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Event: 1789

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Reduction, 17beta-estradiol synthesis by the undifferentiated gonad

Short name

The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. More help

Reduction, E2 Synthesis by the undifferentiated gonad

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Biological Context

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Level of Biological Organization
Cellular

Cell term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place. For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable. For individual/population events, the organ context is not applicable. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Cell term
primordial germ cell

Organ term

Organ term
gonad

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor). Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Process	Object	Action
estrogen biosynthetic process	17beta-estradiol	decreased

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE.Clicking on the name of the AOP will bring you to the individual page for that AOP. More help

AOP Name	Role of event in AOP	Point of Contact	Author Status	OECD Status
Aromatase inhibition leads to male-biased sex ratio via impacts on gonad differentiation	KeyEvent	Brendan Ferreri-Hanberry (send email)	Under Development: Contributions and Comments Welcome	WPHA/WNT Endorsed

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 KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help

Term	Scientific Term	Evidence	Link
Vertebrates	Vertebrates	Moderate	NCBI

Life Stages

An indication of the the relevant life stage(s) for this KE. More help

Life stage	Evidence
Development	Moderate

Sex Applicability

An indication of the the relevant sex for this KE. More help

Term	Evidence
Unspecific	Low

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

Estrogens are essential for normal ovarian differentiation, growth and maintenance. When estrogens bind to estrogen receptors (ER), these then regulate the transcription of downstream estrogen-responsive genes necessary for proper gonad development (Guiguen et al. 2010; Gorelick et al. 2011). Among the different forms of estrogens, 17β-estradiol (E2) is considered the most fundamental in gonad differentiation in most vertebrates, as it is responsible for inducing and maintaining ovarian development (Bondesson et al. 2015; Li et al. 2019). Consequently, disruption of the E2 synthesis by the undifferentiated gonad has been linked to altered gonad differentiation and development in many vertebrates.

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

Estrogen concentrations can be measured via radioimmunoassay (e.g., US EPA 2002) or by analytical methods such as LC/MS/MS (e.g., Gravitte et al. 2021; Jalabert et al. 2021; Nouri et al. 2020). Measurement in the undifferentiated gonad would generally require extraction of tissue homogenates. This tissue mass can be very limited during primordial stages.

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided). More help

Taxonomic applicability: Most of the key enzymes involved in the process of E2 biosynthesis are well conserved among vertebrates (Callard et al. 2001; Thornton et al. 2001; Eick et al. 2011; Coumailleau et al. 2015). Estrogens play a key role in embryonic development particularly during gonadogenesis for most vertebrates (Coumailleauet al., 2015; Callard et al., 2015). Therefore, it is possible that this key event is applicable to most vertebrate taxa. In contrast, this key event is not applicable to organisms that lack the necessary enzymes for estrogen synthesis such as invertebrates and plants (Jones et al. 2017).

Life stage applicability: Endogenous steroid biosynthesis generally begins shortly after birth or hatch.

Sex applicability: This key event applies to the undifferentiated gonad. Therefore, sex is non-specific.

References

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

Bondesson, M., Hao, R., Lin, C. Y., Williams, C., & Gustafsson, J. Å. (2015). Estrogen receptor signaling during vertebrate development. Biochimica et biophysica acta, 1849(2), 142–151.

Callard, G. V., Tarrant, A. M., Novillo, A., Yacci, P., Ciaccia, L., Vajda, S., Chuang, G. Y., Kozakov, D., Greytak, S. R., Sawyer, S., Hoover, C., & Cotter, K. A. (2011). Evolutionary origins of the estrogen signaling system: insights from amphioxus. The Journal of steroid biochemistry and molecular biology, 127(3-5), 176–188.

Cheshenko, K., Pakdel, F., Segner, H., Kah, O., & Eggen, R. I. (2008). Interference of endocrine disrupting chemicals with aromatase CYP19 expression or activity, and consequences for reproduction of teleost fish. General and comparative endocrinology, 155(1), 31–62.

Coumailleau, P., Pellegrini, E., Adrio, F., Diotel, N., Cano-Nicolau, J., Nasri, A., Vaillant, C., & Kah, O. (2015). Aromatase, estrogen receptors and brain development in fish and amphibians. Biochimica et biophysica acta, 1849(2), 152–162.

Eick, G. N., & Thornton, J. W. (2011). Evolution of steroid receptors from an estrogen-sensitive ancestral receptor. Molecular and cellular endocrinology, 334(1-2), 31–38.

Gorelick, D. A., & Halpern, M. E. (2011). Visualization of estrogen receptor transcriptional activation in zebrafish. Endocrinology, 152(7), 2690–2703. https://doi.org/10.1210/en.2010-1257

Gravitte A, Archibald T, Cobble A, Kennard B, Brown S. Liquid chromatography-mass spectrometry applications for quantification of endogenous sex hormones. Biomed Chromatogr. 2021 Jan;35(1):e5036. doi: 10.1002/bmc.5036.

Guiguen, Y., Fostier, A., Piferrer, F., & Chang, C. F. (2010). Ovarian aromatase and estrogens: a pivotal role for gonadal sex differentiation and sex change in fish. General and comparative endocrinology, 165(3), 352–366.

Jalabert C, Ma C, Soma KK. Profiling of systemic and brain steroids in male songbirds: Seasonal changes in neurosteroids. J Neuroendocrinol. 2021 Jan;33(1):e12922. doi: 10.1111/jne.12922.

Jones, B. L., Walker, C., Azizi, B., Tolbert, L., Williams, L. D., & Snell, T. W. (2017). Conservation of estrogen receptor function in invertebrate reproduction. BMC evolutionary biology, 17(1), 65.

Li, M., Sun, L., & Wang, D. (2019). Roles of estrogens in fish sexual plasticity and sex differentiation. General and comparative endocrinology, 277, 9–16. https://doi.org/10.1016/j.ygcen.2018.11.015

Nouri MZ, Kroll KJ, Webb M, Denslow ND. Quantification of steroid hormones in low volume plasma and tissue homogenates of fish using LC-MS/MS. Gen Comp Endocrinol. 2020 Sep 15;296:113543. doi: 10.1016/j.ygcen.2020.113543.

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.

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 endocrinology, 252, 79–87.

Thornton J. W. (2001). Evolution of vertebrate steroid receptors from an ancestral estrogen receptor by ligand exploitation and serial genome expansions. Proceedings of the National Academy of Sciences of the United States of America, 98(10), 5671–5676.

US EPA. 2002. A Short-term test method for assessing the reproductive toxicity of endocrine-disrupting chemicals using the Fathead Minnow (Pimephales promelas). EPA/600/R-01/067. Appendix C.

Warner, D. A., Addis, E., Du, W. G., Wibbels, T., & Janzen, F. J. (2014). Exogenous application of estradiol to eggs unexpectedly induces male development in two turtle species with temperature-dependent sex determination. General and comparative endocrinology, 206, 16–23.

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.