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Inhibition, Aromatase 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|
|Aromatase inhibition leads to male-biased sex ratio via impacts on gonad differentiation||non-adjacent||Moderate||Kelvin Santana Rodriguez (send email)||Under Development: Contributions and Comments Welcome|
Life Stage Applicability
|before or during gonadal sex differentiation||High|
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 (CYP19a1a) 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 CYPa191a expression/activity during gonadal differentiation can lead to an increased occurrence of testis. This can subsequently result in a male-biased sex ratio in the population of interest.
Evidence Collection Strategy
Evidence Supporting this KER
This key event relationship is highly plausible. If inhibition of aromatase (E2 production) overlaps with the critical period of sex differentiation in a susceptible species there will be an increase in the number of organisms developing testes, which would produce a male-biased population.
Uncertainties and Inconsistencies
As noted below, it is uncertain as to the full range of species this KER might be applicable due to susbstantial taxonomic variation in the role that steroid signaling plays in gonadal differentiation and, hence, the number of males in a population.
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 to testis and, consequently, to a male phenotype 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 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.
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
Brown, A. R., Bickley, L. K., Le Page, G., Hosken, D. J., Paull, G. C., Hamilton, P. B., Owen, S. F., Robinson, J., Sharpe, A. D., & Tyler, C. R. (2011). Are toxicological responses in laboratory (inbred) zebrafish representative of those in outbred (wild) populations? - A case study with an endocrine disrupting chemical. Environmental science & technology, 45(9), 4166–4172. https://doi.org/10.1021/es200122r
Brown, A. R., Owen, S. F., Peters, J., Zhang, Y., Soffker, M., Paull, G. C., Hosken, D. J., Wahab, M. A., & Tyler, C. R. (2015). Climate change and pollution speed declines in zebrafish populations. Proceedings of the National Academy of Sciences of the United States of America, 112(11), E1237–E1246. https://doi.org/10.1073/pnas.1416269112
Fenske, M. & Segner, H. (2004). Aromatase modulation alters gonadal differentiation in developing zebrafish (Danio rerio). Aquatic toxicology (Amsterdam, Netherlands). 67. 105-26. DOI 10.1016/j.aquatox.2003.10.008.
Holbech, H., Kinnberg, K. L., Brande-Lavridsen, N., Bjerregaard, P., Petersen, G. I., Norrgren, L., Örn, S., Braunbeck, T., Baumann, L., Bomke, C., Dorgerloh, M., Bruns, E., Ruehl-Fehlert, C., Green, J. W., Springer, T. A., & Gourmelon, A. (2012). Comparison of zebrafish (Danio rerio) and fathead minnow (Pimephales promelas) as test species in the Fish Sexual Development Test (FSDT). Comparative Biochemistry and Physiology - C Toxicology and Pharmacology, 155(2), 407–415. https://doi.org/10.1016/j.cbpc.2011.11.002
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.
Lau, E. S., Zhang, Z., Qin, M., & Ge, W. (2016). Knockout of Zebrafish Ovarian Aromatase Gene (cyp19a1a) by TALEN and CRISPR/Cas9 Leads to All-male Offspring Due to Failed Ovarian Differentiation. Scientific reports, 6, 37357. https://doi.org/10.1038/srep37357
Luzio, A., Matos, M., Santos, D., Fontaínhas-Fernandes, A. A., Monteiro, S. M., & Coimbra, A. M. (2016). Disruption of apoptosis pathways involved in zebrafish gonad differentiation by 17α-ethinylestradiol and fadrozole exposures. Aquatic toxicology (Amsterdam, Netherlands), 177, 269–284. https://doi.org/10.1016/j.aquatox.2016.05.029
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
Luzio, A.,Monteiro, S., Garcia Santos, S., Rocha, E., Fontainhas-Fernandes, A.,& Coimbra, A. (2015). Zebrafish sex differentiation and gonad development after exposure to 17α-ethinylestradiol, fadrozole and their binary mixture: A stereological study. Aquatic Toxicology. 166. 83-95. DOI 10.1016/j.aquatox.2015.07.015.
Miller W. L. (1988). Molecular biology of steroid hormone synthesis. Endocrine reviews, 9(3), 295–318. https://doi.org/10.1210/edrv-9-3-295
Muth-Köhne, E., Westphal-Settele, K., Brückner, J., Konradi, S., Schiller, V., Schäfers, C., Teigeler, M., & Fenske, M. (2016). Linking the response of endocrine regulated genes to adverse effects on sex differentiation improves comprehension of aromatase inhibition in a Fish Sexual Development Test. Aquatic toxicology (Amsterdam, Netherlands), 176, 116–127. https://doi.org/10.1016/j.aquatox.2016.04.018
Payne, A. H., & Hales, D. B. (2004). Overview of steroidogenic enzymes in the pathway from cholesterol to active steroid hormones. Endocrine reviews, 25(6), 947–970. https://doi.org/10.1210/er.2003-0030
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
Simpson, E. R., Mahendroo, M. S., Means, G. D., Kilgore, M. W., Hinshelwood, M. M., Graham-Lorence, S., Amarneh, B., Ito, Y., Fisher, C. R., & Michael, M. D. (1994). Aromatase cytochrome P450, the enzyme responsible for estrogen biosynthesis. Endocrine reviews, 15(3), 342–355. https://doi.org/10.1210/edrv-15-3-342
Thorpe, K. L., Marca Pereira, M. L., Schiffer, H., Burkhardt-Holm, P., Weber, K., & Wheeler, J. R. (2011). Mode of sexual differentiation and its influence on the relative sensitivity of the fathead minnow and zebrafish in the fish sexual development test. Aquatic Toxicology, 105(3–4), 412–420. https://doi.org/10.1016/j.aquatox.2011.07.012
Thresher, R., Gurney, R., & Canning, M. (2011). Effects of lifetime chemical inhibition of aromatase on the sexual differentiation, sperm characteristics and fertility of medaka (Oryzias latipes) and zebrafish (Danio rerio). Aquatic toxicology (Amsterdam, Netherlands), 105(3-4), 355–360. https://doi.org/10.1016/j.aquatox.2011.07.008
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
Uchida, D., Yamashita, M., Kitano, T., & Iguchi, T. (2004). An aromatase inhibitor or high water temperature induce oocyte apoptosis and depletion of P450 aromatase activity in the gonads of genetic female zebrafish during sex-reversal. Comparative biochemistry and physiology. Part A, Molecular & integrative physiology, 137(1), 11–20. https://doi.org/10.1016/s1095-6433(03)00178-8
Wilson, J. Y., McArthur, A. G., & Stegeman, J. J. (2005). Characterization of a cetacean aromatase (CYP19) and the phylogeny and functional conservation of vertebrate aromatase. General and comparative endocrinology, 140(1), 74–83. https://doi.org/10.1016/j.ygcen.2004.10.004
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.