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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||adjacent||High||Brendan Ferreri-Hanberry (send email)||Under Development: Contributions and Comments Welcome|
Life Stage Applicability
Key Event Relationship Description
Cytochrome P450 aromatase (CYP19) is the enzyme responsible for the conversion of C19 androgens to C18 estrogens in brain and gonadal tissues of vertebrates (Castro et al.,2005; Hong et al.,2009 )52,70. During early developmental stages, the hormonal balance between estrogens and androgens is essential particularly durring the sexual differentiation period and this balance is in turn dependent on the availability and activity of steroid synthesizing enzymes such as aromatase (Smirnov & Trukhina, 2019)60. For a bipotential gonad to differentiate into testis, an increase in the level of androgens is required to trigger the male differentiation pathway, while ovary differentiation requires increasing levels of estrogens (DeFalco 2019; Nef & Parada, 2000) 17, 69. As aromatase inhibitors block the synthesis of estrogens (by inhibiting the conversion of androgens to estrogens), the level of androgens in the developing organism increases, inducing testis differentiation and male maturation (Muth-Kohne et al., 2016)7.
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.