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Relationship: 723

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, Chromosome number leads to Increase, Aneuploid offspring

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
Chemical binding to tubulin in oocytes leading to aneuploid offspring 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 High NCBI
mouse Mus musculus High NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Female High

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help
Term Evidence
Adult, reproductively mature 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

Development of a conceptus from a gamete containing an abnormal number of chromosomes results in an aneuploid offspring. Whether the aneuploid conceptus results in a viable offspring is dependent on the chromosome involved in the aneuploidy. Viable aneuploidies in humans include chromosomes 13, 18 and 21, and the sex chromosomes.

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

Strong.

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

It is well established that in the majority of cases of human offspring with an aneuploid condition, the extra chromosome is inherited from one of the parents. In humans, it is known that aneuploidy occurs more frequently in female germ cells. It has been known for a long time that there is a strong association between increasing maternal age and increasing risk of aneuploid offspring.

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

None.

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

There are no studies that have looked at whether specific chromosomes are more prone to undergo chemically induced aneuploidy, thus, it can be assumed, that the fraction of zygotes that are aneuploid for chromosomes that are compatible with life will also show a linear relationship as that observed between aneuploid oocytes and zygotes.

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

As mentioned above, it is difficult to evaluate the response-response relationship between these two KEs because the majority of aneuploid conceptuses are eliminated during pregnancy. There are a few studies that report on the frequency of aneuploidy in oocytes (KEupstream) and the frequency of aneuploidy in zygotes, only a small portion of which will result in an increase in aneuploid offspring  (KEdownstream). Studies with colchicine [Mailhes et al., 1990], griseofulvin [Tiveron et al, 1992; Marchetti et al., 1992] and taxol [Mailhes et al., 199] all show that the frequencies of aneuploid oocytes and aneuploid zygotes are similar suggesting a linear relationship at least between these two events.

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

Chemically induced aneuploidy is occurring around the time of ovulation when the oocyte completes the first meiotic division. Fertilization generally occurs within a few hours from ovulation and thus the generation of the aneuploid conceptus follows the KEupstream by a matter of hours. The KEdownstream, that is aneuploid offspring, is determined by the duration of pregnancy in the species, weeks in the mouse, months in humans, but again, only a small portion of the aneuploid zygotes will result in a live offspring.

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

There are no known feedbacks 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

This is based on evidence in humans and mice, but is broadly applicable to all eukaryotic species.

References

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

Hassold T, Hall H, Hunt P. 2007. The origin of human aneuploidy: Where we have been, where we are going. Hum Mol Genet 16: R203–R208.

Hunt PA, Hassold TJ. 2002. Sex matters in meiosis. Science 296:2181–2183.

Leland S, Nagarajan P, Polyzos A, Thomas S, Samaan G, Donnell R, Marchetti F, Venkatachalam S. 2009. Heterozygosity for a Bub1 mutation causes female-specific germ cell aneuploidy in mice. Proc Natl Acad Sci USA 106:12776-12781.

Mailhes JB, Aardema MJ, Marchetti F. 1990. Cytogenetic analysis of mouse oocytes and one-cell zygotes as a potential assay for heritable germ cell aneuploidy. Mutat Res 242:89-100.

Mailhes JB, Carabatsos MJ, Young D, London SN, Bell M, Albertini DF. 1999. Taxol-induced meiotic maturation delay, spindle defects, and aneuploidy in mouse oocytes and zygotes. Mutat Res 423:79-90.

Marchetti F, C Tiveron, B Bassani and F Pacchierotti. 1992. Griseofulvin-induced aneuploidy and meiotic delay in female mouse germ cells, II. Cytogenetic analysis of one-cell zygotes. Mutat Res 266:151-162.

Nagaoka SI, Hassold TJ, Hunt PA. 2012. Human aneuploidy: Mechanisms and new insights into an age-old problem. Nat Rev Genet 13:493–504.

Tiveron C, F Marchetti, B Bassani and F Pacchierotti. 1992. Griseofulvin-induced aneuploidy and meiotic delay in female mouse germ cells, I. Cytogenetic analysis of metaphase II oocytes. Mutat Res 266:143-150.

Webster A, Schuh M. 2017. Mechanisms of aneuploidy in human eggs. Trends Cell Biol 27:55-68.