Oxy-PAHs: occurrence in the environment and potential genotoxic/mutagenic risk assessment for human health.

Structurally modified polycyclic aromatic hydrocarbons (PAHs) such as nitrated PAHs (nitro-PAHs) and oxygenated PAHs (oxy-PAHs) can be incriminated in the total toxicity of polycyclic aromatic compounds (PACs) fraction in the environment. Compared to nitro-PAHs, oxy-PAHs have been poorly studied. Oxy-PAHs covers compounds with different moieties such as polycyclic aromatic ketones (PAKs) and polycyclic aromatic quinones (PAQs). In this review, we have compiled exhaustively all the data available on the sources, the fate, and the occurrence of oxy-PAHs focusing on the most ubiquitous ones in the environment, ie PAKs and PAQs. Data concerning their genotoxicity, mutagenicity and tumor promotion potential for humans are also provided based on the mode-of-action analysis framework. Mutagenicity results based on the limited number of oxy-PAHs tested, are unequivocal on the concern they represent. Their omission in mutagenic/carcinogenic risk has caused a dramatic underestimation of cancer risk. On the basis of environmental and genotoxicological data, we suggest prioritized 4 major oxy-PAHs molecules in ecotoxicological and toxicological studies, namely 6 H-benzo[cd]pyren-6-one (BPO), 7,12-benz[a]anthracenequinone (BAQ), 5,12-naphthacenequinone (NCQ) and 11 H-benzo[b]fluoren-11-one (B[b]FO). We also propose to develop biomarkers of exposure and/or risk for these compounds, for example by quantification of DNA adducts.

In vitro genotoxicity potential investigation of 7 oxy-PAHs.

Air pollutants include many compounds among them oxygenated polycyclic aromatic hydrocarbons (oxy-PAHs). As they are suspected to generate DNA damage and mutagenicity, an understanding of their mode of action could highlight a carcinogenic potential risk in exposed population. In this article, a prospective study on seven oxy-PAHs selected in terms of occurrence in the environment was conducted on mutagenicity, genotoxicity, and cytotoxicity potentials using in vitro assays including Ames test on five strains, kinetic analysis of cytotoxicity and apoptosis, phosphorylation of histone H2AX, and p53 induction assays on human lung cell line BEAS-2B. Ames test demonstrated that mutagenicity pattern depended on the oxy-PAH tested. Except for BAQ, all oxy-PAHs tested gave mutagenic effect, in the absence and/or in the presence of metabolic activation (S9 fraction). At 24 h of exposure, the majority of oxy-PAHs induced γ-H2AX in BEAS-2B cells and/or phosphorylation of p53 at serine 15 and cell death at highest tested concentrations. Although 9,10-AQ and B[b]FO were mutagenic in bacteria, they failed to induce any of the other genotoxicity biomarkers. In comparison with the benzo[a]pyrene, all oxy-PAHs were less potent in terms of genotoxic potential at the same concentration. These results highlighted the genotoxic and mutagenic potential of these oxy-PAHs and provide preliminary information concerning their possible mechanism of action for toxicity, contributing to a better evaluation of the real associated health risks for human and environment.

Investigation by mass spectrometry and 32P post-labelling of DNA adducts formation from 1,2-naphthoquinone, an oxydated metabolite of naphthalene.

Naphthalene is the simplest representative of polycyclic aromatic hydrocarbons (PAHs). It is detected as major pollutant in the different compartments of the environment. This compound is considered by the international agency for research on cancer (IARC), the specialized cancer agency of the World Health Organisation (WHO), as a possible carcinogenic (group 2B) since 2002, mainly based on studies on chronic inhalation in rodent by the national toxicology program of the U.S. department of health and human services. In humans, its main metabolites correspond to derivatives substituted in position and 1 and 2 as 1,2-naphthoquinone (1,2-NphQ). Based on previous studies, 1,2-NphQ is supposed to react with DNA to form mostly depurinating adducts, a possible initiating step of carcinogenicity. To confirm this potentiality, adducts were synthetized by the reaction of 1,2-NphQ with 2'-deoxyguanosine (2'-dG) in N,N-dimethylformamide (DMF), water and calf thymus DNA. 2'-dG adducts were analyzed by 32P post-labelling, HPLC with ultra-violet detection and ultra-performance liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS). We found stable DNA adducts detected in DNA. We proposed a formation mechanism by a 1,4-Michael addition with 2'-dG. Adducts with 2'-deoxyxanthosine are formed after a spontaneous deamination of 2'-dG. These adducts are good candidates as biomarkers allowing evaluation of exposure to naphthalene and its derivatives in the development of pathologies such as cancer.