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Carine George

Development of an in vitro test for measuring DNA repair activities to identify biomarkers of exposure to genotoxic environmental agents in human cells

Published on 20 October 2017


Thesis presented December 20, 2017

Abstract:
Humans are constantly exposed to environmental genotoxic agents. These agents can induce different types of DNA damage, which have been associated with an increased risk of developing cancer. In order to maintain genomic integrity, cells have multiple DNA repair mechanisms that help protect their DNA from injury. Investigation of the impact of these exogenous genotoxic agents on individuals leads to the emergence of a new field, biomonitoring. This field allows researchers to evaluate individual exposure to genotoxic agents based on the detection of biological markers of exposure. However, up to now, the major limitations in this area are the lack of relevant biomarkers, as well as the availability of methods to detect them. In order to define new biomarkers, two cell lines were exposed to two well-known carcinogenic compounds, benzo[a]pyrene and vinyl chloride, as well as their toxic metabolites, in order to determine the consequences of these exposures. Two methods were used: DNA lesions were quantified by HPLC-MS/MS and DNA repair activities were evaluated using a microarray assay developed by the start-up company, LXRepair. This approach allowed us to gain a global understanding related to the exposure of these compounds by considering different parameters, such as the specificity of different cellular responses to a given genotoxic agent and the minimum concentration needed to observe an effect with respect to its toxicity. This study underlines the complexity to obtain specific cellular responses to a given genotoxic agent. However, DNA repair signatures bring on the intricacy of the regulations of DNA repair mechanisms and open up new research avenues.

Keywords:
DNA damage, Biomonitoring, Biomarker, Genotoxicity, DNA repair, Microarray

On-line thesis.