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Relationship: 737

Title

The title of the KER should clearly define the two KEs being considered and the sequential relationship between them (i.e., which is upstream and which is downstream). Consequently all KER titles take the form “upstream KE leads to downstream KE”.  More help

Disorganization, Meiotic Spindle leads to Altered, Meiotic chromosome dynamics

Upstream event
Upstream event in the Key Event Relationship. On the KER page, clicking on the Event name under Upstream Relationship will bring the user to that individual KE page. More help
Downstream event
Downstream event in the Key Event Relationship. On the KER page, clicking on the Event name under Upstream Relationship will bring the user to that individual KE page. 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

This table is automatically generated upon addition of a KER to an AOP. All of the AOPs that are linked to this KER will automatically be listed in this subsection. Clicking on the name of the AOP in the table will bring you to the individual page for that AOP. More help
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 Francesco Marchetti (send email) Open for citation & comment EAGMST Under Review

Taxonomic Applicability

Select one or more structured terms 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. Authors can indicate the relevant taxa for this KER in this subsection. The process is similar to what is described for KEs (see pages 30-31 and 37-38 of User Handbook) More help
Term Scientific Term Evidence Link
mouse Mus musculus Moderate NCBI

Sex Applicability

Authors can indicate the relevant sex for this KER in this subsection. The process is similar to what is described for KEs (see pages 31-32 of the User Handbook). More help
Sex Evidence
Female Moderate

Life Stage Applicability

Authors can indicate the relevant life stage for this KER in this subsection. The process is similar to what is described for KEs (see pages 31-32 of User Handbook). More help
Term Evidence
All life stages Moderate

Key Event Relationship Description

Provide a brief, descriptive summation of the KER. While the title itself is fairly descriptive, this section can provide details that aren’t inherent in the description of the KEs themselves (see page 39 of the User Handbook). This description section can be viewed as providing the increased specificity in the nature of upstream perturbation (KEupstream) that leads to a particular downstream perturbation (KEdownstream), while allowing the KE descriptions to remain generalised so they can be linked to different AOPs. The description is also intended to provide a concise overview for readers who may want a brief summation, without needing to read through the detailed support for the relationship (covered below). Careful attention should be taken to avoid reference to other KEs that are not part of this KER, other KERs or other AOPs. This will ensure that the KER is modular and can be used by other AOPs. 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 Supporting this KER

Assembly and description of the scientific evidence supporting KERs in an AOP is an important step in the AOP development process that sets the stage for overall assessment of the AOP (see pages 49-56 of the User Handbook). To do this, biological plausibility, empirical support, and the current quantitative understanding of the KER are evaluated with regard to the predictive relationships/associations between defined pairs of KEs as a basis for considering WoE (page 55 of User Handbook). In addition, uncertainties and inconsistencies are considered. More help

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

Biological Plausibility
Define, in free text, the biological rationale for a connection between KEupstream and KEdownstream. What are the structural or functional relationships between the KEs? For example, there is a functional relationship between an enzyme’s activity and the product of a reaction it catalyses. Supporting references should be included. However, it is recognised that there may be cases where the biological relationship between two KEs is very well established, to the extent that it is widely accepted and consistently supported by so much literature that it is unnecessary and impractical to cite the relevant primary literature. Citation of review articles or other secondary sources, like text books, may be reasonable in such cases. The primary intent is to provide scientifically credible support for the structural and/or functional relationship between the pair of KEs if one is known. The description of biological plausibility 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 (see page 40 of the User Handbook for further information).   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
In addition to outlining the evidence supporting a particular linkage, it is also important to identify inconsistencies or uncertainties in the relationship. Additionally, while there are expected patterns of concordance that support a causal linkage between the KEs in the pair, it is also helpful to identify experimental details that may explain apparent deviations from the expected patterns of concordance. Identification of uncertainties and inconsistencies contribute to evaluation of the overall WoE supporting the AOPs that contain a given KER and to the identification of research gaps that warrant investigation (seep pages 41-42 of the User Handbook).Given that AOPs are intended to support regulatory applications, AOP developers should focus on those inconsistencies or gaps that would have a direct bearing or impact on the confidence in the KER and its use as a basis for inference or extrapolation in a regulatory setting. Uncertainties that may be of academic interest but would have little impact on regulatory application don’t need to be described. In general, this section details evidence that may raise questions regarding the overall validity and predictive utility of the KER (including consideration of both biological plausibility and empirical support). It also contributes along with several other elements to the overall evaluation of the WoE for the KER (see Section 4 of the User Handbook).  More help

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

Response-response Relationship
This subsection should be used to define sources of data that define the response-response relationships between the KEs. In particular, information regarding the general form of the relationship (e.g., linear, exponential, sigmoidal, threshold, etc.) should be captured if possible. If there are specific mathematical functions or computational models relevant to the KER in question that have been defined, those should also be cited and/or described where possible, along with information concerning the approximate range of certainty with which the state of the KEdownstream can be predicted based on the measured state of the KEupstream (i.e., can it be predicted within a factor of two, or within three orders of magnitude?). For example, a regression equation may reasonably describe the response-response relationship between the two KERs, but that relationship may have only been validated/tested in a single species under steady state exposure conditions. Those types of details would be useful to capture.  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
This sub-section should be used to provide 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?). This can be useful information both in terms of modelling the KER, as well as for analyzing the critical or dominant paths through an AOP network (e.g., identification of an AO that could kill an organism in a matter of hours will generally be of higher priority than other potential AOs that take weeks or months to develop). Identification of time-scale can also aid the assessment of temporal concordance. For example, for a KER that operates on a time-scale of days, measurement of both KEs after just hours of exposure in a short-term experiment could lead to incorrect conclusions regarding dose-response or temporal concordance if the time-scale of the upstream to downstream transition was not considered. 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 modulating factors
This sub-section presents information regarding modulating factors/variables known to alter the shape of the response-response function that describes the quantitative relationship between the two KEs (for example, an iodine deficient diet causes a significant increase in the slope of the relationship; a particular genotype doubles the sensitivity of KEdownstream to changes in KEupstream). Information on these known modulating factors should be listed in this subsection, along with relevant information regarding the manner in which the modulating factor can be expected to alter the relationship (if known). Note, this section should focus on those modulating factors for which solid evidence supported by relevant data and literature is available. It should NOT list all possible/plausible modulating factors. In this regard, it is useful to bear in mind that many risk assessments conducted through conventional apical guideline testing-based approaches generally consider few if any modulating factors. More help

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

Known Feedforward/Feedback loops influencing this KER
This subsection should define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits? In some cases where feedback processes are measurable and causally linked to the outcome, they should be represented as KEs. However, in most cases these features are expected to predominantly influence the shape of the response-response, time-course, behaviours between selected KEs. For example, if a feedback loop acts as compensatory mechanism that aims to restore homeostasis following initial perturbation of a KE, the feedback loop will directly shape the response-response relationship between the KERs. Given interest in formally identifying these positive or negative feedback, it is recommended that a graphical annotation (page 44) indicating a positive or negative feedback loop is involved in a particular upstream to downstream KE transition (KER) be added to the graphical representation, and that details be provided in this subsection of the KER description (see pages 44-45 of the User Handbook).  More help

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

Domain of Applicability

As for the KEs, there is also a free-text section of the KER description that the developer can use to explain his/her rationale for the structured terms selected with regard to taxonomic, life stage, or sex applicability, or provide a more generalizable or nuanced description of the applicability domain than may be feasible using standardized 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 using the appropriate format. Ideally, the list of references should conform, to the extent possible, with the OECD Style Guide (OECD, 2015). 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.