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Event: 752

Key Event Title

The KE title should describe a discrete biological change that can be measured. It should generally define the biological object or process being measured and whether it is increased, decreased, or otherwise definably altered relative to a control state. For example “enzyme activity, decreased”, “hormone concentration, increased”, or “growth rate, decreased”, where the specific enzyme or hormone being measured is defined. More help

Altered, Meiotic chromosome dynamics

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. The short name should be less than 80 characters in length. More help
Altered, Meiotic chromosome dynamics

Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. Note, KEs should be defined within a particular level of biological organization. Only KERs should be used to transition from one level of organization to another. Selection of the level of biological organization defines which structured terms will be available to select when defining the Event Components (below). More help
Level of Biological Organization

Cell term

Further information on Event Components and Biological Context may be viewed on the attached pdf.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable. More help
Cell term
eukaryotic cell

Organ term

Further information on Event Components and Biological Context may be viewed on the attached pdf.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable. More help

Key Event Components

Further information on Event Components and Biological Context may be viewed on the attached pdf.Because one of the aims of the AOP-KB is to facilitate de facto construction of AOP networks through the use of shared KE and KER elements, authors are also asked to define their KEs using a set of structured ontology terms (Event Components). In the absence of structured terms, the same KE can readily be defined using a number of synonymous titles (read by a computer as character strings). In order to make these synonymous KEs more machine-readable, KEs should also be defined by one or more “event components” consisting of a biological process, object, and action with each term originating from one of 22 biological ontologies (Ives, et al., 2017; See List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signalling by that receptor).Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. More help
Process Object Action
chromosome movement towards spindle pole chromosome abnormal

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE. Clicking on the name of the AOP will bring you to the individual page for that AOP. More help
AOP Name Role of event in AOP Point of Contact Author Status OECD Status
Tubulin binding and aneuploidy KeyEvent Francesco Marchetti (send email) Open for citation & comment EAGMST Under Review
Deposition of ionizing energy leads to population decline via impaired meiosis KeyEvent Erica Maremonti (send email) Under development: Not open for comment. Do not cite
Deposition of ionising energy leads to population decline via pollen abnormal KeyEvent Li Xie (send email) Under development: Not open for comment. Do not cite


This is a structured field used to identify specific agents (generally chemicals) that can trigger the KE. Stressors identified in this field will be linked to the KE in a machine-readable manner, such that, for example, a stressor search would identify this as an event the stressor can trigger. NOTE: intermediate or downstream KEs in one AOP may function as MIEs in other AOPs, meaning that stressor information may be added to the KE description, even if it is a downstream KE in the pathway currently under development.Information concerning the stressors that may trigger an MIE can be defined using a combination of structured and unstructured (free-text) fields. For example, structured fields may be used to indicate specific chemicals for which there is evidence of an interaction relevant to this MIE. By linking the KE description to a structured chemical name, it will be increasingly possible to link the MIE to other sources of chemical data and information, enhancing searchability and inter-operability among different data-sources and knowledgebases. The free-text section “Evidence for perturbation of this MIE by stressor” can be used both to identify the supporting evidence for specific stressors triggering the MIE as well as to define broad chemical categories or other properties that classify the stressors able to trigger the MIE for which specific structured terms may not exist. More help

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected from an ontology. In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help
Term Scientific Term Evidence Link
mouse Mus musculus Moderate NCBI

Life Stages

The structured ontology terms for life-stage are more comprehensive than those for taxa, but may still require further description/development and explanation in the free text section. More help
Life stage Evidence
All life stages Moderate

Sex Applicability

The authors must select from one of the following: Male, female, mixed, asexual, third gender, hermaphrodite, or unspecific. More help
Term Evidence
Mixed Moderate

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. For example, the biological state being measured could be the activity of an enzyme, the expression of a gene or abundance of an mRNA transcript, the concentration of a hormone or protein, neuronal activity, heart rate, etc. The biological compartment may be a particular cell type, tissue, organ, fluid (e.g., plasma, cerebrospinal fluid), etc. The role in the biology could describe the reaction that an enzyme catalyses and the role of that reaction within a given metabolic pathway; the protein that a gene or mRNA transcript codes for and the function of that protein; the function of a hormone in a given target tissue, physiological function of an organ, etc. Careful attention should be taken to avoid reference to other KEs, KERs or AOPs. Only describe this KE as a single isolated measurable event/state. This will ensure that the KE is modular and can be used by other AOPs, thereby facilitating construction of AOP networks. More help

The majority of work for this key event has been conducted in mouse oocytes in vitro. The key event is altered chromosome dynamics at metaphase/anaphase transition. Normal chromosome dynamics refers to the proper alignment and separation of the chromosomes at metaphase and anaphase, respectively. Altered chromosome dynamics refers to the incorrect separation of chromosomes involving an abnormal spindle and a defective cell cycle checkpoint [reviewed in Marchetti et al., 2016].

In oocytes, the meiotic cell division is characterized by unique features with respect to the mitotic process, including: (1) the process by which the meiotic spindle is formed; (2) chromosome organization in bivalents (homologous pairs) with sister kinetochores acting as a functional unit; (3) the role of homologous recombination to ensure proper biorientation and stability of the bivalent structure; (4) the direct entry of oocytes into the second meiotic division, following the first anaphase; and, (5) the lack of chromatin decondensation and formation of the nuclear membrane.

