To the extent possible under law, AOP-Wiki has waived all copyright and related or neighboring rights to KER:738

Relationship: 738

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

Altered, Meiotic chromosome dynamics leads to Altered, Chromosome number

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 Low Cataia Ives (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

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

Chromosome dynamics refers to the ability of chromosomes to congress at the metaphase plate before segregation and attach in an amphitelic orientation [Mailhes and Marchetti, 2010]. Amphitelic refers to the proper attachment of homologous chromosomes to a bipolar spindle and their orientation to opposite poles. Each daughter cell is then expected to receive one chromosome (composed of two chromatids), resulting in a haploid state. Cells have the SAC that monitors chromosome dynamics and should prevent anaphase from occurring in the presence of misaligned chromosomes, however, especially in oocytes, the SAC is not always able to arrest meiotic progression in the presence of misaligned chromosomes.

In this KER, alterations in chromosome dynamics lead to incorrect congression and alignment. In addition, the SAC fails to prevent chromosome segregation, resulting in an aneuploid cell.

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

Weak.

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 weak. The mechanistic aspects of chromosome dynamics are well understood [Bennabi et al., 2016; Touati and Wassmann, 2016]. It is broadly understood that correct chromosome alignment is required for to produce an egg with the correct number of chromosomes and that the probability of an aneuploid egg is increased when chromosomes fail to align correctly. However, chromosome misalignment does not always lead to subsequent errors in chromosome segregation. This may be due in part to the important role of the SAC in blocking chromosome segregation when chromosomes are not correctly aligned [Amon, 1999; Musacchio and Salmon, 2007; Polanski, 2013; Musacchio, 2015]. At this time, there is not complete mechanistic understanding of every step in this process.

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

Although there are no inconsistent results reported, it is important to note that very few studies have measured chromosome dynamics and induction of aneuploidy in oocytes.

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

Data are available on the dose-response relationship for aneuploidy induction in oocytes (KEdownstream) treated with colchicine [Mailhes et al., 1988; Mailhes et al., 1990], vinblastine [Russo and Pacchierotti, 1988; Mailhes et al., 1993] or 2-methoxyestradiol [Eichenlaub-Ritter et al., 2007], which are consistent with the threshold relationship established in mitotic cells [Elhajouji et al., 2011]. Unfortunately, dose-effect relationships have not been established for chromosome dynamics alterations (KEupstream) at the first meiotic division. Thus, it is not possible to establish the shape of the response-response relationship between chromosome dynamics alteratiions (KEupstream) and altered chromosome nubmer in oocytes (KEdownstream).

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

As noted before, chromosome dynamics on the metaphase plate of oocytes may last a few hours before anaphase onset. The first meiotic anaphase lasts about 25 min equally distributed between anaphase-1, characterized by increased spindle length and movement of chromosomes towards the poles, and anaphase-2 at the end of which chromosomes reach the poles and aggregate into condensed clusters [Wei et al., 2018]. Thus, it is expected that alterations of chromosome number in the oocyte (KEdownstream) would lag alterations of meiotic chromosome dynamics (KEupstream) by hours, although no studies have been carried out until now to specifically address the time-scale of events linking chromosome dynamics alteratiions (KEupstream) and altered chromosome nubmer in oocytes (KEdownstream).

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 information about the shape of 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

In mitotic and meiotic cells, anaphase onset and ensuing chromosome distribution is under checkpoint control that may delay anaphase onset until chromosomes are correctly aligned on the spindle equator, as signaled by specific molecular events [Nagaoka et al., 2012; Musacchio et al., 2015; Webster and Schuh, 2017]. Although the SAC in mammalian oocytes is deemed to be more tolerant to the presence of unaligned chromosomes, its role in preventing aneuploidy is proven in genetically modified or silenced systems [Mailhes and Marchetti 2010]. These checkpoint and signaling mechanisms therefore are expected to act as feedback loops, which may influence the time-scale of the KER between KEupstream (altered chromosome dynamics) and altered chromosome number in the oocyte (KEdownstream).

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

Amon A. 1999. The spindle checkpoint. Curr Opin Genet Dev 9:69-75.

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.

Bennabi I, Terret ME, Verlhac MH. 2016. Meiotic spindle assembly and chromosome segregation in oocytes. J Cell Biol 215:611-619.

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.

Elhajouji A, Lukamowicz M, Cammerer Z, Kirsch-Volders M. 2011. Potential thresholds for genotoxic effects by micronucleus scoring. Mutagenesis 26:199-204.

Hunt PA, Koehler KE, Susiarjo M, Hodges CA, Ilagan A, Voigt RC, Thomas S, Thomas BF, Hassold TJ. 2003. Bisphenol a exposure causes meiotic aneuploidy in the female mouse. Curr Biol 13:546-553.

Mailhes JB, Preston RJ, Yuan ZP, Payne HS. 1988. Analysis of mouse metaphase II oocytes as an assay for chemically induced aneuploidy. Mutat Res 198:145–152.

Mailhes JB, Yuan ZP, Aardema MJ. 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, 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.

Mailhes JB, Marchetti F. 2010. Advances in understanding the genetic causes and mechanisms of female germ cell aneuploidy. Exp Rev Obst Gyn 5:687–706.

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.

Musacchio A. 2015. The molecular biology of spindle assembly checkpoint signaling dynamics. Curr Biol 25:R1002-R1018.

Musacchio A, Salmon ED. 2007. The spindle-assembly checkpoint in space and time. Nat Rev Mol Cell Biol 2007; 8:379-93.

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

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.

Polanski Z. 2013. Spindle assembly checkpoint regulation of chromosome segregation in mammalian oocytes. Reprod Fertil Dev 25:472-483.

Russo A, Pacchierotti F. 1988. Meiotic arrest and aneuploidy induced by vinblastine in mouse oocytes. Mutat Res 202:215–221.

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.

Touati SA, Wassmann K. 2016. How oocytes try to get it right: spindle checkpoint control in meiosis. Chromosoma 125:321-335.

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

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.