Latest Publications

@article{holme_lung_2023,

title = {Lung cancer associated with combustion particles and fine particulate matter (PM(2.5)) - The roles of polycyclic aromatic hydrocarbons (PAHs) and the aryl hydrocarbon receptor (AhR).},

author = {Jørn A. Holme and Jan Vondráček and Miroslav Machala and Dominique Lagadic-Gossmann and Christoph F. A. Vogel and Eric Le Ferrec and Lydie Sparfel and Johan Øvrevik},

doi = {10.1016/j.bcp.2023.115801},

issn = {1873-2968 0006-2952},

year  = {2023},

date = {2023-10-01},

journal = {Biochemical pharmacology},

volume = {216},

pages = {115801},

abstract = {Air pollution is the leading cause of lung cancer after tobacco smoking, contributing to 20% of all lung cancer deaths. Increased risk associated with living near trafficked roads, occupational exposure to diesel exhaust, indoor coal combustion and cigarette smoking, suggest that combustion components in ambient fine particulate matter (PM(2.5)), such as polycyclic aromatic hydrocarbons (PAHs), may be central drivers of lung cancer. Activation of the aryl hydrocarbon receptor (AhR) induces expression of xenobiotic-metabolizing enzymes (XMEs) and increase PAH metabolism, formation of reactive metabolites, oxidative stress, DNA damage and mutagenesis. Lung cancer tissues from smokers and workers exposed to high combustion PM levels contain mutagenic signatures derived from PAHs. However, recent findings suggest that ambient air PM(2.5) exposure primarily induces lung cancer development through tumor promotion of cells harboring naturally acquired oncogenic mutations, thus lacking typical PAH-induced mutations. On this background, we discuss the role of AhR and PAHs in lung cancer development caused by air pollution focusing on the tumor promoting properties including metabolism, immune system, cell proliferation and survival, tumor microenvironment, cell-to-cell communication, tumor growth and metastasis. We suggest that the dichotomy in lung cancer patterns observed between smoking and outdoor air PM(2.5) represent the two ends of a dose-response continuum of combustion PM exposure, where tumor promotion in the peripheral lung appears to be the driving factor at the relatively low-dose exposures from ambient air PM(2.5), whereas genotoxicity in the central airways becomes increasingly more important at the higher combustion PM levels encountered through smoking and occupational exposure.},

note = {Place: England},

keywords = {*Air Pollutants/toxicity, *Lung Neoplasms/chemically induced/genetics, *Polycyclic Aromatic Hydrocarbons/toxicity, Air pollution, Aryl Hydrocarbon/genetics, Carcinogenesis, Diesel exhaust, Environmental Monitoring, Genotoxicity, Humans, Inflammation, Occupational exposure, Particulate Matter/toxicity, Receptors, Smoking, Tumor metastasis, Tumor microenvironment, Tumor promotion},

pubstate = {published},

tppubtype = {article}

}

@article{vondracek_environmental_2020,

title = {Environmental six-ring polycyclic aromatic hydrocarbons are potent inducers of the AhR-dependent signaling in human cells.},

author = {Jan Vondráček and Kateřina Pěnčíková and Miroslav Ciganek and Jakub Pivnička and Martina Karasová and Martina Hýžďalová and Simona Strapáčová and Lenka Pálková and Jiří Neča and Jason Matthews and Michal Vojtíšek Lom and Jan Topinka and Alena Milcová and Miroslav Machala},

doi = {10.1016/j.envpol.2020.115125},

issn = {1873-6424 0269-7491},

year  = {2020},

date = {2020-11-01},

journal = {Environmental pollution (Barking, Essex : 1987)},

volume = {266},

number = {Pt 2},

pages = {115125},

abstract = {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.},

note = {Place: England},

keywords = {*Polycyclic Aromatic Hydrocarbons, *Receptors, AhR, Anti-estrogenicity, Aryl Hydrocarbon, Carcinogenic PAHs, Genotoxicity, Humans, Lung cell toxicity, Particulate Matter, Signal Transduction, Vehicle Emissions},

pubstate = {published},

tppubtype = {article}

}

@article{mccarrick_vitro_2019,

title = {In vitro and in vivo genotoxicity of oxygenated polycyclic aromatic hydrocarbons.},

author = {Sarah McCarrick and Virginia Cunha and Ondřej Zapletal and Jan Vondráček and Kristian Dreij},

doi = {10.1016/j.envpol.2018.12.092},

issn = {1873-6424 0269-7491},

year  = {2019},

date = {2019-03-01},

journal = {Environmental pollution (Barking, Essex : 1987)},

volume = {246},

pages = {678–687},

abstract = {Oxygenated polycyclic aromatic hydrocarbons (oxy-PAHs) are a group of environmental pollutants found in complex mixtures together with PAHs. In contrast to the extensively studied PAHs, which have been established to have mutagenic and carcinogenic properties, much less is known about the effects of oxy-PAHs. The present work aimed to investigate the genotoxic potency of a set of environmentally relevant oxy-PAHs along with environmental soil samples in human bronchial epithelial cells (HBEC). We found that all oxy-PAHs tested induced DNA strand breaks in a dose-dependent manner and some of the oxy-PAHs further induced micronuclei formation. Our results showed weak effects in response to the oxy-PAH containing subfraction of the soil sample. The genotoxic potency was confirmed in both HBEC and HepG2 cells following exposure to oxy-PAHs by an increased level of phospho-Chk1, a biomarker used to estimate the carcinogenic potency of PAHs in vitro. We further exposed zebrafish embryos to single oxy-PAHs or a binary mixture with PAH benzo[a]pyrene (B[a]P) and found the mixture to induce comparable or greater effects on the induction of DNA strand breaks compared to the sum of that induced by B[a]P and oxy-PAHs alone. In conclusion, oxy-PAHs were found to elicit genotoxic effects at similar or higher levels to that of B[a]P which indicates that oxy-PAHs may contribute significantly to the total carcinogenic potency of environmental PAH mixtures. This emphasizes further investigations of these compounds as well as the need to include oxy-PAHs in environmental monitoring programs in order to improve health risk assessment.},

note = {Place: England},

keywords = {*DNA Damage, Animals, Cell Culture Techniques, Cell Survival/drug effects/genetics, Comet assay, Embryonic Development/drug effects/genetics, Environmental Monitoring/*methods, Epithelial Cells/drug effects/pathology, Genotoxicity, Hep G2 Cells, Humans, Micronucleus assay, Mutagens/analysis/*toxicity, Oxygen/chemistry, Oxygenated PAH, Polycyclic Aromatic Hydrocarbons/analysis/*toxicity, Zebrafish, Zebrafish/embryology},

pubstate = {published},

tppubtype = {article}

}