INTRODUCTION: Studies have correlated living close to major roads with Alzheimer's disease (AD) risk. However, the mechanisms responsible for this link remain unclear. METHODS: We exposed olfactory mucosa (OM) cells of healthy individuals and AD patients to diesel emissions (DE). Cytotoxicity of exposure was assessed, mRNA, miRNA expression, and DNA methylation analyses were performed. The discovered altered pathways were validated using data from the human population-based Rotterdam Study. RESULTS: DE exposure resulted in an almost four-fold higher response in AD OM cells, indicating increased susceptibility to DE effects. Methylation analysis detected different DNA methylation patterns, revealing new exposure targets. Findings were validated by analyzing data from the Rotterdam Study cohort and demonstrated a key role of nuclear factor erythroid 2-related factor 2 signaling in responses to air pollutants. DISCUSSION: This study identifies air pollution exposure biomarkers and pinpoints key pathways activated by exposure. The data suggest that AD individuals may face heightened risks due to impaired cellular defenses. HIGHLIGHTS: Healthy and AD olfactory cells respond differently to DE exposure. AD cells are highly susceptible to DE exposure. The NRF2 oxidative stress response is highly activated upon air pollution exposure. DE-exposed AD cells activate the unfolded protein response pathway. Key findings are also confirmed in a population-based study.

• Keywords
• Alzheimer's disease (AD), air pollution, air–liquid interface (ALI), heat shock protein (HSP), next‐generation sequencing (NGS), nuclear factor erythroid 2–related factor 2 (NRF2), traffic emissions, traffic‐related air pollution (TRAP) olfactory mucosa (OM),
• MeSH
• Alzheimer Disease * genetics   metabolism   MeSH
• Olfactory Mucosa metabolism   MeSH
• Epigenomics MeSH
• NF-E2-Related Factor 2 genetics   metabolism   MeSH
• Air Pollutants adverse effects   MeSH
• Middle Aged MeSH
• Humans MeSH
• DNA Methylation * MeSH
• MicroRNAs metabolism   genetics   MeSH
• Aged MeSH
• Gene Expression Profiling MeSH
• Transcriptome MeSH
• Vehicle Emissions * toxicity   MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• NF-E2-Related Factor 2 MeSH
• Air Pollutants MeSH
• MicroRNAs MeSH
• NFE2L2 protein, human MeSH Browser
• Vehicle Emissions * MeSH

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 (PM2.5), 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 PM2.5 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 PM2.5 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 PM2.5, whereas genotoxicity in the central airways becomes increasingly more important at the higher combustion PM levels encountered through smoking and occupational exposure.

• Keywords
• Air pollution, Carcinogenesis, Diesel exhaust, Genotoxicity, Inflammation, Occupational exposure, Smoking, Tumor metastasis, Tumor microenvironment, Tumor promotion,
• MeSH
• Air Pollutants * toxicity   MeSH
• Humans MeSH
• Environmental Monitoring MeSH
• Tumor Microenvironment MeSH
• Lung Neoplasms * chemically induced   genetics   MeSH
• Particulate Matter toxicity   MeSH
• Polycyclic Aromatic Hydrocarbons * toxicity   MeSH
• Receptors, Aryl Hydrocarbon genetics   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• Air Pollutants * MeSH
• Particulate Matter MeSH
• Polycyclic Aromatic Hydrocarbons * MeSH
• Receptors, Aryl Hydrocarbon MeSH

Apart from its role in the metabolism of carcinogens, the aryl hydrocarbon receptor (AhR) has been suggested to be involved in the control of inflammatory responses within the respiratory tract. However, the mechanisms responsible for this are only partially known. In this study, we used A549 cell line, as a human model of lung alveolar type II (ATII)-like cells, to study the functional role of the AhR in control of inflammatory responses. Using IL-1β as an inflammation inducer, we found that the induction of cyclooxygenase-2 and secretion of prostaglandins, as well as expression and release of pro-inflammatory cytokines, were significantly higher in the AhR-deficient A549 cells. This was linked with an increased nuclear factor-κB (NF-κB) activity, and significantly enhanced phosphorylation of its regulators, IKKα/β, and their target IκBα, in the AhR-deficient A549 cells. In line with this, when we mimicked the exposure to a complex mixture of airborne pollutants, using an organic extract of reference diesel exhaust particle mixture, an exacerbated inflammatory response was observed in the AhR-deficient cells, as compared with wild-type A549 cells. Together, the present results indicate that the AhR may act as a negative regulator of the inflammatory response in the A549 model, via a direct modulation of NF-κB signaling. Its role(s) in the control of inflammation within the lung alveoli exposed to airborne pollutants, especially those which simultaneously activate the AhR, thus deserve further attention.

