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Understanding the Mechanism of Genotoxicity using a High Content Screening Approach

Genotoxicity is a leading cause of attrition in drug discovery and development and therefore it is important to understand liability early to avoid late stage failures. Existing preclinical genotoxicity assessment may not decipher the mechanism of genotoxicity and often require large amounts of test article.

Research presented during Eurotox 2017 in Bratislava, demonstrates a new high content imaging approach for identifying aneugens (compounds which cause an abnormal number of chromosomes) and clastogens (compounds which cause breaks in chromosomes and lead to sections of the chromosome being deleted, added or rearranged). The approach monitors the markers γH2AX and pH3 in HepG2 cells in the presence and absence of the metabolising system, S9, and can be used to screen larger numbers of compounds with reduced compound requirements.

γH2AX is phosphorylated in response to double strand DNA breaks and is a classical marker for DNA damage. Phospho-histone 3 (pH3) is upregulated in cells arrested in G2/M and is a marker of mitosis. Using these markers it is possible to distinguish between aneugens and clastogens, with aneugens exhibiting an increase in pH3 expression and either no effect or an increase in γH2AX, and clastogens exhibiting an increase in γH2AX only.

To learn more, download the poster

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