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Reduction, E2 Synthesis by the undifferentiated gonad 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||adjacent||Moderate||Kelvin Santana Rodriguez (send email)||Under Development: Contributions and Comments Welcome||WPHA/WNT Endorsed|
Life Stage Applicability
Key Event Relationship Description
Prior to sex determination, 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 (Graves et al. 2010; 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.
Evidence Collection Strategy
Evidence Supporting this KER
Among the different forms of estrogens, E2 is considered the most fundamental to gonad differentiation in most vertebrates, as it is responsible for inducing and maintaining ovarian development (Bondesson et al., 2015; Li et al., 2019). Estrogens bind to estrogen receptors (ER), that regulate the transcription of estrogen-responsive genes necessary for proper gonad development of for a female pathway (Guiguen et al., 2010; Gorelick et al., 2011). However, reductions in E2 biosynthesis during the critical period of sexual differentiation of the bipotential gonad would logically lead to decreased E2 signaling necessary for ovarian development, thereby leading to morphological development of testis. Therefore, it is plausible that E2 reduction in the undifferentiated gonad at the onset of sexual differentiation promotes the preferential occurrence of testis.
Uncertainties and Inconsistencies
Even for vertebrate classes known to be subject to environmental sex determination, the relative importance of genetic versus environmental factors in terms of influencing local production of steroids by the bipotential gonad is not well characterized, nor readily predicted based on phylogeny (Angelopoulou et al. 2012, Sarre et al. 2004). Consequently, both the occurrence and importance of this relationship may vary considerably among species.
Known modulating factors
Various environmental and genetic factors are known to influence differentiation of the bipotential gonad. However, quantitative understanding of this relationship is inadequate to precisely define the effect of such factors on the concentrations of E2 required to support differentiation to testis versus ovary, particularly in a manner that could be generalized across multiple species.
There are not sufficient data to support derivation of a generalizable relationship between levels of E2 in differentiating gonad tissue and development to a testis phenotype.
The timeframe for differentiation of the bipotential gonad is species-dependent occurring, for example, over the course of days to weeks in most fishes.
Known Feedforward/Feedback loops influencing this KER
Undefined at present.
Domain of Applicability
The upstream event in for this KER is associated with the undifferentiated bipotential gonad. Therefore, this relationship is relevant to early life-stages prior to sexual development/differentation.
Because the upstream event in this relationship pertains to the undifferentiated gonad, the sex applicability of this relationship is non-specific.
This relationship is most applicable to vertebrates subject to environmental sex determination. The relevance to species with predominantly genetic sex determination is less clear, likely depending on species-specific plasticity.
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Bondesson, M., Hao, R., Lin, C. Y., Williams, C., & Gustafsson, J. Å. (2015). Estrogen receptor signaling during vertebrate development. Biochimica et biophysica acta, 1849(2), 142–151. https://doi.org/10.1016/j.bbagrm.2014.06.005.
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Yin, Y., Tang, H., Liu, Y., Chen, Y., Li, G., Liu, X., & Lin, H. (2017). Targeted Disruption of Aromatase Reveals Dual Functions of cyp19a1a During Sex Differentiation in Zebrafish. Endocrinology, 158(9), 3030–3041. https://doi.org/10.1210/en.2016-1865.
Zhang, Xianbo & Li, Mengru & Ma, He & Liu, Xingyong & Shi, Hongjuan & Li, Minghui & Wang, Deshou. (2017). Mutation of foxl2 or cyp19a1a Results in Female to Male Sex Reversal in XX Nile Tilapia. Endocrinology. 158. 10.1210/en.2017-00127.