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Relationship: 724

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

Binding, Tubulin leads to Altered, Chromosome number

Upstream event

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

Binding, Tubulin

Downstream event

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

Altered, Chromosome number

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
Chemical binding to tubulin in oocytes leading to aneuploid offspring	non-adjacent	High		Cataia Ives (send email)	Open for citation & comment	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
Homo sapiens	Homo sapiens	Moderate	NCBI
mouse	Mus musculus	High	NCBI
rat	Rattus norvegicus	Moderate	NCBI

Sex Applicability

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

Sex	Evidence
Mixed	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

In this KER, chemicals that bind to tubulin indirectly lead to altered chromosome numbers. This is because tubulin binding by chemicals interferes with tubulin polymerization leading to microtubule depolymerization, abnormal spindle structure/morphology and subsequent chromosome mis-segregation. The relationship is indirect because there are no studies that have measured all KEs leading up to the AO. However, as described in more details below, there are plenty of studies showing that exposure to spindle poisons induces aneuploidy in female germ cells. This relationship has been shown in vitro and in vivo, and in somatic cells as well as in germ cells.

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

We are not aware of any chemical that bind to tubulin and does not cause aneuploidy, providing that a high enough dose/concentration was tested.

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

As described above, time of exposure with respect to ovulation is a modulating factor.

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

Although quantitative models have not been developed, the qualitative relationship is described above. In vivo studies indicate that timing prior to meiotic division must be carefully considered because of the different half lives of the chemicals bound to tubulin. Depending on dose and time, chemicals that bind to tubulin can induce aneuploidy in almost 100% of oocytes [Mailhes and Marchetti, 2005], suggesting that the disruption of microtubule and spindle dynamics is a very sensitive target for the induction of aneuploidy in female germ cells.

Response-response Relationship

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

It is difficult to compare the response-response relationship between these two KEs, as binding to tubuline (KEupstream) is generally measured in an acellular system or in vitro, while altered chromosome nubmer (KEdownstream) is measured in vivo. However, Brunner et al. [1991] and Wallin and Hartely-Asp [1993] analyzing the ability of 10 chemicals to interfere with microtubule assembly reported that there is a good correlation between the efficiency of microtubule assembly interference and the anuegenic potential of each chemical. That is, chemicals that interfered with microtubule assembly at low concentrations are strong aneugens (eg, colchicine, vinblastine); while chemicals that did not affect the steady state of microtubule assembly do not induced aneuploidy or are very weak inducers (eg, diazepam, cadmium chloride).

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

Binding to tubulin is occurring on the time scale seconds (acellular systems) and minutes (in vitro). In vivo, the time-scale is determined by the route of administration and the ADME characteristics of the chemical. For the induction of aneuploidy, chemical binding to tubulin must occur within a short time range before the completion of the first meiotic division. Mailhes and Yuan [1987] showed that the induction of aneuploid oocytes following exposure to colchicine is maximum when administered 12 hr before ovulation and is reduced when given more or less than 12 hours.

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 known feedback loops.

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

Data for this KER are available in vitro and in vivo, and in a variety of mammalian species including humans.