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Relationship: 2260

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Agonism, Androgen receptor leads to Increased, Differentiation to Testis

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Agonism, Androgen receptor

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Increased, Differentiation to Testis

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes. Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name	Adjacency	Weight of Evidence	Quantitative Understanding	Point of Contact	Author Status	OECD Status
Androgen receptor agonism leading to male-biased sex ratio	adjacent			Dan Villeneuve (send email)	Open for citation & comment

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER. More help

Term	Scientific Term	Evidence	Link
zebrafish	Danio rerio	High	NCBI
medaka	Oryzias latipes		NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help

Sex	Evidence
Unspecific	High

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER. More help

Term	Evidence
Development	High

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

This key event relationship links androgen receptor agonism in teleost fish during gonadogenesis to increased differentiation to testis. Sex determination in teleost fishes is highly plastic; it can be genetically or environmentally influenced. Species with environmentally-based sex determination in particular can be very sensitive to exogenous chemicals during the period of differentiation. Exogenous hormones are of ecological concern because they have the potential to alter gonad development and sex differentiation. Activation of the androgen receptor (AR) by endogenous androgens plays a crucial role in normal sex differentiation, sexual maturation, and spermatogenesis in vertebrates and inappropriate signaling by exogenous AR agonists can disrupt theses processes. For example, studies have shown that during early development in some teleost species, exposure to androgenic steroids can induce complete gonadal sex inversion, resuting in increased differentiation to testis.

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings. Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

See below.

Biological Plausibility

Addresses the biological rationale for a connection between KEupstream and KEdownstream. This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured. More help

The biological plausibility linking AR activation to increased differentiation to testis is very strong. Actions of androgens are mediated by the AR, a ligand-dependent transcription factors (Hossain et al., 2008). Steroidal androgens act by entering the cell and forming a complex with the AR, resulting in conformational change (Bohen et al., 1995; Pratt and Toft, 1997). The ligand-AR complex is translocated to the nucleus where it binds to specific short DNA sequences thereby activating transcripton of androgen regulated genes (Harbott et al., 2009). During sexual development, endogenous androgen can therefore induce the upregulation of many genes involved in the male developmental pathway, including gonad development/differentiation.

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

Several studies with zebrafish (Danio rerio) with the known AR agonist 17β-trenbolone has shown to cause a concentration dependent increased differentiation to testis when exposed during the critical period of differentiation. This was evidenced via histological examinations to determine gonad maturation and sperm stage (Orn et al., 2006; Holbech et al. 2006; Morthorst et al., 2010; Baumann et al., 2015).

Additional studies with zebrafish exposed to dihydrotestosterone, another well established AR agonist, increased differentiation to testes was evidenced via the upregulation of dmrt1 and apoptosis-related genes but suppressed the transcription of cyp19a1a (aromtatase) during the sex differentiation period (Shi et al., 2018).

In similar studies using Japanese medaka (Oryzias latipes) exposure to 17β-trenbolone and dihydrotestosterone induced masculinization of both secondary sex characteristics and gonads when fish were exposed during development (Seki et al., 2004; Orn et al., 2006).

Uncertainties and Inconsistencies

Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

Due to substantial taxonomic variation in the role that steroid signaling plays in gonadal differentiation, the range of species that this key event relationship applies to is uncertain.

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references. More help

There are almost certainly many factors that could modulate this KER, but a systematic description of these is not currently possible.

Modulating Factor (MF)	MF Specification	Effect(s) on the KER	Reference(s)

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

There are too few data to develop a quatitative understanding of the linkage between AR activation and increased differentiation to testis.

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

Not applicable.

Time-scale

Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

The timeframe for differentiation of the bipotential gonad is species-dependent occurring, for example, over the course of days to weeks in most fishes. However, this period of time could be substantially longer in long-lived species.

Known Feedforward/Feedback loops influencing this KER

Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

None known.

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

Life Stage

The life stage applicable to this KER is developing embryos and juveniles prior to- or during the gonadal developmental stage. This KER is not applicable to sexually differentiated adults.

Sex

The molecular initiating event for this KER occurs prior to gonad differentiation. Therefore, this AOP is only applicable to sexually undifferentiated individuals.

