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Increased, Differentiation to Testis 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||adjacent||High||Kelvin Santana Rodriguez (send email)||Under Development: Contributions and Comments Welcome||WPHA/WNT Endorsed|
|Androgen receptor agonism leading to male-biased sex ratio||adjacent||Dan Villeneuve (send email)||Open for citation & comment||WPHA/WNT Endorsed|
Life Stage Applicability
Key Event Relationship Description
Prior to gonadal sex determination in vertebrates, the developing organism has a primordial bipotential gonad that can be fated to either sex depending on the genetic makeup of the embryo (genetic sex determination; GSD) or environmental conditions (environmental sex determination; ESD) or a combination of both factors.
Regardless of whether gonadal development is controlled via GSD or ESD (or both), the operational definition of male versus female in terms of function usually is defined by the presence, respectively, of testes versus ovaries. For species exhibiting sex-specific secondary sexual characteristics preferential differentiation to testis can be accompanied by easily discerned external phenotypic changes as well. If there is increased differentiation to testis in individuals of a population of organisms this will by default produce a male biased sex ratio as defined by what would be considered normal for that species.
Evidence Collection Strategy
Evidence Supporting this KER
It is highly plausible that as a gonadal phenotype increases toward testis formation, male-biased sex ratios in a defined cohort of organisms will occur. If this condition persists for repeated or prolonged periods of times within the habitat of given species, this will result in a male-biased sex ratio.
Uncertainties and Inconsistencies
A major uncertainty for this KER involves what would be defined as "normal" for degree of testis differentiation and by extension sex ratio. There needs to be knowledge as to baseline expectations for testis differentiation for a given species in a given habitiat (or lab setting) to ascertain whether increases are occurring. Baseline information of this type is available or can be inferred for some species but certainly not for all that might be considered.
A second significant uncertainty involves situations where the gonad cannot be clearly defined as either testis or ovary. This can occur in some fish and amphibian species, where the gonad has cell types indicative of both testes and ovaries (Abdul-moneim et al. 2015). In these instances classification of individuals as male versus female may not be possible, requiring a third category related to an intersex condition. There are seemingly multiple underlying causes of intersex, one of which appears to be exposure to estrogenic chemicals during gonad differentiation (Jobling et al. 1998; Norris et al. 2018; Grim et al. 2020).
A third uncertainty involves whether all individuals defined as males based on gonad phenotype will have the same degree of function in terms of producing viable gametes. It is possible, for example, that genotypic females which develop a male phenotype due to an environmental factor such as exposure to an endocrine-active chemical may not be functionally equivalent to a genetic male relative to sperm production/viability. This could be an important consideration relative to the types of predictions attempted based on a male-biased sex ratio in a population.
Known modulating factors
Timescales will vary based on species-specific developmental rates, but since one KE often will define the second (i.e., an animal is defined as a male based on the presence of testis) timescale may not be a relevant consideration.
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
This KER is applicable to any species in which males are defined by the occurrence of testis and/or associated male secondary sexual characteristics.
Abul-moneim, A, DP Coulter, CT Mahapatra and MS Sepulveda. 2015. Intersex in fishes and amphibians: Population implications, prevalance, mechanisms and molecular biomarkers. J Appl Toxicol 35:1228-1240.
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.
Grim, KC, EE Henderson, MJ Wolfe and JC Wolfe. 2020. Histopathological prevalance and severity of testicualr oocytes in smallmouth bass from two archival collections. J Aquat Anim Health 32:32-43.
Jobling, M Nolan, CR Tyler, G. Brighty and JP Sumpter. 1998. Widespread sexual disruption in wild fish. Environ Sci Technol 32:2498-2506.
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.
Luzio, A., Matos, M., Santos, D., Fontaínhas-Fernandes, A. A., Monteiro, S. M., & Coimbra, A. M. (2016a). 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. (2016b). 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.
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
Norris, DO, AL Bolden and AM Vajda. 2018. The occurrence of intersex fishes in Boulder Creek, Colorado is a recent phenomenon. Gen. Comp. Endocrinol. 265:56-60.
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
Shen ZG, Fan QX, Yang W, Zhang YL, Hu PP, Xie CX. Effects of non-steroidal aromatase inhibitor letrozole on sex inversion and spermatogenesis in yellow catfish Pelteobagrus fulvidraco. Biol Bull. 2013 Sep;225(1):18-23. doi: 10.1086/BBLv225n1p18. PMID: 24088793.
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., and 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.
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