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Metabolism and genotoxicity of polycyclic aromatic hydrocarbons in human skin explants: mixture effects and modulation by sunlight

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Abstract

Cutaneous exposure to carcinogenic polycyclic aromatic hydrocarbons (PAH) occurs frequently in the industrialized workplace. In the present study, we addressed this topic in a series of experiments using human skin explants and organic extracts of relevant industrial products. PAH mixtures were applied topically in volumes containing either 10 or 1 nmol B[a]P. We first observed that although mixtures were very efficient at inducing expression of CYP450 1A1, 1A2, and 1B1, formation of adducts of PAH metabolites to DNA, like those of benzo[a]pyrene diol epoxide (BPDE), was drastically reduced as the complexity of the surrounding matrix increased. Interestingly, observation of a nonlinear, dose-dependent response with the least complex mixture suggested the existence of a threshold for this inhibitory effect. We then investigated the impact of simulated sunlight (SSL) on the effects of PAH in skin. SSL was found to decrease the expression of CYP450 genes when applied either after or more efficiently before PAH treatment. Accordingly, the level of DNA-BPDE adducts was reduced in skin samples exposed to both PAH and SSL. The main conclusion of our work is that both increasing chemical complexity of the mixtures and co-exposure to UV radiation decreased the production of adducts between DNA and PAH metabolites. Such results must be taken into account in risk management.

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Acknowledgements

The authors wish to thank the team of the “Service de Chirurgie Plastique et Maxillo-faciale CHU Grenoble Alpes” for their help in skin sample collection. This work was supported by grants #ENV201411 and #ENV201604 from INSERM and Plan Cancer.

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  1. Univ. Grenoble Alpes, UGA, CEA, CNRS, IRIG, SyMMES, 38000, Grenoble, France

    Anne von Koschembahr, Antonia Youssef, David Béal & Thierry Douki

  2. Equipe EPSP Environnement et Prédiction de la Santé des Populations-laboratoire TIMC-IMAG (UMR 5525 UGA-CNRS), Université Grenoble Alpes, Faculté de Médecine, La Tronche, France

    Etienne Bourgart, Alex Rivier, Marie Marques & Anne Maitre

  3. Service de Dermatologie, Allergologie et Photobiologie, Centre Hospitalier Universitaire Grenoble Alpes, La Tronche, France

    Marie-Thérèse Leccia

  4. Service de Chirurgie Plastique et Maxillo-Faciale, Centre Hospitalier Universitaire Grenoble Alpes, La Tronche, France

    Jean-Philippe Giot

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  1. Anne von Koschembahr
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von Koschembahr, A., Youssef, A., Béal, D. et al. Metabolism and genotoxicity of polycyclic aromatic hydrocarbons in human skin explants: mixture effects and modulation by sunlight. Arch Toxicol 94, 495–507 (2020). https://doi.org/10.1007/s00204-019-02650-z

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