To the extent possible under law, AOP-Wiki has waived all copyright and related or neighboring rights to KER:2167
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, 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.
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 leads to an increased occurrence of testis.
Evidence Supporting this KER
Inhibition of cytochrome P450 aromatase (CYP19) during the critical period of sexual differentiation of non-mammalian vertebrates can induce a male differentiation pathway due to an increasing imbalance in the androgen-to-estrogen ratio. Androgens have a critical physiological role in reproductive biology and sexual differentiation, particularly in the development of male first and secondary sex characteristics(DeFalco 2019) 17. After sex has been determined, the increasing levels of androgens during the critical period of sexual differentiation will allow the morphological development of the testis, for which the early presence of three main differentiating cell types is fundamental; the gamete forming cells (spermatogonia), support cells (sertoli cells) and hormone secreting cells (leydig or interstitial cells) (Cotton & Wedekind, 2009)44. As gonads continue to differentiate into testes, the secretion of testicular hormones will be sufficient to promote the complete masculinization of the embryo (Nef & Parada, 2000) 69.
Uncertainties and Inconsistencies
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Phylogenetic analysis among mammalian, amphibian, reptile, bird, and fish has shown that aromatase is well conserved among all vertebrates (Wilson JY et al., 2005)70. However in eutherian mammals (where sex determination is purely dependent on the chromosomal composition of the embryo) aromatase is expressed later in embryonic development and gonadal sex is formed independently of sex hormones 41, 43, 60. Therefore, this key event relationship is only applicable to most non-mammalian vertebrates that do require sex steroid hormones for sex differentiation.
The life stage applicable to this key event relationship is developing embryos and juveniles prior to- or during the gonadal developmental stage. Since the sexually dimorphic expression of aromatase plays a crucial role in the differentiation to either testis or ovaries in the undifferentiated bipotential gonad, this key event relationship can be applicable to the exact stage of development at which the aromatase enzyme works to influence gonadal differentiation. This key event relationship is not applicable to sexually differentiated adults.
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
Norris, D. O. Vertebrate Endocrinology, 3rd ed.; Academic Press: San Diego, CA, 1997.
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
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
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