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Relationship: 2144

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Inhibition, Aromatase leads to Reduction, E2 Synthesis by the undifferentiated gonad

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes. Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

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

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help
Term Scientific Term Evidence Link
Oreochromis niloticus Oreochromis niloticus Low NCBI
zebrafish Danio rerio Moderate NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Unspecific Moderate

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help
Term Evidence
before or during gonadal sex differentiation High

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

Aromatase (cyp191a) is a cytochrome P450-based enzyme that is rate limiting for the synthesis of 17ß-estradiol (E2) from testosterone in vertebrates (Simpson et al. 1994; Miller 1988; Payne and Hale 2004).  The expression and activity of aromatase in the bipotential gonad of developing organisms, and subsequent autocrine and/or paracrine signaling mediated by E2 interactions with 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 Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER.  For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

   See below

Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help

There is little direct evidence of E2 production by the bipotential gonad, or that inhibition of aromatase decreases in E2 production in same. However, given the well-established role of aromatase in 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 just one of multiple determinants that ultimately influences differentiation of the gonad (Angelopoulou et al. 2012).

Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

As noted below it is difficult to predict the full suite of vertebrate species this KER might apply to. In addition, studies directly examining synthesis of E2 by bipotential gonads in organisms exposed to aromatase inhibitors are lacking.

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help

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.

Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help

To date, none of the studies reviewed have offered insights into the quantitative relationship between the degree of aromatase inhibition and E2 synthesis by the undifferentiated, bipotential gonad.

Time-scale
Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help
  • Based on studies in mature adult fish (fathead minnows, Pimephales promelas) effects of model aromatase inhibitors on E2 production (e.g., plasma concentrations) can be detected within a few hours of exposure in vivo (Schroeder et al. 2017; Skolness et al. 2011).
  • Based on in vitro studies, significant reductions in aromatase activity and associated E2 synthesis can be detected in 90 min or less (Villeneuve et al. 2006).
Known Feedforward/Feedback loops influencing this KER
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Aromatase expression and E2 synthesis in adult fish of several species are subject to feedback regulation via the brain-pituitary-gonadal axis (e.g., Villeneuve et al. 2009; 2013; Ankley et al. 2009; Yu et al. 2020; Norris 1997; Miller 1988; Callard et al. 2001).

However, it is unclear whether these feedback mechanisms are active during gonadal differentiation.

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

Life Stage

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. 

Sex

Because this KER occurs during differentiation, the relationship is relevant to animals with an undetermined (non-specific) sex.

Taxonomic Applicability 

Sequencing studies 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 between species.

References

List of the literature that was cited for this KER description. More help

Angelopoulou, R., Lavranos, G., & Manolakou, P. (2012). Sex determination strategies in 2012: towards a common regulatory model?. Reproductive biology and endocrinology : RB&E10, 13. https://doi.org/10.1186/1477-7827-10-13

 

Ankley, G. T., Bencic, D. C., Cavallin, J. E., Jensen, K. M., Kahl, M. D., Makynen, E. A., Martinovic, D., Mueller, N. D., Wehmas, L. C., & Villeneuve, D. L. (2009). Dynamic nature of alterations in the endocrine system of fathead minnows exposed to the fungicide prochloraz. Toxicological sciences : an official journal of the Society of Toxicology112(2), 344–353. https://doi.org/10.1093/toxsci/kfp227

 

Callard, G. V., Tchoudakova, A. V., Kishida, M., & Wood, E. (2001). Differential tissue distribution, developmental programming, estrogen regulation and promoter characteristics of cyp19 genes in teleost fish. The Journal of steroid biochemistry and molecular biology79(1-5), 305–314. https://doi.org/10.1016/s0960-0760(01)00147-9

 

D'Cotta, H., Fostier, A., Guiguen, Y., Govoroun, M., & Baroiller, J. F. (2001). Aromatase plays a key role during normal and temperature-induced sex differentiation of tilapia Oreochromis niloticus. Molecular reproduction and development59(3), 265–276. https://doi.org/10.1002/mrd.1031

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.

