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Inhibition, Aromatase leads to Increased, Differentiation to Testis
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Aromatase inhibition leads to male-biased sex ratio via impacts on gonad differentiation||non-adjacent||High||Kelvin Santana Rodriguez (send email)||Under Development: Contributions and Comments Welcome|
Life Stage Applicability
Key Event Relationship Description
Prior to sex determination, many vertebrates have a bipotential gonad that can develop into testis or ovary depending on genetic makeup (genetic sex determination), environmental conditions during development (environmental sex determination) or a combination of both (Trukhina et al. 2013).
A key variable influencing gonad differentiation is the production of sex steroids such as 17ß-estradiol (E2) and testosterone (T). In many vertebrates, including a variety of fish species, the "default" gonadal sex is male, with the presence of E2 (or perhaps the relative relationship between E2 and T production/levels) controlling the alternative path to development of ovaries (Angelopoulou et al. 2012).
Cytochrome P450 aromatase (CYP191a) is the enzyme responsible for the conversion of T to E2 in gonadal tissues of vertebrates (Miller 1988; Simpson et al. 1994). Consequently, inhibition of CYP191a expression/activity during gonadal differentiation can lead to an increased occurrence of testis.
Evidence Collection Strategy
Evidence Supporting this KER
Plausibility is high. CYP19a1 aromatase is rate-limiting for the synthesis of E2 in vertebrates (Simpson et al. 1994; Payne et al. 2004), so inhibition of the enzyme reduces E2 levels. Gonadal differentiation of many non-mammalian vertebrates, including a number of fish species, is dependent upon signaling associated with the sex steroids T and E2 (Guiguen et al. 2010; Nakamura 2010). In many of these species there exists a bipotential gonad during early development that, based on steroidal signaling, can differentiate into either testis of ovary. When the "default" differentiation pathway is to testis, as is often the case (Angelopoulou et al. 2012), decreases in E2 plausibly favor the development of testis.
Uncertainties and Inconsistencies
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.
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
Domain of Applicability
The life stage applicable to this KER is developing embryos and juveniles during the gonadal differentiation. This KER is not applicable to sexually differentiated adults.
Because this KER occurs during differentiation, the relationship is relevant to animals with an undetermined (non-specific) sex.
Sequencing studies studies with mammalian, amphibian, reptile, bird, and fish species have shown that aromatase is well conserved among all vertebrates (Wilson et al. 2005; LaLone et al. 2018).
However, it is difficult to predict the biological domain of applicability of this KER based on phylogenetic characteristics. There is considerable within class variability, for example, among both fish and reptile species as to the role of aromatase expression and estrogen signaling in determining gonadal sex (Angelopoulou et al. 2012; Sarre et al. 2004). Thus susceptibility and relative sensitivities may vary considerably among species.
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Bannister, S. C., Smith, C. A., Roeszler, K. N., Doran, T. J., Sinclair, A. H., & Tizard, M. L. (2011). Manipulation of estrogen synthesis alters MIR202* expression in embryonic chicken gonads. Biology of reproduction, 85(1), 22–30. https://doi.org/10.1095/biolreprod.110.088476
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D'Cotta, H., Fostier, A., Guiguen, Y., Govoroun, M., & Baroiller, J. F. (2001). Aromatase plays a key role during normal and temperature-induced sex differentiation of tilapia Oreochromis niloticus. Molecular reproduction and development, 59(3), 265–276. https://doi.org/10.1002/mrd.1031
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Guiguen, Y., Fostier, A., Piferrer, F., & Chang, C. F. (2010). Ovarian aromatase and estrogens: a pivotal role for gonadal sex differentiation and sex change in fish. General and comparative endocrinology, 165(3), 352–366. https://doi.org/10.1016/j.ygcen.2009.03.002
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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.
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Luzio, A., Monteiro, S. M., Rocha, E., Fontaínhas-Fernandes, A. A., & Coimbra, A. M. (2016). Development and recovery of histopathological alterations in the gonads of zebrafish (Danio rerio) after single and combined exposure to endocrine disruptors (17α-ethinylestradiol and fadrozole). Aquatic toxicology (Amsterdam, Netherlands), 175, 90–105. https://doi.org/10.1016/j.aquatox.2016.03.014
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Nakamura M. (2010). The mechanism of sex determination in vertebrates-are sex steroids the key-factor?. Journal of experimental zoology. Part A, Ecological genetics and physiology, 313(7), 381–398. https://doi.org/10.1002/jez.616
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