Upstream eventAltered, Meiotic chromosome dynamics
Altered, Chromosome number
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Chemical binding to tubulin in oocytes leading to aneuploid offspring||adjacent||Low|
Life Stage Applicability
Key Event Relationship Description
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
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.
There are insufficient empirical data examining the concordance between chromosome dynamics and generation of aneuploidy oocytes because very few studies have examined chromosome dynamics in these cells.
Two in vitro studies have investigated chromosome congression defects and aneuploidy in mouse oocytes. Using nocodazole and 2-methoxyestradiol these studies demonstrated that there is a temporal and dose-response related consistency among the events; i.e., downstream KEs are occurring at higher doses and later time points than upstream KEs [Shen et al., 2005; Eichenlaub-Ritter et al., 2007]. Specifically, exposure of mouse oocytes to increasing concentrations of 2-methoxyestradiol demonstrates: 1) abnormal spindle formation beginning at 3.75 uM (53% of cells), and increasing to 75% at 5 uM, and 100% by 7.5 uM; 2) hyperploidy occurring at 6%, 23% and 100% at 3.75, 5 and 7.5 uM, respectively; and 3) abnormal spindle forming as early as 9 hr, and aneuploidy arising by 16 hrs. Similarly, in Shen et al. (2005), mouse oocytes exposed to nocodazole showed abnormal chromosome alignment in 9%, 22% and 23% of oocytes, which is concordant with a 0%, 3% and 10% increase in hyperploid oocytes at 20nM, 30nM and 40nM, respectively. Moreover, alignment errors were measured at 13 hr, whereas aneuploidy was found at 16 hr. Both of these studies demonstrate that errors in chromosome alignment occur earlier and at higher rates than aneuploidy in eggs. A causal correlation between chromosome misalignment and generation of aneuploid oocytes has been reported after exposure to bisphenol A [Hunt et al., 2003].
Additional evidence is coming from some studies investigating the effects of protein deficiencies in mouse oocytes, and reporting a relationship between altered chromosome dynamics and aneuploidy [Mc Guinness et al., 2009; Ou et al., 2010; Baumann et al., 2017]. Targeting deletion of Bub1 in mouse oocytes leads to defective chromosome segregation and aneuploidy is monitored for the whole chromosome set by the multicoloured SKY FISH approach [Mc Guinness et al. 2009]. After depletion in mouse oocytes of the MTOC component p38a chromosome congression defects are 8 times more frequent than in controls, and under these conditions the incidence of aneuploid oocytes is about 8-fold higher [Ou et al., 2010]. In a study carried out using a oocyte conditional pericentrin knockout mouse model and live cell imaging, it has been demonstrated that unattached kinetochores, merotelic attachments, misaligned and uncongressed chromosomes are significantly increased and this is causing an increase of ploidy defects [Baumann et al., 2017]. Although based on genetic models, these data provide a direct evidence of the mechanisms involved in this KER.
Uncertainties and Inconsistencies
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.
Quantitative Understanding of the Linkage
There is a large amount of uncertainty surrounding the qualitative and quantitative association between these two endpoints.
Data are available on the dose-response relationship for aneuploidy induction in oocytes (KE4) 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 KE3, chromosome dynamics alterations at the first meiotic division. Thus, it is not possible to establish the shape of the response-response relationship between KE3 and KE4.
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 (KE4) would lag alterations of meiotic chromosome dynamics (KE3) by hours, although no studies have been carried out until now to specifically address the time-scale of events linking KE3 and KE4.
Known modulating factors
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
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 KE3 (altered chromosome dynamics) and altered chromosome number in the oocyte (KE4).
Domain of Applicability
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.
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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.
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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.
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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.