Synthesis and characterization by UHPLC-MS/MS of DNA adducts from 4 oxy-PAHs for the evaluation of their genotoxicity
Résumé
The exposome can be defined as the association of all the exposure to which one is subjected during his entire life. It was developed with the aim to understand the etiology of chronic diseases such as cancer. However, the evaluation of the genotoxicity of some compounds is impacted by the lack of appropriate biomarkers such as DNA adducts1. These latter are considered as particularly relevant because they are specific of the structure of the genotoxic compound. Polycyclic Aromatic Hydrocarbons (PAHs) have been widely studied because of their persistence, potential of bioaccumulation, and toxic effects in the environment. Toxicities depends of the targeted compounds, considered alone or more rarely as mixtures. Our research is focused on genotoxicity studies which encompass alteration of DNA in connection with cancer risk.
Generally, studies about toxicity are realized according to the US-EPA priority PAHs. It has been demonstrated that PAHs derivatives such as oxygenated-PAHs (oxy-PAHs) and nitrated-PAHs were responsible of a large part of the PAHs toxicity. This work focuses on oxy-PAHs because, although they are ubiquitous compounds in the environment, they remain still largely under studied in terms of toxicity2,3.
In this study, a panel of 4 oxy-PAHs (1,2-naphthoquinone, 7,12-benzo[a]anthracenequinone, 6H-benzo[cd]pyrene-6-one, and 9,10-anthraquinone) has been selected and their adducts to 2’-deoxy-guanosine have been synthesized and their possible structures are proposed. Calf thymus DNA was also exposed to these compounds.
For the first time, the spontaneous and direct interaction between DNA base and these oxy-PAHs was highlighted. These adducts have been detected in 32P post-labelling from cell cultured DNA for most of them. A genotoxicity study with the aim to characterize the structure of the adducts has been realized. In addition, mutagenicity assays were realized by the Ame’s test and demonstrate that some of these oxy-PAHs possess mutagenic properties.