, Cumulative fecundity and spawning leads to Decrease, Population growth rate adjacent Moderate Moderate
Agonism, Androgen receptor leads to Reduction, Testosterone synthesis by ovarian theca cells non-adjacent Moderate Low
Agonism, Androgen receptor leads to Reduction, 17beta-estradiol synthesis by ovarian granulosa cells non-adjacent Moderate Low
Agonism, Androgen receptor leads to Reduction, Vitellogenin synthesis in liver non-adjacent High Low
Reduction, Plasma 17beta-estradiol concentrations leads to Reduction, Plasma vitellogenin concentrations non-adjacent High 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

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
Pimephales promelas Pimephales promelas NCBI

Sex Applicability

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

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
Attached file:

Annex 1 Table, Assessment of the relative level of confidence in the overall AOP based on rank ordered weight of evidence elements is attached in PDF format.

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 non-aromatizable androgens. Compounds which can bind the AR in vitro, but are converted to high potency estrogens in vivo through aromatization do not produce the profile of effects described in the present AOP (e.g., methyltestosterone [Ankley et al. 2001; Pawlowski et al. 2004]; androstenedione [OECD 2007]).

Sex: The AOP applies to females only.

Life stages: The relevant life stages for this AOP are reproductively mature adults. This AOP does not apply to adult stages that lack a sexually mature ovary, for example as a result of seasonal or environmentally-induced gonadal senescence (i.e., through control of temperature, photo-period, etc. in a laboratory setting).

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

  • However, to date the majority of toxicological data on which this AOP is based has been limited to several small fish species, fathead minnow (Pimephales promelas), Japanese medaka (Oryzias latipes), and mummichog (Fundulus heteroclitus) with asynchronous oocyte development and a repeat spawning reproductive strategy.
  • Species dependent differences in endocrine feedback responses, likely associated with different reproductive strategies, have been reported. Thus, the applicability domain may prove more restricted than currently assumed. In particular, the applicability to fish species with synchronous or group synchronous oocyte development patterns (see Wallace and Selman 1981) is unclear.
  • European eel may be an exception to the generalizability of the negative feedback response to a non-aromatizable xenoandrogen (Huang et al. 1997).
  • Reductions in plasma VTG concentrations and/or hepatic VTG mRNA abundance in females following exposure to 17β-trenbolone has been observed in Pimephales promelas, Oryzias latipes, Danio rerio, (Seki et al. 2006), Cyprinodon variegatus (Hemmer et al. 2008), Gambusia holbrooki and Gambusia affinis (Brockmeier et al. 2013)

[Assessment provided by Ioanna Katsiadaki - reviewer]:  This is restricted clearly to female fish only as adversity is linked to reduced oestrogen synthesis (via reduced androgen synthesis); it is also limited to fully reproductive mature fish (not fish entering puberty or juvenile fish) and importantly is limited to fish that once they reach sexual maturity they spawn constantly. The latter is a reproductive strategy employed by fish that tend to occupy tropical areas (around the equator). Unfortunately most fish species have different reproductive strategies (annual life cycle) hence the level of gonadotropin expression (and consequently steroid production) is regulated by photoperiodic and temperature changes throughout the year. Even if a negative feedback mechanism operates in all of these species and in all life stages (which is certainly not the case) we still need to establish what is the relative strength of the AR agonist induced negative feedback to the environment-induced stimulation of gonadotropins! This link has never been studied and is critical if we really mean to protect wildlife.

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
  • In general, few studies have directly addressed the essentiality of the proposed sequence of key events.
  • Ekman et al. 2011 provide evidence that in fathead minnow, cessation of trenbolone exposure resulted in recovery of plasma E2 and VTG concentrations which were depressed by continuous exposure to 17beta trenbolone. This provides some support for the essentiality of these two key events.
  • Essentiality of the proposed negative feedback key event is supported by experimental work that evaluated the ability of AR agonists to reduce T or E2 production in vitro. There are no known reports of 17β-trenbolone directly inhibiting steroid biosynthesis. When tested in an in vitro steroidogenesis assay using H295R adrenal carcinoma cells, trenbolone caused a concentration-dependent increase in estradiol production, as opposed to any reductions in steroid hormone concentrations, an effect that was concurrent with increased transcription of CYP19 (aromatase) in the cell line (Gracia et al. 2007).

