Solar simulated light exposure alters metabolization and genotoxicity induced by benzo[a]pyrene in human skin

Anne Von Koschembahr,Etienne Bourgart,Thierry Douki,Clément Calissi,Jean-Philippe Giot,Anne Maitre,David Béal,Marie-Thérèse Leccia,Marie Marques,Antonia Youssef

doi:10.1038/s41598-018-33031-8

Abstract

Skin is a major barrier against external insults and is exposed to combinations of chemical and/or physical toxic agents. Co-exposure to the carcinogenic benzo[a]pyrene (B[a]P) and solar UV radiation is highly relevant in human health, especially in occupational safety. In vitro studies have suggested that UVB enhances B[a]P genotoxicity by activating the AhR pathway and overexpressing the cytochrome P450 enzymes responsible for the conversion of B[a]P into DNA damaging metabolites. Our present work involved more realistic conditions, namely ex vivo human skin explants and simulated sunlight (SSL) as a UV source. We found that topically applied B[a]P strongly induced expression of cutaneous cytochrome P450 genes and formation of DNA adducts. However, gene induction was significantly reduced when B[a]P was combined with SSL. Consequently, formation of BPDE-adducts was also reduced when B[a]P was associated with SSL. Similar results were obtained with primary cultures of human keratinocytes. These results indicate that UV significantly impairs B[a]P metabolism, and decreases rather than increases immediate toxicity. However, it cannot be ruled out that decreased metabolism leads to accumulation of B[a]P and delayed genotoxicity.

Highlights

Skin is the outer barrier of the body and plays a major defensive role against chemical and physical genotoxic agents
Genotoxicity was established through the quantification of BPDE-N2-dGuo, the most frequent BDPE-DNA adduct
In order to provide valuable data on this subject, we performed a series of ex vivo and in vitro experiments aimed at determining whether exposure to solar UV radiation modulates the metabolization of B[a] P and the formation of BPDE-N2-dGuo after B[a]P treatment

Summary

Introduction

Skin is the outer barrier of the body and plays a major defensive role against chemical and physical genotoxic agents. Metabolization via phase I enzymes, mainly cytochrome P450 (CYP) oxygenases, convert PAH into reactive metabolite intermediaries[10]. These metabolites undergo conjugation by phase II enzymes, like glutathione-S-transferases (GST) and UDP-glucuronosyltransferases (UGT), to yield eliminated water-soluble compounds. PAH can be converted into photoproducts more toxic than their parental compounds[28,29] or induce a photosensitized oxidative stress, as demonstrated in vitro[30,31,32,33]. A less studied mechanism is how UV may modulate the formation of PAH-DNA adducts. In vitro experiments have shown that UVB induced the expression of CYP1A1 and favored the formation of DNA adducts upon subsequent exposure to B[a]P35. We report on how SSL modulates metabolization of B[a]P and adduct formation, whether SSL irradiations were performed before or after B[a]P treatment

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Results

Conclusion