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.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
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.
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.
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, 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.
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
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.