Evidence Assessment

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

Biological Plausibility

  • The biochemistry of steroidogenesis and the predominant role of the gonad in synthesis of the sex steroids are well established.
  • Similarly, the role of E2 as the major regulator of hepatic vitellogenin production is widely documented in the literature.
  • The direct link between reduced VTG concentrations in the plasma and reduced uptake into oocytes is highly plausible, as the plasma is the primary source of the VTG.
  • The direct connection between reduced VTG uptake and impaired spawning/reduced cumulative fecundity is more tentative. It is not clear, for instance whether impaired VTG uptake limits oocyte growth and failure to reach a critical size in turn impairs physical or inter-cellular signaling processes that promote release of the oocyte from the surrounding follicles. In at least one experiment, oocytes with similar size to vitellogenic oocytes, but lacking histological staining characteristic of vitellogenic oocytes was observed (R. Johnson, personal communication). At present, the link between reductions in circulating VTG concentrations and reduced cumulative fecundity are best supported by the correlation between those endpoints across multiple experiments, including those that impact VTG via other molecular initiating events (Miller et al. 2007).
  • At present, negative feedback is the most biologically plausible explanation for the reductions in ex vivo T and E2 production following exposure to 17β-trenbolone.There are no known reports of 17β-trenbolone directly inhibiting steroid biosynthesis. When tested in an in vitro steroidogenesis assay using H295R adrenal carcinoma cells, trenbolone caused a concentration-dependent increase in estradiol production, as opposed to any reductions in steroid hormone concentrations, an effect that was concurrent with increased transcription of CYP19 (aromatase) in the cell line (Gracia et al. 2007). Given the lack of any established direct effect on steroidogenic enzyme activity, negative feedback is currently the most likely explanation for the consistent effects observed in vivo. That said, many uncertainties regarding the exact mechanisms through which an exogenous, non-aromatizable, AR agonist elicits negative feedback remain.

Concordance of dose-response relationships:  See Concordance Table  (available in Excel and PDF format)

There are a limited number of studies in which multiple key events were considered in the same study following exposure to known, non-aromatizable, AR agonists. These were considered the most useful for evaluating the concordance of dose-response relationships. In general, effects on downstream key events occurred at concentrations equal to or greater than those at which upstream events occurred. For exposures to 17b-trenbolone, key events related to steroid production and circulating estradiol and vitellogenin concentrations were impacted at the same dose at which effects on cumulative fecundity were observed. Effects on vitellogenin transcription were only observed at greater concentrations, but data for comparable species and dose ranges were unavailable at present. For two other AR agonists tested in fish, available studies examined a single time-point only. Consequently, it was unclear whether lower effect concentrations for certain downstream KEs, relative to upstream were due to a lack of dose-response concordance, or due to decreased sensitivity of the upstream later in the exposure time-course.

While not directly addressing dose-response concordance, the dependence of the key events on the concentration of the androgen agonist has been established for all key events starting at and down-stream of reduced T synthesis. However, to date we are not aware of any studies that have established a concentration-response relationship between exposure to non-endogenous AR agonists (e.g., xenobiotics, pharmaceuticals) and circulating gonadotropin concentrations in fish or other vertebrates.

  • Exposure of female fathead minnows to the AR agonist 17β-trenbolone for 21 d caused concentration-dependent reductions in circulating T, E2, and VTG concentrations over a range from 0.005 to 0.5 μg/L. The concentration response for all three variables had a “U”-shaped concentration response curve which may indicate concentration-dependent differences in the feedback response and/or compensatory processes. Histological evidence of reduced VTG uptake and reduced gonad stage were evident, although the concentration-response of histological effects was not determined. Despite the “U”-shaped concentration-response at the biochemical level, concentration-dependent reductions in cumulative fecundity were observed (Ankley et al. 2003). Effective concentrations were consistent with those causing phenotypic masculinization in female fish.
  • Jensen et al. (2006) also demonstrated concentration-dependent reductions in circulating T, E2, and VTG following 21 d of in vivo exposure to 17α-trenbolone (Jensen et al. 2006).
  • In a time-course experiment in which female fathead minnows were exposed to to 33 or 472 ng 17β-trenbolone/L ex vivo T, ex vivo E2, plasma E2, and plasma VTG all showed concentration-dependent reductions that were consistent with the AOP (Ekman et al. 2011).
  • Exposure of female fathead minnows to spironolactone, a pharmaceutical that binds the fathead minnow AR, for 21 d caused concentration-dependent reductions in cumulative fecundity, plasma VTG and VTG mRNA expression, and plasma E2 concentrations. The frequency and severity of females with decreased yolk accumulation, and increased oocyte atresia was concentration-dependent. The chemical also induced phenotypic masculinization in female fish. (Lalone et al. 2013).
  • Exposure of female medaka to spironolactone caused concentration-dependent reductions in cumulative fecundity and VTG mRNA expression (impacts on steroid hormone concentrations were not measured). Spironolactone also caused phenotypic masculinization of female medaka (Lalone et al. 2013).

