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Relationship: 2145
Title
Reduction, E2 Synthesis by the undifferentiated gonad leads to Increased, Differentiation to Testis
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 |
---|---|---|---|---|---|---|
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 |
Taxonomic Applicability
Sex Applicability
Sex | Evidence |
---|---|
Mixed | Moderate |
Life Stage Applicability
Term | Evidence |
---|---|
Development | Low |
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
See below
Biological Plausibility
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.
Empirical Evidence
There are multiple lines of indirect empirical evidence for this KER.
- During sexual differentiation (10-40 days post-fertilization), depression of E2 production through inhibition of aromatase (cytochrome P450 19a [cyp 19a1]] was associated with temperature-induced masculinization (35°C) of genetic male and female Nile tilapia (Oreochromis niloticus) indicating the critical role of estrogen synthesis in causing sexual differentiation to testis (D'cotta et al. 2001).
- Zhang et al. (2017) found that control XY and cyp19a1a -/- (deficient and double knockout) XX Nile tilapia had significantly lower levels of serum E2 compared to the control XX and cyp19a1a+/- XX fish, which corresponded with increased differentiation to testis.
- Rucksana et al. (2010) treated early life stage Nile tilapia with the aromatase inhibitor exemestane and found at 120 days posthatch in exposed fish complete testes differentiation with efferent ducts and with all stages of spermatogenic germ cells, from spermatogonia to spermatozoa.
- In zebrafish (Danio rerio), generation of cyp19a1a and cyp19a1b (gonad and brain aromatase isoforms, respectively) gene mutant lines and a cyp19a1a;cyp19a1b double knockout using transcription activator like effector nucleases (TALENs) showed that all cyp19a1a-deficient and double knockout fish were phenotypic males, corresponding with significantly lower levels of E2 than in wild-type and cyp19a1b-deficient fish (Yin et al. 2017).
- Rashid et al. (2007) reported that dietary expsoure to fadrozole decreased ovary cavity formation and increased testicular differentiation in fugu (Takifugu rubripes).
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.
Quantitative Understanding of the Linkage
At present, the quantitative understanding of this relationship is weak.
Response-response Relationship
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.
Time-scale
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
Life stage
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.
Sex
Because the upstream event in this relationship pertains to the undifferentiated gonad, the sex applicability of this relationship is non-specific.
Taxonomic applicability
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.
References
Angelopoulou, R., Lavranos, G., & Manolakou, P. (2012). Sex determination strategies in 2012: towards a common regulatory model?. Reproductive biology and endocrinology : RB&E, 10, 13. https://doi.org/10.1186/1477-7827-10-13
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.
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
Gorelick, D. A., & Halpern, M. E. (2011). Visualization of estrogen receptor transcriptional activation in zebrafish. Endocrinology, 152(7), 2690–2703. https://doi.org/10.1210/en.2010-1257
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
Marshall Graves, J. A., & Peichel, C. L. (2010). Are homologies in vertebrate sex determination due to shared ancestry or to limited options?. Genome biology, 11(4), 205. https://doi.org/10.1186/gb-2010-11-4-205.
Rashid, H., Kitano, H., Lee, K. H., Nii, S., Shigematsu, T., Kadomura, K., Yamaguchi, A., & Matsuyama, M. (2007). Fugu (Takifugu rubripes) sexual differentiation: CYP19 regulation and aromatase inhibitor induced testicular development. Sexual development : genetics, molecular biology, evolution, endocrinology, embryology, and pathology of sex determination and differentiation, 1(5), 311–322.
Ruksana, S., Pandit, N. P., & Nakamura, M. (2010). Efficacy of exemestane, a new generation of aromatase inhibitor, on sex differentiation in a gonochoristic fish. Comparative biochemistry and physiology. Toxicology & pharmacology : CBP, 152(1), 69–74. https://doi.org/10.1016/j.cbpc.2010.02.014.
Sarre, S. D., Georges, A., & Quinn, A. (2004). The ends of a continuum: genetic and temperature-dependent sex determination in reptiles. BioEssays : news and reviews in molecular, cellular and developmental biology, 26(6), 639–645. https://doi.org/10.1002/bies.20050
Trukhina, A. V., Lukina, N. A., Wackerow-Kouzova, N. D., & Smirnov, A. F. (2013). The variety of vertebrate mechanisms of sex determination. BioMed research international, 2013, 587460. https://doi.org/10.1155/2013/587460
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.