Detection and characterization of mechanisms of action of aneugenic chemicals

Introduction:
This text discusses the detection and characterization of mechanisms of action of aneugenic chemicals, which are chemicals that can cause numerical chromosome aberrations, leading to aneuploidy. aneuploidy is a significant cause of human reproductive failure and an important contributor to cancer. The text describes the use of the in vitro binucleate cell micronucleus assay to determine the ability of a chemical to induce chromosome damage, and the application of an anti-kinetochore antibody to micronuclei to classify their origin as either aneugenic or clastogenic. The text also explores the use of chromosome-specific centromere probes to analyze the segregation of chromosomes into the daughter nuclei of binucleate cells.

Key Points:

* aneuploidy is caused by chromosome loss or non-disjunction, and can be induced by chemical action on various cellular targets involved in cell division.
* The in vitro binucleate micronucleus assay is a powerful tool to determine the ability of a chemical to induce chromosome damage, and can classify micronuclei into kinetochore-positive and kinetochore-negative, indicating their origin by aneugenic or clastogenic mechanisms, respectively.
* The availability of chromosome-specific centromere probes allows the analysis of the segregation of chromosomes into the daughter nuclei of binucleate cells, enabling the quantitative relationships between the two major causes of aneuploidy, chromosome loss and non-disjunction, to be determined.
* The mechanisms leading to chromosome loss and non-disjunction can be investigated by analyzing morphological and structural changes in the cell division apparatus using specific stains and antibodies for various cell division components.
* The text demonstrates the interaction of the monomer bisphenol-a with the centrosome of the mitotic spindle and the folic acid antagonist pyrimethamine with the centromeres of chromosomes, both of which lead to the induction of aneuploidy in exposed cells.
* The text also implicates the products of the p53 and XPD genes in the regulation of the fidelity of chromosome segregation at mitosis.

Main Message:
The text highlights the importance of recognizing and controlling any increase in aneuploidy frequency due to chemical exposures. The in vitro binucleate cell micronucleus assay is a valuable tool in determining the ability of a chemical to induce chromosome damage and classifying the origin of micronuclei based on their kinetochore status. The use of chromosome-specific centromere probes enables the analysis of chromosome segregation into the daughter nuclei of binucleate cells, providing insights into the mechanisms leading to aneuploidy. The text also emphasizes the need for further research to fully understand the complex mechanisms underlying aneuploidy, which will aid in the development of effective strategies to mitigate the risks associated with chemical exposures.

Parry, E.M. “Detection and Characterization of Mechanisms of action of aneugenic Chemicals.” Mutagenesis 17, no. 6 (November 1, 2002): 509–21. https://doi.org/10.1093/mutage/17.6.509.