Upstream eventDisorganization, Spindle
Altered, Meiotic chromosome dynamics
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||Moderate|
Life Stage Applicability
Key Event Relationship Description
Incorrect spindle organization refers to lack of the bipolar organization of the spindle within the cell. This bipolar organization is required to assure that chromosomes will align correctly to the metaphase plate prior to equal division between the daughter cells. Alternatively, incorrect spindle formation can lead to shorter spindle fibers and/or incorrect length of these fibers, which leads to chromosome misalignment.
In this KER chemicals that cause spindle disorganization lead to altered meiotic chromosome dynamics. The relationship between spindle disorganization and altered chromosome dynamics can occur in both somatic and in germ cells; however, this relationship focusses on female meiotic chromosomes because of the differences in how the meiotic chromosome is assembled in oocytes with respect to other cell types (i.e., lack of centrioles and dependency on microtubule organizing centers).
Evidence Supporting this KER
Moderate, based on strong biological plausibility and weak emprical evidence.
It is well understood that the proper organization of the meiotic spindle is necessary in order for chromosomes to correctly align. This process has been extensively described in the literature. For a recent comprehensive review on this topic, please see Bennabi et al. (2016).
Although it is very common to measure spindle abnormalities (i.e., spindle disorganization), few studies have examined meiotic chromosome dynamics. Thus, there are insufficient empirical data examining the concordance between spindle abnormalities and chromosome dynamics.
However, two in vitro studies on mouse eggs have investigated spindle abnormalities and chromosome congression defects within individual studies (i.e., both endpoints measured). These studies used nocodazole and 2-methoxyestradio to demonstrate 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].
Uncertainties and Inconsistencies
Although there are no inconsistent results reported, it is important to note that very few studies have measured chromosome dynamics in oocytes in general. Thus, there is a large amount of uncertainty surrounding the qualitative and quantitative association between these two endpoints.
Quantitative Understanding of the Linkage
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 similar across mammalian species.