Temporal concordance among the key events and adverse effect: Temporal concordance between activation of the AR as a nuclear transcription factor and onset of a negative feedback response resulting in decreased gonadotropin secretion has not been established. Temporal concordance of the key events starting with reduced T biosynthesis and proceeding through reductions in plasma vitellogenin has been established (Concordance Table). Temporal concordance beyond the key event of reductions in plasma vitellogenin has not been established, in large part due to disconnect in the time-scales over which the events can be measured. For example, most small fish used in reproductive toxicity testing can spawn anywhere from once daily to several days per week. Given the variability in daily spawning rates, it is neither practical nor effective to evaluate cumulative fecundity at a time scale shorter than roughly a week. Since the impacts at lower levels of biological organization can be detected within hours of exposure, lack of impact on cumulative fecundity before the other key events are impacted cannot be effectively measured. Overall, among those key events whose temporal concordance can reasonably be evaluated based on currently available data, the temporal profile observed is consistent with the AOP.

Consistency: We are aware of no cases where the pattern of key events described was observed without also observing a significant impact on cumulative fecundity. Due to variability in the cumulative fecundity endpoint and potential compensatory responses ((Villeneuve et al. 2009; Villeneuve et al. 2013; Ankley et al. 2009b; Zhang et al. 2008; Ekman et al. 2012), the cumulative fecundity endpoint can be less sensitive than key events measured at lower levels of biological organization. Nonetheless, the occurrence of the final adverse outcome when the other key events are observed is very consistent. The final adverse effect is not specific to this AOP. Many of the key events included in this AOP overlap with AOPs linking other molecular initiating events to reproductive dysfunction in small fish.

  • In general, there is a consistent body of evidence linking exposure to an AR agonist to decreased T synthesis, E2 synthesis, circulating E2 and VTG concentrations, and cumulative fecundity in female fish. For example, the association between 17β-trenbolone exposure and reduced vitellogenin concentrations in females has been replicated in over a dozen independent experiments (Ekman et al. 2011; Ankley et al. 2003; Jensen et al. 2006; Ankley et al. 2010; Hemmer et al. 2008; Seki et al. 2006; Brockmeier et al. 2013). However, relatively few exogenous, non-aromatizable, AR agonists have been tested. Other than recent work with spironolactone (Lalone et al. 2013), we are not aware of the profile of responses being demonstrated for other AR agonists.

Uncertainties, inconsistencies, and data gaps: There are three major areas of uncertainty and data gaps in the current AOP: 

  • First, there remains considerable uncertainty as to the specific mechanism(s) through which AR agonism elicits a negative feedback response at the level of the hypothalamus and/or pituitary. There is also a substantial data gap relative to establishing that exposure to an AR agonist like 17β-trenbolone causes concentration-dependent reductions in circulating gonadotropins. That uncertainty is amplified further by the variation in feedback control along the endocrine axis for fish species employing different reproductive strategies. For example, gonadotropin regulation may be very different in species with synchronous oocyte maturation and annual or once per life-time reproductive strategies. Thus, there are considerable uncertainties related to the taxonomic relevance of this AOP to a broader range of fish species or other vertebrates.
  • The second major uncertainty in this AOP relates to whether there is a direct biological linkage between impaired VTG uptake into oocytes and impaired spawning/reduced cumulative fecundity. Plausible biological connections have been hypothesized, but have not yet been tested experimentally.
  • A third uncertainty pertains to the chemical domain of applicability. In vivo, a number of chemicals that are detected as androgens in in vitro screening assays such as receptor binding assays or ligand-activated transcriptional assay can be aromatized to functional estrogens. Thus, in vivo such compounds may produce a profile of effects more consistent with estrogen receptor activation than AR activation or may produced mixed effects characteristic of either estrogen or androgen exposures (e.g., Pawlowski et al. 2004; Hornung et al. 2004). Examples of such aromatizable androgens include, testosterone, methyltestosterone, and androstenedione. Consequently, caution is warranted in applying this AOP based on in vitro screening data alone, without consideration for possible conversion to estrogens.

