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Inhibition, Aromatase leads to Reduction, E2 Synthesis by the undifferentiated gonad
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|
Life Stage Applicability
|before or during gonadal sex differentiation||High|
Key Event Relationship Description
Aromatase (cyp19; EC 22.214.171.124) is a cytochrome P450 enzyme that is rate limiting for estrogen synthesis (Simpson et al. 1994; Miller 1988; Payne and Hale, 2004). The expression and activity of aromatase in the bipotential gonad, and subsequent autocrine and/or paracrine signaling mediated by the action of estrogens on the estrogen receptor (or lack thereof), are thought to be key regulators of sex determination and gonadal differentation in vertebrates (Angelopoulou et al. 2012; Nakamura 2010).
Evidence Supporting this KER
Literature search to date has provided relatively little direct evidence of 17β-estradiol (E2) production in the bipotential gonad or decreases in E2 production upon aromatase inhibition in the same. However, given the well-established role of aromatase as a rate limiting enzyme for E2 production (Simpson et al. 1994; Payne and Hale, 2004) and the close association between aromatase expression and activity and gonadal sex determination/differentiation (Angelopoulou et al. 2012; Nakamura 2010), it is highly plausible that local estrogen production in the bipotential gonad plays a significant role in gonadal differentiation. However, particularly for species with genetic sex determination, it is one just one of multiple determinants that ultimately influence differentiation of the gonad (Angelopoulou et al. 2012, Sarre et al. 2004).
Uncertainties and Inconsistencies
Even in some of the most studied classes with regard to the role of aromatase in gonad differentiation (e.g., fish, reptiles) there is considerable variability in the determinants that influence aromatase expression and work with estrogen signaling to influence differentiation. These are not easily predicted from phylogenetic relationships (Angelopoulou et al. 2012, Sarre et al. 2004). Thus susceptibility and relative sensitivities may vary considerably between species.
To date, none of the studies reviewed have offered insight into the quantitative relationship between aromatase inhibition and estradiol synthesis by the undifferentiated, bipotential, gonad.
- Based on studies in adults, post-differentiation, effects on estradiol production can be detected within a few hours of administering an aromatase inhibitor in vivo (Schroeder et al. 2017; Skolness et al. 2011).
- Based on in vitro studies, significant reductions in aromatase activity and/or E2 synthesis can be detected in 90 min or less (Villeneuve et al. 2006).
Known modulating factors
Aromatase expression during gonadal differentiation is subject to both environmental and genetic controls to various degrees depending on species (Angelopoulou et al. 2012, Sarre et al. 2004). However, generalizable relationships that account for effects of specific parameters in the response-response relationships underlying this KER are currently unknown.
Known Feedforward/Feedback loops influencing this KER
Aromatase expression and E2 synthesis in adults is known to be under feedback regulation via the brain-pituitary-gonadal axis (Villeneuve et al. 2009; Ankley et al. 2009; Villeneuve et al. 2013; Yu et al. 2020; Norris 1997; Miller 1988; Callard et al. 2001).
It is unclear whether these same feedback mechanisms are active during gonadal differentiation.
Domain of Applicability
The life stage applicable to this key event relationship is developing embryos and juveniles prior to or during the gonadal differentiation stage. This key event relationship is not applicable to sexually differentiated adults.
Because this KER is relevant prior to or during sexual differentiation, the relationship is relevant to animals with an undetermined (non-specific) sex.
Phylogenetic analysis among mammalian, amphibian, reptile, bird, and fish has shown that aromatase is well conserved among all vertebrates (Wilson JY et al., 2005). Additionally, CYP19 was detected in the amphioxus suggesting that it has possible origin in primitive chordates. However this relationship probably only applicable to vertebrates.
As noted above, even in some of the most studied classes with regard to the role of aromatase in gonad differentiation (e.g., fish, reptiles) there is considerable variability in the determinants that influence aromatase expression and work with estrogen signaling to influence differentiation. These are not easily predicted from phylogenetic relationships (Angelopoulou et al. 2012, Sarre et al. 2004). Thus susceptibility and relative sensitivities may vary considerably between species.
Angelopoulou R, Lavranos G, Manolakou P. Sex determination strategies in 2012: towards a common regulatory model? Reprod Biol Endocrinol. 2012 Feb 22;10:13. doi: 10.1186/1477-7827-10-13. PMID: 22357269; PMCID: PMC3311596.
Ankley GT, Bencic DC, Cavallin JE, Jensen KM, Kahl MD, Makynen EA, Martinovic D, Mueller ND, Wehmas LC, Villeneuve DL. Dynamic nature of alterations in the endocrine system of fathead minnows exposed to the fungicide prochloraz. Toxicol Sci. 2009 Dec;112(2):344-53. doi: 10.1093/toxsci/kfp227. Epub 2009 Sep 18. PMID: 19767443.
Callard GV, Tchoudakova AV, Kishida M, Wood E. Differential tissue distribution, developmental programming, estrogen regulation and promoter characteristics of cyp19 genes in teleost fish. J Steroid Biochem Mol Biol. 2001 Dec;79(1-5):305-14. doi: 10.1016/s0960-0760(01)00147-9. PMID: 11850237.
