Defining a genotoxic profile with mouse embryonic stem cells

Abstract

Many genotoxins are found in the environment from synthetic to natural, yet very few have been studied in depth. This means we fail to understand many molecules that damage DNA, we do not understand the type of damage they cause and the repair pathways required to correct their lesions. It is surprising so little is known about the vast majority of genotoxins since they have potential to cause disease from developmental defects to cancer to degenerative ailments. By contrast, some of these molecules have commercial and medical potential and some can be weaponized. Therefore, we need a systematic method to efficiently generate a genotoxic profile for these agents. A genotoxic profile would include the type of damage the genotoxin causes, the pathways used to repair the damage and the resultant mutations if repair fails. Mouse embryonic stem (ES) cells are well suited for identifying pathways and mutations. Mouse ES cells are genetically tractable and many DNA repair mutant cells are available. ES cells have a high mitotic index and form colonies so experiments can be completed quickly and easily. Furthermore, ES cells have robust DNA repair pathways to minimize genetic mutations at a particularly vulnerable time in life, early development when a mutation in a single cell could ultimately contribute to a large fraction of the individual. After an initial screen, other types of cells and mouse models can be used to complement the analysis. This review discusses the merging field of genotoxic screens in mouse ES cells that can be used to discover and study potential genotoxic activity for chemicals commonly found in our environment.