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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

Inhibition, Aromatase

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Reduction, E2 Synthesis by the undifferentiated gonad

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	EAGMST Under Review

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 Map 2.0

ID	Experimental Design	Species	Upstream Observation	Downstream Observation	Citation (first author, year)	Notes

Evidence Map

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

Title	First Author	Biological Plausibility	Dose Concordance	Temporal Concordance	Incidence Concordance

Biological Plausibility

Dose Concordance Evidence

Temporal Concordance Evidence

Incidence Concordance Evidence

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.

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

Quantitative understanding of this linkage is currently weak.

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.