How It Is Measured or Detected

One of the primary considerations in evaluating AOPs is the relevance and reliability of the methods with which the KEs can be measured. The aim of this section of the KE description is not to provide detailed protocols, but rather to capture, in a sentence or two, per method, the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements. Methods that can be used to detect or measure the biological state represented in the KE should be briefly described and/or cited. These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA).Key considerations regarding scientific confidence in the measurement approach include whether the assay is fit for purpose, whether it provides a direct or indirect measure of the biological state in question, whether it is repeatable and reproducible, and the extent to which it is accepted in the scientific and/or regulatory community. Information can be obtained from the OECD Test Guidelines website and the EURL ECVAM Database Service on Alternative Methods to Animal Experimentation (DB-ALM). ?

Altered chromosome dynamics at metaphase/anaphase is generally assessed by confocal microscopy or enhanced polarizing microscopy on fixed or live cells [Schatten et al., 1985; Shen et al., 2005; Eichenlaub-Ritter et al., 2007; Schuh and Ellenberg, 2007]. Antibodies against centromeric proteins and multicolour fluorescence in situ hybridization (FISH) are useful approaches to follow chromosome congression: for example, distances between kinetochores and spindle midzone are used to evaluate the dynamics of chromosome congression; interkinetochore distances may be measured to verify a correct biorientation [Shen et al. 2005; Eichenlaub-Ritter et al., 2007; Schuh and Ellenberg, 2007; McGuinness et al., 2009; Lane et al., 2012; Mogessie and Schuh, 2017]. A quantitative description of microtubule dynamics and chromosome movement has also been obtained by time-lapse movies of mitotic cells expressing green fluorescence protein (GFP)-conjugate-tubulin [He and Cimini, 2016; Silkworth et al., 2012].

Domain of Applicability

This free text section should be used to elaborate on the scientific basis for the indicated domains of applicability and the WoE calls (if provided). While structured terms may be selected to define the taxonomic, life stage and sex applicability (see structured applicability terms, above) of the KE, the structured terms may not adequately reflect or capture the overall biological applicability domain (particularly with regard to taxa). Likewise, the structured terms do not provide an explanation or rationale for the selection. The free-text section on evidence for taxonomic, life stage, and sex applicability can be used to elaborate on why the specific structured terms were selected, and provide supporting references and background information.  More help

Studies are available reporting defects of chromosome congression after in vitro exposure of mouse oocytes to spindle poisons [Shen et al., 2005; Eichenlaub-Ritter et al., 2007, Hu et al., 2018]. These studies showed that even exposure to low doses of spindle poisons, such as nocodazole, induced significant spindle abnormalities that manifested as loss of spindle organization, reduced spindle length at both meiosis I and II and congressional failure among other [Shen et al., 2005; Eichenlaub-Ritter et al., 2007]. Studies on altered chromosome dynamics in human oocytes are scarce. Long-term confocal imaging of chromosome dynamics in 50 human oocytes, collected from women undergoing intracytoplasmic sperm injection showed tri-directional anaphase and other types of chromosomal misalignment in many of them [Haverfield et al., 2017].

Evidence for Perturbation by Stressor


After in vitro exposure, bipolar spindle formation and chromosome alignment at the metaphase plate are severely disturbed in oocytes. Six hr later, the percentage of aneuploid oocytes is significantly increased about the control level (Eichenlaub-RItter et al 2007).


All tested concentrations induce spindle abnormalities in vitro. The lowest effective concentration for chromosome congression defects is 40 nM. The dose-response relationship are congruent with the proposed AOP (Shen et al 2005)


List of the literature that was cited for this KE description. Ideally, the list of references, should conform, to the extent possible, with the OECD Style Guide ( (OECD, 2015). More help

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.

Haverfield J, Dean NL, Noel D, Remillard-Labrosse G, Paradis V, Kadoch IJ, FitzHarris G. 2017. Tri-directional anaphases as a novel chromosome segregation defect in human oocytes. Hum Reprod 32:1293-1303.

He B, Cimini D. 2016. Using photoactivable GFP to study microtubule dynamics and chromosome segregation. Methods Mol Biol 1413:15-31.

Hu L-L, Zhou X, Zhang H-L, Wu L-L, Tang L-S, Chen L-L, Duan JL. 2018. Exposure to podophyllotoxin inhibits oocyte meiosis by disturbing meiotic spindle formation. Sci Report 8:10145.

Lane SI, Yun Y, Jones KT. 2012. Timing of anaphase-promoting complex activation in mouse oocytes is predicted by microtubule-kinetochore attachment but not by bivalent alignment or tension. Development 139:1947-1955.

Marchetti F, Massarotti A, Yauk CL, Pacchierotti F, Russo A. 2016. The adverse outcome pathway (AOP) for chemical binding to tubulin in oocytes leading to aneuploid offspring. Environ Mol Mutagen 57:87-113.

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.

Mogessie B, Schuh M. 2017. Actin protects mammalian eggs against chromosome segregation errors. Science 357, eaal1647.

Schuh M, Ellenberg J. 2007. Self-organization of MTOCs replaces centrosome function during acentrosomal spindle assembly in live mouse oocytes. Cell 130:484-498.

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, Nardi IK, Paul R, Mogilner A, Cimini D (2012) Timing of centrosome separation is important for accurate chromosome segregation. Mol Cell Biol 23:401-411.