Miller WL. Molecular biology of steroid hormone synthesis. Endocr Rev. 1988 Aug;9(3):295-318. doi: 10.1210/edrv-9-3-295. PMID: 3061784.
Nakamura M. The mechanism of sex determination in vertebrates-are sex steroids the key-factor? J Exp Zool A Ecol Genet Physiol. 2010 Aug 1;313(7):381-98. doi: 10.1002/jez.616. PMID: 20623803.
Norris, D. O. Vertebrate Endocrinology, 3rd ed.; Academic Press: San Diego, CA, 1997.
Payne AH, Hales DB. Overview of steroidogenic enzymes in the pathway from cholesterol to active steroid hormones. Endocr Rev. 2004 Dec;25(6):947-70. doi: 10.1210/er.2003-0030. PMID: 15583024.
Sarre SD, Georges A, Quinn A. The ends of a continuum: genetic and temperature-dependent sex determination in reptiles. Bioessays. 2004 Jun;26(6):639-45. doi: 10.1002/bies.20050. PMID: 15170861.
Schroeder AL, Ankley GT, Habib T, Garcia-Reyero N, Escalon BL, Jensen KM, Kahl MD, Durhan EJ, Makynen EA, Cavallin JE, Martinovic-Weigelt D, Perkins EJ, Villeneuve DL. Rapid effects of the aromatase inhibitor fadrozole on steroid production and gene expression in the ovary of female fathead minnows (Pimephales promelas). Gen Comp Endocrinol. 2017 Oct 1;252:79-87. doi: 10.1016/j.ygcen.2017.07.022. Epub 2017 Jul 21. PMID: 28736226; PMCID: PMC6010346.
Skolness SY, Durhan EJ, Garcia-Reyero N, Jensen KM, Kahl MD, Makynen EA, Martinovic-Weigelt D, Perkins E, Villeneuve DL, Ankley GT. Effects of a short-term exposure to the fungicide prochloraz on endocrine function and gene expression in female fathead minnows (Pimephales promelas). Aquat Toxicol. 2011 Jun;103(3-4):170-8. doi: 10.1016/j.aquatox.2011.02.016. Epub 2011 Mar 2. PMID: 21470553.
Simpson ER, Mahendroo MS, Means GD, Kilgore MW, Hinshelwood MM, Graham-Lorence S, Amarneh B, Ito Y, Fisher CR, Michael MD, et al. Aromatase cytochrome P450, the enzyme responsible for estrogen biosynthesis. Endocr Rev. 1994 Jun;15(3):342-55. doi: 10.1210/edrv-15-3-342. PMID: 8076586.
Villeneuve DL, Breen M, Bencic DC, Cavallin JE, Jensen KM, Makynen EA, Thomas LM, Wehmas LC, Conolly RB, Ankley GT. Developing predictive approaches to characterize adaptive responses of the reproductive endocrine axis to aromatase inhibition: I. Data generation in a small fish model. Toxicol Sci. 2013 Jun;133(2):225-33. doi: 10.1093/toxsci/kft068. Epub 2013 Mar 14. PMID: 23492810.
Villeneuve DL, Mueller ND, Martinović D, Makynen EA, Kahl MD, Jensen KM, Durhan EJ, Cavallin JE, Bencic D, Ankley GT. Direct effects, compensation, and recovery in female fathead minnows exposed to a model aromatase inhibitor. Environ Health Perspect. 2009 Apr;117(4):624-31. doi: 10.1289/ehp.11891. Epub 2008 Dec 12. PMID: 19440503; PMCID: PMC2679608.
Villeneuve DL, Knoebl I, Kahl MD, Jensen KM, Hammermeister DE, Greene KJ, Blake LS, Ankley GT. Relationship between brain and ovary aromatase activity and isoform-specific aromatase mRNA expression in the fathead minnow (Pimephales promelas). Aquat Toxicol. 2006 Mar 10;76(3-4):353-68. doi: 10.1016/j.aquatox.2005.10.016. Epub 2005 Dec 2. PMID: 16330110.
Wilson JY, McArthur AG, Stegeman JJ. Characterization of a cetacean aromatase (CYP19) and the phylogeny and functional conservation of vertebrate aromatase. Gen Comp Endocrinol. 2005 Jan 1;140(1):74-83. doi: 10.1016/j.ygcen.2004.10.004. PMID: 15596073.
Yin Y, Tang H, Liu Y, Chen Y, Li G, Liu X, Lin H. Targeted Disruption of Aromatase Reveals Dual Functions of cyp19a1a During Sex Differentiation in Zebrafish. Endocrinology. 2017 Sep 1;158(9):3030-3041. doi: 10.1210/en.2016-1865. PMID: 28575219.
Yu Q, Peng C, Ye Z, Tang Z, Li S, Xiao L, Liu S, Yang Y, Zhao M, Zhang Y, Lin H. An estradiol-17β/miRNA-26a/cyp19a1a regulatory feedback loop in the protogynous hermaphroditic fish, Epinephelus coioides. Mol Cell Endocrinol. 2020 Mar 15;504:110689. doi: 10.1016/j.mce.2019.110689. Epub 2019 Dec 28. PMID: 31891771.