Influence of exposure dose, complex mixture, and ultraviolet radiation on skin absorption and bioactivation of polycyclic aromatic hydrocarbons ex vivo
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Combined exposure to complex mixtures of polycyclic aromatic hydrocarbons (PAHs) and ultraviolet radiation (UVR) is suspected to enhance PAH skin permeability and skin cancer risk depending on PAH bioactivation. The impact of PAH mixtures (exposure dose, composition, and complexity) and UVR was assessed for PAH cutaneous absorption and metabolism using realistic exposure conditions and human skin explants. PAH complex mixtures were extracted from the industrial products coal tar pitch (CTP-I) and petroleum coke (PC-I). The synthetic mixture (CTP-S) was identically reconstituted using PAH standards. The applied dose was adjusted to 1 (PC-I, CTP-I) or 10 nmol (CTP-I, CTP-S) of benzo[a]pyrene (B[a]P). Unmetabolized PAHs were recovered from the skin surface, skin and medium, and then quantified by HPLC-fluorescence detection. PAH metabolites were collected from the medium and analyzed by GC–MS/MS. B[a]P and PAH penetration was lower for the highest B[a]P dose, industrial mixtures, and CTP-I compared to PC-I. Skin irradiation increased PAH penetration only for CTP-I. PAH uptake was poorly influenced by the different experimental conditions. PAH metabolism markedly decreased in the application of mixtures, leading to unmetabolized PAH accumulation in human skin. PAH metabolism was similar between CTP-I and PC-I, but was lower for the highest dose and the industrial mixtures, suggesting a saturation of xenobiotic metabolizing enzymes, as confirmed in a time-course study. UVR strongly inhibited all PAH metabolism. Altogether, these results underline the necessity to consider the reality of human exposure (PAH complex mixtures and UVR) during in vitro experiments to properly estimate skin absorption and metabolism.
KeywordsPolycyclic aromatic hydrocarbons Mixtures Toxicological interactions Ultraviolet radiation Biotransformation Skin absorption
This work was funded by the French National Institute of Health and Medical Research (INSERM) (Grant number ENV201412) and the Agence Nationale de Sécurité Sanitaire, de l’alimentation, de l’environnement et du travail (ANSES) (Grant number EST-2014/1/176). The authors wish to thank the team of the “Service de Chirurgie Plastique et Maxillo-faciale CHU Grenoble Alpes” for skin sample collection.
This work was funded by the French National Institute of Health and Medical Research (INSERM) (Grant number ENV201412) and the Agence Nationale de Sécurité Sanitaire, de l’alimentation, de l’environnement et du travail (ANSES) (Grant number EST-2014/1/176). These funders had no role in study design, in the collection, analysis or interpretation of data, in the writing of the report, and in the decision to submit the article for publication.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
Experiments were conducted in accordance with the article L1245-2 of the French Public Health Code on the use of surgical wastes for research purposes. Collection, storage and use of human skin samples were made anonymously, declared to the French authorities and validated in the CODECOH DC-2008-444 document.
Informed consent was obtained from all skin donors.
The data sets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
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