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Métabolisme cutané et biomarqueurs d'exposition aux mélanges complexes d'hydrocarbures aromatiques polycycliques

Abstract : Polycyclic aromatic hydrocarbons (PAH) are ubiquitous carcinogens emitted as complex mixtures whose composition depends on emission sources. Because of their abundance and genotoxicity, PAHs are classified as priority substances, to which people can be exposed via dermal absorption during occupational activities. Biomonitoring takes into account skin absorption as well as inhalation and allows the identification of hazardous exposure situations. To assess Benzo[a]pyrene (B[a]P) exposure, which is classified as carcinogenic to human, quantification of 3-hydroxybenzo[a]pyrene (3-OHB[a]P) and (±)trans-anti-B[a]P-tetrol (B[a]P-tetrol) was recently proposed. This PhD thesis aimed at studying the skin absorption and metabolism of B[a]P and PAH mixtures to improve the understanding of their genotoxicity and develop relevant biomarker for health risk assessment. The first part of this work consisted in developing a simple and realistic skin model from human skin explants. Further to the development of adequate extraction and analytical methods, cutaneous toxicokinetic and metabolism from low B[a]P doses were studied. B[a]P skin penetration and metabolism were inversely proportional to applied dose. Nevertheless, metabolic pathways are impacted differently. While 3-OHB[a]P production formed during detoxification was dose-dependent, the formation of B[a]P-tetrol, resulting from the hydrolysis of B[a]P ultimate carcinogenic metabolite, saturates rapidly. Therefore, B[a]P-tetrol is the most relevant biomarker for estimating B[a]P carcinogenic risk. In addition, unmetabolized B[a]P poorly diffused through skin indicating that B[a]P toxicity is mainly local. The second part of this work consisted of a literature review focusing on 7 other carcinogenic PAH biotransformation to identify 16 marketed metabolites of interest. In fine, GC-MS/MS analysis was developed for 10 previously identified metabolic intermediates that are either involved in bioactivation or detoxification pathways of 5 PAH. Urinary quantification of those new biomarkers should improve the biomonitoring of populations to carcinogenic PAH. Finally, we evaluated the impact of synthetic or industrial mixtures (coal tar pitch and petroleum coke extracts) composition at different doses on carcinogenic PAH skin absorption and metabolism combined or not with ultraviolet radiations (UVR). PAH penetration diminished when mixture complexity and dose increased. While UVR increased PAH penetration when industrial complex mixtures were applied, no effect was observed on pure B[a]P or synthetic mixtures. PAH bioactivation decreased with mixtures and UVR, inducing unmetabolized PAH accumulation in the skin which may delay the occurrence of genotoxic effects. Similarly to B[a]P, other carcinogenic PAH toxicity seems to be mainly local and depends on skin exposure scenario. This work underlines the importance of mixtures study owing to more complex chemical interactions than simple additive effects.
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Etienne Bourgart. Métabolisme cutané et biomarqueurs d'exposition aux mélanges complexes d'hydrocarbures aromatiques polycycliques. Médecine humaine et pathologie. Université Grenoble Alpes, 2019. Français. ⟨NNT : 2019GREAS026⟩. ⟨tel-02503982⟩



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