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Relationship: 2468

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

Altered, inner ear development leads to Reduced, Hearing

Upstream event

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

Altered, inner ear development

Downstream event

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

Reduced, Hearing

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
GSK3beta inactivation leading to increased mortality via defects in developing inner ear	adjacent	High	Low	Vid Modic (send email)	Open for citation & comment

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
zebrafish	Danio rerio	High	NCBI

Sex Applicability

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

Sex	Evidence
Unspecific	High

Life Stage Applicability

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

Term	Evidence
All life stages	Moderate

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

The inner ear is the vertebrate organ of hearing and balance (Whitfield, 2002).

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

Inner ear develops from an ectodermal thickening, the otic placode, visible on either side of the hindbrain from mid-somite stages. In the zebrafish, this placode cavitates to form a hollow ball of epithelium, the otic vesicle, from which all structures of the membranous labyrinth and the neurons of the statoacoustic (VIIIth) ganglion arise (Haddon and Lewis, 1996; Whitfield et al., 2002).

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

Zebrafish serves as a model organism for hearing and deafness. Mutations in several genes connected to development of inner ear affect morphology and patterning of the inner ear epithelium, including formation of the semicircular canals and, in some, development of sensory patches (maculae and cristae). Zebrafish mutant embryos fail to balance correctly, and may swim on their sides, upside down, or in circles (Whitfield et al., 1996). This is reminiscent of the behavior of deaf mouse mutants, which often display hyperactive circling or head bobbing due to vestibular dysfunction (Whitfield, 2002).

Dog-eared mutants show abnormal development of semicircular canals and lack cristae within the ear (Kozlowski et al., 2005), while in van gogh, semicircular canals fail to form altogether, resulting in a tiny otic vesicle containing a single sensory patch. Both mutants show irregular swimming pattern (Whitfield et al., 1996).

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

No Data.

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

No Data.

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

No Data.

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

No Data.

Response-response Relationship

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

No Data.

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

No Data.

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

No Data.

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

Key event relationship is applicable to wide range of vertebrates (Whitfield, 2015).

References

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

Haddon, C. and Lewis, J. (1996) ‘Early ear development in the embryo of the zebrafish, Danio rerio’, Journal of Comparative Neurology, 365(1), pp. 113–128. doi: 10.1002/(SICI)1096-9861(19960129)365:1<113::AID-CNE9>3.0.CO;2-6.

Kozlowski, D. J. et al. (2005) ‘The zebrafish dog-eared mutation disrupts eya1, a gene required for cell survival and differentiation in the inner ear and lateral line’, Developmental Biology, 277(1), pp. 27–41. doi: 10.1016/j.ydbio.2004.08.033.

Whitfield, T. T. et al. (1996) ‘Mutations affecting development of the zebrafish inner ear and lateral line’, Development, 123, pp. 241–254. doi: 10.1242/dev.123.1.241.

Whitfield, T. T. et al. (2002) ‘Development of the zebrafish inner ear’, Developmental Dynamics, 223(4), pp. 427–458. doi: 10.1002/dvdy.10073.

Whitfield, T. T. (2002) ‘Zebrafish as a Model for Hearing and Deafness’, J Neurobiol, 53, pp. 157–171. doi: 10.1002/neu.10123.

Whitfield, T. T. (2015) ‘Development of the inner ear’, Current Opinion in Genetics and Development, 32, pp. 112–118. doi: 10.1016/j.gde.2015.02.006.