The toxicities of many environmental polycyclic aromatic hydrocarbons (PAHs), in particular those of high-molecular-weight PAHs (with MW higher than 300), remain poorly characterized. The objective of this study was to evaluate the ability of selected environmentally relevant PAHs with MW 302 (MW302 PAHs) to activate the aryl hydrocarbon receptor (AhR), since this represents a major toxic mode of action of PAHs. A large number of the evaluated compounds exhibited strong AhR-mediated activities, in particular in human models. The studied MW302 PAHs also significantly contributed to the overall calculated AhR activities of complex environmental mixtures, including both defined standard reference materials and collected diesel exhaust particles. The high AhR-mediated activities of representative MW302 PAHs, e.g. naphtho[1,2-k]fluoranthene, corresponded with the modulation of expression of relevant AhR target genes in a human lung cell model, or with the AhR-dependent suppression of cell cycle progression/proliferation in estrogen-sensitive cells. This was in a marked contrast with the limited genotoxicity of the same compound(s). Given the substantial levels of the AhR-activating MW302 PAHs in combustion particles, it seems important to continue to investigate the toxic modes of action of this large group of PAHs associated with airborne particulate matter.

Center for Sustainable Mobility Faculty of Mechanical Engineering Czech Technical University Prague Technická 4 160 00 Prague 6 Czech Republic

Department of Chemistry and Toxicology Veterinary Research Institute Hudcova 70 62100 Brno Czech Republic

Department of Cytokinetics Institute of Biophysics of the Czech Academy of Sciences Královopolská 135 61265 Brno Czech Republic

Department of Cytokinetics Institute of Biophysics of the Czech Academy of Sciences Královopolská 135 61265 Brno Czech Republic; Department of Chemistry and Toxicology Veterinary Research Institute Hudcova 70 62100 Brno Czech Republic

Department of Cytokinetics Institute of Biophysics of the Czech Academy of Sciences Královopolská 135 61265 Brno Czech Republic; Department of Experimental Biology Faculty of Science Masaryk University Kotlářská 2 61137 Brno Czech Republic

Department of Genetic Toxicology and Nanotoxicology Institute of Experimental Medicine of the Czech Academy of Sciences Vídeňská 1083 142 20 Prague Czech Republic

Department of Nutrition Institute of Basic Medical Sciences University of Oslo Sognsvannsveien 9 0372 Oslo Norway; Department of Pharmacology and Toxicology Faculty of Medicine University of Toronto 1 King's College Circle M5S 1A8 Toronto Canada

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