Upstream eventAltered, Meiotic chromosome dynamics
Altered, Chromosome number
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Directness||Weight of Evidence||Quantitative Understanding|
|Chemical binding to tubulin in oocytes leading to aneuploid offspring||directly leads to||Weak|
Life Stage Applicability
How Does This Key Event Relationship Work
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 a spindle assembly checkpoint that monitors chromosome dynamics and should prevent anaphase from occurring in the presence of misaligned chromosomes.
In this KER, alterations in chromosome dynamics lead to incorrect congression and alignment. In addition, the spindle assembly checkpoint fails to prevent chromosome segregation, resulting in an aneuploid cell.
Weight of Evidence
The mechanistic aspects of chromosome dynamics are well understood ADD REFERENCE. It is broadly understood that correct chromosome alignment is required for to produce an egg with the correct number of chromosomes. 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 spindle assembly checkpoint in blocking chromosome segregation when chromosome are not correctly aligned. At this time, there is not complete mechanistic understanding of every step in this process. ADD REFENCES on SAC.
Empirical Support for Linkage
There are insufficient empirical data examining the concordance between chromosome dynamics and generation of aneuploidy oocytes because very few studies have examined chromosome dynamics.
Two in vitro studies have investigated chromosome congression defects and aneuploidy in mouse oocytes. Using used 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.
Uncertainties or Inconsistencies
There are no inconsistencies to our knowledge, but the database supporting this KER is limited.
Quantitative Understanding of the Linkage
Evidence Supporting Taxonomic Applicability
All of the evidence for this KER is in the mouse. However, the biology underlying these processes are very similar across mammalian species.