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{pencikova_vitro_2018,

title = {In vitro profiling of toxic effects of prominent environmental lower-chlorinated PCB congeners linked with endocrine disruption and tumor promotion.},

author = {Kateřina Pěnčíková and Lucie Svržková and Simona Strapáčová and Jiří Neča and Iveta Bartoňková and Zdeněk Dvořák and Martina Hýžďalová and Jakub Pivnička and Lenka Pálková and Hans-Joachim Lehmler and Xueshu Li and Jan Vondráček and Miroslav Machala},

doi = {10.1016/j.envpol.2018.02.067},

issn = {1873-6424 0269-7491},

year  = {2018},

date = {2018-06-01},

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

volume = {237},

pages = {473–486},

abstract = {The mechanisms contributing to toxic effects of airborne lower-chlorinated PCB congeners (LC-PCBs) remain poorly characterized. We evaluated in vitro toxicities of environmental LC-PCBs found in both indoor and outdoor air (PCB 4, 8, 11, 18, 28 and 31), and selected hydroxylated metabolites of PCB 8, 11 and 18, using reporter gene assays, as well as other functional cellular bioassays. We focused on processes linked with endocrine disruption, tumor promotion and/or regulation of transcription factors controlling metabolism of both endogenous compounds and xenobiotics. The tested LC-PCBs were found to be mostly efficient anti-androgenic (within nanomolar - micromolar range) and estrogenic (at micromolar concentrations) compounds, as well as inhibitors of gap junctional intercellular communication (GJIC) at micromolar concentrations. PCB 8, 28 and 31 were found to partially inhibit the aryl hydrocarbon receptor (AhR)-mediated activity. The tested LC-PCBs were also partial constitutive androstane receptor (CAR) and pregnane X receptor (PXR) agonists, with PCB 4, 8 and 18 being the most active compounds. They were inactive towards other nuclear receptors, such as vitamin D receptor, thyroid receptor α, glucocorticoid receptor or peroxisome proliferator-activated receptor γ. We found that only PCB 8 contributed to generation of oxidative stress, while all tested LC-PCBs induced arachidonic acid release (albeit without further modulations of arachidonic acid metabolism) in human lung epithelial cells. Importantly, estrogenic effects of hydroxylated (OH-PCB) metabolites of LC-PCBs (4-OH-PCB 8, 4-OH-PCB 11 and 4'-OH-PCB 18) were higher than those of the parent PCBs, while their other toxic effects were only slightly altered or suppressed. This suggested that metabolism may alter toxicity profiles of LC-PCBs in a receptor-specific manner. In summary, anti-androgenic and estrogenic activities, acute inhibition of GJIC and suppression of the AhR-mediated activity were found to be the most relevant modes of action of airborne LC-PCBs, although they partially affected also additional cellular targets.},

note = {Place: England},

keywords = {Air Pollutants/*toxicity, Airborne polychlorinated biphenyls, Cell Line, Constitutive Androstane Receptor, Cytoplasmic and Nuclear/metabolism, Endocrine disruption, Endocrine Disruptors/metabolism/*toxicity, Epithelial Cells/drug effects, Humans, HydroxyLated PCBs, Hydroxylation, Metabolism of xenobiotics, Neoplasms/metabolism, Polychlorinated Biphenyls/metabolism/*toxicity, Pregnane X receptor, Receptors, Signal Transduction/drug effects, Steroid/metabolism, Tumor promotion},

pubstate = {published},

tppubtype = {article}

}