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Benzo[a]pyrene-induced DNA damage associated with mutagenesis in primary human activated T lymphocytes

Abstract : Polycyclic aromatic hydrocarbons (PAHs), such as benzo[a]pyrene (B[a]P), are widely distributed environmental contaminants exerting toxic effects such as genotoxicity and carcinogenicity, mainly associated with aryl hydrocarbon receptor (AhR) activation and the subsequent induction of cytochromes P-450 (CYP) 1-metabolizing enzymes. We previously reported an up-regulation of AhR expression and activity in primary cultures of human T lymphocyte by a physiological activation. Despite the suggested link between exposure to PAHs and the risk of lymphoma, the potential of activated human T lymphocytes to metabolize AhR exogenous ligands such as B[a]P, and produce DNA damage has not been investigated. In the present study, we characterized the genotoxic response of primary activated T lymphocytes to B[a] P. We demonstrated that, following T lymphocyte activation, B[a]P treatment triggers a marked increase in CYP1 expression and activity generating, upon metabolic activation, DNA adducts and double-strand breaks (DSBs) after a 48-h treatment. At this time point, B[a]P also induces a DNA damage response with ataxia telangiectasia mutated kinase activation, thus producing a p53-dependent response and T lymphocyte survival. B[a]P activates DSB repair by mobilizing homologous recombination machinery but also induces gene mutations in activated human T lymphocytes which could consequently drive a cancer process. In conclusion, primary cultures of activated human T lymphocytes represent a good model for studying genotoxic effects of environmental contaminants such as PAHs, and predicting human health issues.
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Submitted on : Thursday, July 13, 2017 - 2:24:04 PM
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Marie Liamin, Elisa Boutet-Robinet, Emilien L. Jamin, Morgane Fernier, Laure Khoury, et al.. Benzo[a]pyrene-induced DNA damage associated with mutagenesis in primary human activated T lymphocytes. Biochemical Pharmacology, Elsevier, 2017, 137, pp.113-124. ⟨10.1016/j.bcp.2017.04.025⟩. ⟨hal-01560145⟩

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