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Relationship: 737

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

Disorganization, Meiotic Spindle leads to Altered, Meiotic chromosome dynamics

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 Moderate 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
mouse Mus musculus Moderate NCBI

Sex Applicability

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

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

Incorrect spindle organization refers to lack of the bipolar organization of the spindle within the cell. This bipolar organization is required to assure that chromosomes will align correctly to the metaphase plate prior to equal division between the daughter cells. Alternatively, incorrect spindle formation can lead to shorter spindle fibers and/or incorrect length of these fibers, which leads to chromosome misalignment.

In this KER, chemicals that cause spindle disorganization lead to altered meiotic chromosome dynamics. The relationship between spindle disorganization and altered chromosome dynamics can occur in both somatic and in germ cells; however, this relationship focuses on female meiotic chromosomes because of the differences in how the meiotic spindle is assembled in oocytes with respect to other cell types (i.e., lack of centrioles and dependency on microtubule organizing centers). Interestingly, some studies investigating the effects of protein deficiencies in mouse oocytes provide direct evidence of the events involved in the KER [McGuinnes et al., 2009; Ou et al., 2010; Baumann et al., 2017]. For example, targeting deletion of Bub1 in mouse oocytes caused dysregulation of spindle assembly and leads to defective chromosome congression [McGuinness et al., 2009]. After depletion of p38a in mouse oocytes, a MTCO component, aberrant spindle organization, including defective or multipolar spindles are more than 3 times more frequent than in control mice, while there is an 8-fold increase in chromosome congression defects [Ou et al., 2010]. Finally, in a study carried out using an oocyte conditional pericentrin knockout mouse model and live cell imaging, alterations in spindle size have been observed, together with delay in meiotic spindle formation following in vitro culture of cumulus-enclosed oocytes. These abnormalities were associated with a significant increase in the number of unattached kinetochores and merotelic attachments, as well as, an increase in misaligned and uncongressed chromosomes [Baumann et al., 2017].

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

Moderate, based on strong biological plausibility and weak emprical evidence.

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

The weight of evidence for this KER is moderate. It is well understood that the proper organization of the meiotic spindle is necessary in order for chromosomes to correctly align. This process has been extensively described in the literature. For a recent comprehensive review on this topic, please see Bennabi et al. [2016].

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

There is not extensive empirical data this KER, however, the available data does not show inconsistencies.

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

Due to the lack of solid evidence about the response-response relationship modulating factors cannot be identified in this KER.

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

As noted above, very few studies have examined both spindle abnormalities (KEupstream) and altered chromosome dynamids (KEdownstream) under the same experimental conditions, especially in oocytes. In addition, spindle abnormalities (KEupstream) and altered chromosome dynamics (KEdownstream) in oocytes treated with tubulin binding chemicals have not been quantitated by detailed dose-response relationships. Thus, the dataset is too limited to allow defining a response-response relationship between spindle abnormalities (KEupstream) and altered chromosome dynamics (KEdownstream). A study on mouse oocytes treated in vitro with nocodazole [Shen et al., 2005] showed that KEdownstream occurred at a dose higher than doses inducing KEustream, suggesting that a certain level of spindle abnormalities (KEupstream) is to be reached before altered chromosome dynamics (KEdownstream) occur, but data are too limited to draw a firm conclusion on the shape of the response-response relationship.

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

Spindle formation (KEupstream) and chromosome congression on the metaphase plate (KEdownstream) are highly dynamic processes. In mouse oocytes, the first meiotic spindle is assembled in 3–4 h, and 3 more hours are needed for it to migrate to the cortex [Wei et al., 2018]. During the following 2 hours, chromosome congress at the spindle equator by a trial and error process connecting kinetochores with kinetochore fibres. The establishment of complete and correct connections is monitored by checkpoint mechanisms that control anaphase triggering. Live imaging studies of oocytes treated with tubulin binding chemicals are not available that could allow the timing of changes in KEdownstream in relation to the start of changes in KEupstream. However, live imaging studies under impaired spindle assembly conditions [Yi et al., 2019] suggest that spindle disorganization (KEupstream) induces altered chromosome dynamics (KEdownstream) in a matter of minutes. Alterations may last for hours, if spindle damage is sustained by continuous chemical exposure. In fact, anaphase onset may be delayed by hours when oocytes are exposed to spindle disrupting chemicals [Mailhes et al., 1993; Mailhes and Marchetti, 1994].

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

To our knowledge, there are no feedback loops influencing this KER.

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

Although this KER has only been measured in mouse oocytes, the process of meiosis, spindle formation and chromosome congression in eggs is thought to be similar across mammalian species.

References

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

Baumann C, Wang X, Yang L, Viveiros MM. 2017. Error-prone meiotic division and subfertility in mice with oocyte-conditional knockdown of pericentrin. J Cell Sci 130:1251-1262.

Eichenlaub-Ritter U, Winterscheidt U, Vogt E, Shen Y, Tinneberg HR, Sorensen R. 2007. 2-methoxyestradiol induces spindle aberrations, chromosome congression failure, and nondisjunction in mouse oocytes. Biol Reprod 76:784–793.

Mailhes JB, Marchetti F. 1994. Chemically-induced aneuploidy in mammalian oocytes. Mutat Res 320:87-111.

Mailhes JB, Aardema MJ, Marchetti F. 1993. Investigation of aneuploidy induction in mouse oocytes following exposure to vinblastine-sulfate, pyrimethamine, diethylstilbestrol diphosphate, or chloral hydrate. Environ Mol Mutagen 22:107–114.

McGuinness BE, Anger M, Kouznetsova A, Gil-Bernabe AM, Helmhart W, Kudo NR, Wuensche A, Taylor S, Hoog C, Novak B, Nasmyth K. 2009. Regulation of APC/C activity in oocytes by a Bub1-dependent spindle assembly checkpoint. Curr Biol 19:369-380.

Ou XH, Li S, Xu BZ, Wang ZB, Quan S, Li M, Zhang QH, Ouyang YC, Schatten H, Xing FQ, Sun QY. 2010. p38alpha MAPK is a MTOC-associated protein regulating spindle assembly, spindle length and accurate chromosome segregation during mouse oocyte meiotic maturation. Cell Cycle 9:4130-4143

Shen Y, Betzendahl I, Sun F, Tinneberg HR, Eichenlaub-Ritter U. 2005. Non-invasive method to assess genotoxicity of nocodazole interfering with spindle formation in mammalian oocytes. Reprod Toxicol 19:459–471.

Silkworth WT, Cimini D. 2012. Transient defects of mitotic spindle geometry and chromosome segregation errors. Cell Div 7:19.

Yi Z-Y, Liang Q-X, Meng T-G, Li J, Dong M-Z, Hou Y, Ouyang Y-C, Zhang C-H, Schatten H, Sun Q-Y, Qiao J, Qian WP. 2019. PKCβ1 regulates meiotic cell cycle in mouse oocyte. Cell Cycle, DOI: 10.1080/15384101.2018.1564492

Wei Z, Greaney J, Zhou C, Homer H. 2018. Cdk1 inactivation induces post-anaphase-onset spindle migration and membrane protrusion required for extreme asymmetry in mouse oocytes. Nature Comm 9:4029. DOI: 10.1038/s41467-018-06510-9.