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Relationship: 2349
Title
Agonism, Androgen receptor leads to Increased, Male Biased Sex Ratio
Upstream event
Downstream event
Key Event Relationship Overview
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 | non-adjacent | Dan Villeneuve (send email) | Open for citation & comment | WPHA/WNT Endorsed |
Taxonomic Applicability
Sex Applicability
Sex | Evidence |
---|---|
Unspecific | High |
Life Stage Applicability
Term | Evidence |
---|---|
Development | High |
Key Event Relationship Description
This key event relationship (KER) links androgen receptor agonism in teleost fish during gonadogenesis to a male-biased sex ratio in a population. 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 some steroid hormones 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. This will result in a male-biased sex ratio in a population.
Evidence Collection Strategy
Evidence Supporting this KER
See below.
Biological Plausibility
The biological plausibility linking AR activation to a male-biased sex ratio in a population 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.
If the conditions that favor a male developmental pathway (in this case, exposure to AR agonsts) overlap with the critical period of sex differentiation in a given population, it is reasonable that more phenotypic males will be produced (Orn et al., 2003; Seki et al., 2004; Bogers et al., 2006; Morthorst et al., 2010; Baumann et al., 2014; Golan & Levavi-Sivian 2014). Therefore, androgen exposure for repeated or prolonged periods of time conceptually will result in a male-biased population.
Empirical Evidence
There have been several studies with teleost fish exposed to known androgen receptor agonists during early development that have documented a consequent occurrence of male-biased sex ratios.
- Exposure of fish to androgens during early development has been used as a technique to preferentially produce male-biased populations in aquaculture for decades. Pandian and Sheela (1995) provided a comprehensive overview of effects of hormones on sex inversion in the context of aquacultural practices. They reported, for example, that the synthetic androgen 17alpha-methyltestosterone had been used to successfully produce male-biased sex ratios in 25 different teleost species.
- Controlled expoure of zebrafish (Danio rerio) to the synthetic androgen 17β-trenbolone during development has been shown to result in male biased sex ratios (Holbech et al., 2006; Orn et al., 2006; Larsen & Baatrup, 2010; Morthorst et al., 2010; Baumann et al., 2013, 2015; Golan & Levavi-Sivian 2014). Zebrafish studies using binary mixtures of 17β-trenbolone with 17alpha-ethynylestradiol administered via the water also reported an elevated occurrence of males even when the estrogen was present (Orn et al., 2016)
- Exposure to methyltestosterone resulted in male biased cohorts in zebrafish, fathead minnows (Pimephales promelas), and Japanese medaka (Oryzias latipes) (Bogers et al., 2006; Orn et al., 2003; Seki et al., 2004)
- Exposure of zebrafish to dihydrotestosterone, an endogenous AR agonist, during early development reulted in a male biased sex ratio (Baumann et al., 2013; Shi et al., 2018).
- Two-hour immersion of newly hatched, homogametic female Chinook salmon (Oncorhynchus tshawytscha) in different synthetic and natural androgens (methyltestosterone, methyldihydrotestosterone and 11-ketotestosterone) reulted in a concentration dependent increase in male sex ratio in the treated fish (Piferrer & Donaldson, 1993)
- A concentration-dependent increase in percentage of males was observed in channel catfish (Ictalurus punctatus) that were orally administered trenbolone acetate for 60 days starting with swim-up fry (Galvez et al., 1995)
Uncertainties and Inconsistencies
Some studies with sexually undifferentiated channel catfish have demonstrated that oral administration of androgens (methyltestosterone, 17a-ethynyltestosterone, dihydrotestosterone) during development can produce all female populations (Goudie et al., 1983; Davis et al., 1990, 1992). In some instances this could be due to the use of aromatizable androgens such as methyltestosterone that can lead both to masculinization and feminization of fish (e.g., Piferrer et al. 1993), due to conversion of the androgen to its corresponding estrogen analogue (i.e., methylestradiol; Hornung et al. 2004 ). In the cases of non-aromatizable androgens (e.g., dihydrotestosterone) that have been reported to feminize fish exposed during early development, the mechanism underlying this is uncertain, but plausibly could involve activation of the estrogen receptor, which is known to interact with a variety of steroids, including androgens at comparatively high test concentrations.
Also, as noted below, it is uncertain as to the full range of species this key event relationship might be applicable due to susbtantial taxonomic variation in the role that steroid signaling plays in gonadal differentiation.
Known modulating factors
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
There are too few data to develop a quatitative understanding of the linkage between AR activation and male biased sex ratio in fish.
Response-response Relationship
Not applicable.
Time-scale
The timeframe for differentiation of the bipotential gonad and subsequent phenotypic expression of sex 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
None known.
Domain of Applicability
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 vertebrates (e.g., LaLone et al. 2018). This KER is not expected to apply to mammals, birds, or other 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
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Bogers, R., De Vries-Buitenweg, S., Van Gils, M., Baltussen, E., Hargreaves, A., van de Waart, B., De Roode, D., Legler, J., & Murk, A. (2006). Development of chronic tests for endocrine active chemicals. Part 2: an extended fish early-life stage test with an androgenic chemical in the fathead minnow (Pimephales promelas). Aquatic toxicology (Amsterdam, Netherlands), 80(2), 119–130. https://doi.org/10.1016/j.aquatox.2006.07.020
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
Davis, K. B., Goudie, C. A., Simco, B. A., Tiersch, T. R., & Carmichael, G. J. (1992). Influence of dihydrotestosterone on sex determination in channel catfish and blue catfish: period of developmental sensitivity. General and comparative endocrinology, 86(1), 147–151. https://doi.org/10.1016/0016-6480(92)90136-8
Davis, K. B., Simco, B. A., Goudie, C. A., Parker, N. C., Cauldwell, W., & Snellgrove, R. (1990). Hormonal sex manipulation and evidence for female homogamety in channel catfish. General and comparative endocrinology, 78(2), 218–223. https://doi.org/10.1016/0016-6480(90)90008-a
Galvez, J., Mazik, P., Phelps, R., Mulvaney, D. (1995) Masculinization of Channel Catfish Ictalurus punctatus by Oral Administration of Trenbolone Acetate. World Aquaculture Society, 26(4), 378-383. https://doi.org/10.1111/j.1749-7345.1995.tb00832.x
Goudie, C., Redner, B., Simco, B. Davis, K. (1983), Feminization of Channel Catfish by Oral Administration of Steroid Sex Hormones. Transactions of the American Fisheries Society, 112: 670-672. https://doi.org/10.1577/1548-8659(1983)112<670:FOCCBO>2.0.CO;2
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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
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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
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