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Agonism, Androgen receptor leads to Increased, Male Biased Sex Ratio
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|
Life Stage Applicability
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
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.
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)|
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
Domain of Applicability
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.
The molecular initiating event for this KER occurs prior to gonad differentiation. Therefore, this AOP is only applicable to sexually undifferentiated individuals.
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).
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