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Event: 752

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Altered, Meiotic chromosome dynamics

Short name

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Biological Context

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Level of Biological Organization
Cellular

Cell term

The location/biological environment in which the event takes place.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. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Cell term
eukaryotic cell

Organ term

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling). 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 signaling 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. Further information on Event Components and Biological Context may be viewed on the attached pdf. 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	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

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 KE.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

An indication of the the relevant life stage(s) for this KE. More help

Life stage	Evidence
All life stages	Moderate

Sex Applicability

An indication of the the relevant sex for this KE. 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. 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

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.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). Do not provide detailed protocols. More help

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

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided). 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].

References

List of the literature that was cited for this KE description. 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.