Miller W. L. (1988). Molecular biology of steroid hormone synthesis. Endocrine reviews9(3), 295–318. https://doi.org/10.1210/edrv-9-3-295

 

Nakamura M. (2010). The mechanism of sex determination in vertebrates-are sex steroids the key-factor?. Journal of experimental zoology. Part A, Ecological genetics and physiology313(7), 381–398. https://doi.org/10.1002/jez.616

 

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 reviews25(6), 947–970. https://doi.org/10.1210/er.2003-0030

 

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 biology26(6), 639–645. https://doi.org/10.1002/bies.20050

 

Schroeder, A. L., Ankley, G. T., Habib, T., Garcia-Reyero, N., Escalon, B. L., Jensen, K. M., Kahl, M. D., Durhan, E. J., Makynen, E. A., Cavallin, J. E., Martinovic-Weigelt, D., Perkins, E. J., & Villeneuve, D. L. (2017). Rapid effects of the aromatase inhibitor fadrozole on steroid production and gene expression in the ovary of female fathead minnows (Pimephales promelas). General and comparative endocrinology252, 79–87. https://doi.org/10.1016/j.ygcen.2017.07.022

 

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 reviews15(3), 342–355. https://doi.org/10.1210/edrv-15-3-342

 

Skolness, S. Y., Durhan, E. J., Garcia-Reyero, N., Jensen, K. M., Kahl, M. D., Makynen, E. A., Martinovic-Weigelt, D., Perkins, E., Villeneuve, D. L., & Ankley, G. T. (2011). Effects of a short-term exposure to the fungicide prochloraz on endocrine function and gene expression in female fathead minnows (Pimephales promelas). Aquatic toxicology (Amsterdam, Netherlands)103(3-4), 170–178. https://doi.org/10.1016/j.aquatox.2011.02.016

 

Villeneuve, D. L., Breen, M., Bencic, D. C., Cavallin, J. E., Jensen, K. M., Makynen, E. A., Thomas, L. M., Wehmas, L. C., Conolly, R. B., & Ankley, G. T. (2013). Developing predictive approaches to characterize adaptive responses of the reproductive endocrine axis to aromatase inhibition: I. Data generation in a small fish model. Toxicological sciences : an official journal of the Society of Toxicology133(2), 225–233. https://doi.org/10.1093/toxsci/kft068

 

Villeneuve, D. L., Knoebl, I., Kahl, M. D., Jensen, K. M., Hammermeister, D. E., Greene, K. J., Blake, L. S., & Ankley, G. T. (2006). Relationship between brain and ovary aromatase activity and isoform-specific aromatase mRNA expression in the fathead minnow (Pimephales promelas). Aquatic toxicology (Amsterdam, Netherlands)76(3-4), 353–368. https://doi.org/10.1016/j.aquatox.2005.10.016

 

Villeneuve, D. L., Mueller, N. D., Martinović, D., Makynen, E. A., Kahl, M. D., Jensen, K. M., Durhan, E. J., Cavallin, J. E., Bencic, D., & Ankley, G. T. (2009). Direct effects, compensation, and recovery in female fathead minnows exposed to a model aromatase inhibitor. Environmental health perspectives117(4), 624–631. https://doi.org/10.1289/ehp.11891

 

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 endocrinology140(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

 

Yu, Q., Peng, C., Ye, Z., Tang, Z., Li, S., Xiao, L., Liu, S., Yang, Y., Zhao, M., Zhang, Y., & Lin, H. (2020). An estradiol-17β/miRNA-26a/cyp19a1a regulatory feedback loop in the protogynous hermaphroditic fish, Epinephelus coioides. Molecular and cellular endocrinology504, 110689. https://doi.org/10.1016/j.mce.2019.110689

 

Zhang, X., Li, M., Ma, H., Liu, X., Shi, H., Li, M., & Wang, D. (2017). Mutation of foxl2 or cyp19a1a Results in Female to Male Sex Reversal in XX Nile Tilapia. Endocrinology158(8), 2634–2647. https://doi.org/10.1210/en.2017-00127