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

Assessment of quantitative understanding of the AOP: At present, the quantitative understanding of the AOP is insufficient to directly link a measure of chemical potency as an AR agonist (e.g., as measured in a transcriptional activation assay) to a predicted effect concentration at the level of cumulative fecundity. However, a number of mechanistic and statistical models are sufficiently developed to facilitate predictions of cumulative outcomes based on intermediate key event measurements such as circulating vitellogenin concentrations. Because the current models were developed based on a fairly limited range of model compounds and species, the general applicability and degree of accuracy and precision in the model-derived predictions remains uncertain.

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

optional

References

List of the literature that was cited for this AOP. More help
  • Amano M, Iigo M, Ikuta K, Kitamura S, Yamada H, Yamamori K. 2000. Roles of melatonin in gonadal maturation of underyearling precocious male masu salmon. General and comparative endocrinology 120(2): 190-197.
  • Ankley GT, Bencic D, Cavallin JE, Jensen KM, Kahl MD, Makynen EA, et al. 2009. Dynamic nature of alterations in the endocrine system of fathead minnows exposed to the fungicide prochloraz. Toxicol Sci 112(2): 344-353.
  • Ankley GT, Cavallin JE, Durhan EJ, Jensen KM, Kahl MD, Makynen EA, et al. 2012. A time-course analysis of effects of the steroidogenesis inhibitor ketoconazole on components of the hypothalamic-pituitary-gonadal axis of fathead minnows. Aquatic toxicology 114-115: 88-95.
  • Ankley GT, Jensen KM, Durhan EJ, Makynen EA, Butterworth BC, Kahl MD, et al. 2005. Effects of two fungicides with multiple modes of action on reproductive endocrine function in the fathead minnow (Pimephales promelas). Toxicol Sci 86(2): 300-308.
  • Ankley GT, Jensen KM, Kahl MD, Durhan EJ, Makynen EA, Cavallin JE, et al. 2010. Use of chemical mixtures to differentiate mechanisms of endocrine action in a small fish model. Aquatic toxicology 99(3): 389-396.
  • Ankley GT, Jensen KM, Kahl MD, Korte JJ, Makynen EA. 2001. Description and evaluation of a short-term reproduction test with the fathead minnow (Pimephales promelas). Environ Toxicol Chem 20:1276-1290.
  • Ankley GT, Jensen KM, Kahl MD, Makynen EA, Blake LS, Greene KJ, et al. 2007. Ketoconazole in the fathead minnow (Pimephales promelas): reproductive toxicity and biological compensation. Environ Toxicol Chem 26(6): 1214-1223.
  • Ankley GT, Jensen KM, Makynen EA, Kahl MD, Korte JJ, Hornung MW, et al. 2003. Effects of the androgenic growth promoter 17-b-trenbolone on fecundity and reproductive endocrinology of the fathead minnow. Environmental Toxicology and Chemistry 22(6): 1350-1360.
  • Ankley GT, Kahl MD, Jensen KM, Hornung MW, Korte JJ, Makynen EA, et al. 2002. Evaluation of the aromatase inhibitor fadrozole in a short-term reproduction assay with the fathead minnow (Pimephales promelas). Toxicological Sciences 67: 121-130.
  • Ankley GT, Miller DH, Jensen KM, Villeneuve DL, Martinovic D. 2008. Relationship of plasma sex steroid concentrations in female fathead minnows to reproductive success and population status. Aquatic toxicology 88(1): 69-74.
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