Taxonomic

Most evidence for this KER is derived from fish in the class Osteichthyes. Both phylogenetic analysis and evaluation of protein sequence conservation via SeqAPASS (https://seqapass.epa.gov/seqapass/) has shown that the structure of the AR is well conserved among most jawed vertebrates (LaLone et al. 2018). This KER is not expected to apply to mammals, birds, or other jawed vertebrates with genetic sex determination. However, it may be applicable to fishes, amphibians, and reptiles with environmentally-dependent sex determination, although outcomes may differ across physiologically different taxa. The present KER is not considered relevant to Agnathans since the AR appears not to be present in jawless fishes (Thornton 2001; Hossain et al 2008).

References

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

Baumann, L., Knörr, S., Keiter, S., Nagel, T., Rehberger, K., Volz, S., Oberrauch, S., Schiller, V., Fenske, M., Holbech, H., Segner, H., & Braunbeck, T. (2014). Persistence of endocrine disruption in zebrafish (Danio rerio) after discontinued exposure to the androgen 17β-trenbolone. Environmental toxicology and chemistry, 33(11), 2488–2496. https://doi.org/10.1002/etc.2698

Bohen, S. P., Kralli, A., & Yamamoto, K. R. (1995). Hold 'em and fold 'em: chaperones and signal transduction. Science (New York, N.Y.), 268(5215), 1303–1304. https://doi.org/10.1126/science.7761850

Harbott, L. K., Burmeister, S. S., White, R. B., Vagell, M., & Fernald, R. D. (2007). Androgen receptors in a cichlid fish, Astatotilapia burtoni: structure, localization, and expression levels. The Journal of comparative neurology, 504(1), 57–73. https://doi.org/10.1002/cne.21435

Hossain, M. S., Larsson, A., Scherbak, N., Olsson, P. E., & Orban, L. (2008). Zebrafish androgen receptor: isolation, molecular, and biochemical characterization. Biology of reproduction, 78(2), 361–369. https://doi.org/10.1095/biolreprod.107.062018

LaLone, C.A., D.L. Villeneuve, J.A. Doering, B.R. Blackwell, T.R. Transue, C.W. Simmons, J. Swintek, S.J. Degitz, A.J. Williams and G.T. Ankley. 2018. Evidence for cross-species extrapolation of mammalian-based high-throughput screening assay results. Environ. Sci. Technol. 52, 13960-13971.

Morthorst, J. E., Holbech, H., & Bjerregaard, P. (2010). Trenbolone causes irreversible masculinization of zebrafish at environmentally relevant concentrations. Aquatic toxicology (Amsterdam, Netherlands), 98(4), 336–343. https://doi.org/10.1016/j.aquatox.2010.03.008

Orn, S., Yamani, S., & Norrgren, L. (2006). Comparison of vitellogenin induction, sex ratio, and gonad morphology between zebrafish and Japanese medaka after exposure to 17alpha-ethinylestradiol and 17beta-trenbolone. Archives of environmental contamination and toxicology, 51(2), 237–243. https://doi.org/10.1007/s00244-005-0103-y

Pratt, W. B., & Toft, D. O. (1997). Steroid receptor interactions with heat shock protein and immunophilin chaperones. Endocrine reviews, 18(3), 306–360. https://doi.org/10.1210/edrv.18.3.0303

Seki, M., Yokota, H., Matsubara, H., Maeda, M., Tadokoro, H., & Kobayashi, K. (2004). Fish full life-cycle testing for androgen methyltestosterone on medaka (Oryzias latipes). Environmental toxicology and chemistry, 23(3), 774–781. https://doi.org/10.1897/03-26

Shi, W. J., Jiang, Y. X., Huang, G. Y., Zhao, J. L., Zhang, J. N., Liu, Y. S., Xie, L. T., & Ying, G. G. (2018). Dydrogesterone Causes Male Bias and Accelerates Sperm Maturation in Zebrafish ( Danio rerio). Environmental science & technology, 52(15), 8903–8911. https://doi.org/10.1021/acs.est.8b02556

Thornton J. W. (2001). Evolution of vertebrate steroid receptors from an ancestral estrogen receptor by ligand exploitation and serial genome expansions. Proceedings of the National Academy of Sciences of the United States of America, 98(10), 5671–5676. https://doi.org/10.1073/pnas.091553298