• Keywords
• AhR, NF-κB, alveolar epithelial type II cells, cytokines, inflammation, prostaglandins,
• MeSH
• A549 Cells MeSH
• Environmental Pollutants * toxicity   MeSH
• Humans MeSH
• NF-kappa B * metabolism   MeSH
• Receptors, Aryl Hydrocarbon * metabolism   MeSH
• Inflammation * pathology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Environmental Pollutants * MeSH
• NF-kappa B * MeSH
• Receptors, Aryl Hydrocarbon * MeSH

Inhalation exposures to polycyclic aromatic hydrocarbons (PAHs) have been associated with various adverse health effects, including chronic lung diseases and cancer. Using human bronchial epithelial cell line HBE1, we investigated the effects of structurally different PAHs on tissue homeostatic processes, namely gap junctional intercellular communication (GJIC) and MAPKs activity. Rapid (<1 h) and sustained (up to 24 h) inhibition of GJIC was induced by low/middle molecular weight (MW) PAHs, particularly by those with a bay- or bay-like region (1- and 9-methylanthracene, fluoranthene), but also by fluorene and pyrene. In contrast, linear low MW (anthracene, 2-methylanthracene) or higher MW (chrysene) PAHs did not affect GJIC. Fluoranthene, 1- and 9-methylanthracene induced strong and sustained activation of MAPK ERK1/2, whereas MAPK p38 was activated rather nonspecifically by all tested PAHs. Low/middle MW PAHs can disrupt tissue homeostasis in human airway epithelium via structure-dependent nongenotoxic mechanisms, which can contribute to their human health hazards.

• Keywords
• Gap junctional intercellular communication, Human bronchial epithelial cell line, Methylated anthracenes, Mitogen-activated protein kinases, Nongenotoxic mechanisms, Polycyclic aromatic hydrocarbons,
• MeSH
• Bronchi cytology   MeSH
• Cell Line MeSH
• Epithelial Cells drug effects   physiology   MeSH
• Humans MeSH
• Gap Junctions drug effects   MeSH
• Cell Communication drug effects   MeSH
• Mitogen-Activated Protein Kinases metabolism   MeSH
• Polycyclic Aromatic Hydrocarbons toxicity   MeSH
• Cell Survival drug effects   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Mitogen-Activated Protein Kinases MeSH
• Polycyclic Aromatic Hydrocarbons MeSH

Polycyclic aromatic hydrocarbons (PAHs) are widespread environmental contaminants that interact in a complex manner with both the aryl hydrocarbon receptor (AhR) and estrogen receptors (ER). Their potential endocrine-disrupting activities may depend on both inhibitory AhR-ER cross-talk and on AhR-dependent metabolic production of estrogenic PAH metabolites. Here, we analyzed the impact of AhR on estrogen-like effects of PAHs, such as benzo[a]pyrene (BaP), in particular, on control of cell cycle progression/cell proliferation. Using AhR knockout variant of estrogen-sensitive human breast cancer MCF-7 cells (MCF-7 AhRKO cells), we observed that the AhR-dependent control of cytochrome P450 family 1 (CYP1) expression played a major role in formation of estrogenic BaP metabolites, most notably 3-OH-BaP, which contributed to the ER-dependent induction of cell cycle progression/cell proliferation. Both BaP metabolism and the BaP-induced S-phase transition/cell proliferation were inhibited in MCF-7 AhRKO cells, whereas these cells remained sensitive towards both endogenous estrogen 17β-estradiol or hydroxylated BaP metabolites. BaP was found to increase the activity of ER-dependent luciferase reporter gene in wild-type MCF-7 cells; however, unlike its hydroxylated metabolite, BaP failed to stimulate luciferase activity in MCF-7 AhRKO cells. Similarly, estrogen-like effects of other known estrogenic PAHs, such as benz[a]anthracene or 3-methylcholanthrene, were diminished in MCF-7 AhRKO cells. Ectopic expression of human CYP1A1 and CYP1B1 enzymes partly restored both BaP metabolism and its effects on cell proliferation. Taken together, our data suggest that the AhR-dependent metabolism of PAHs contributes significantly to the impact of PAHs on cell proliferation in estrogen-sensitive cells.

• MeSH
• Cell Culture Techniques MeSH
• Cell Cycle drug effects   genetics   MeSH
• Cytochrome P-450 CYP1A1 genetics   metabolism   MeSH
• Cytochrome P-450 CYP1B1 genetics   metabolism   MeSH
• Endocrine Disruptors metabolism   toxicity   MeSH
• Gene Expression drug effects   MeSH
• Genetic Vectors MeSH
• Gene Knockdown Techniques MeSH
• Humans MeSH
• MCF-7 Cells MeSH
• Plasmids MeSH
• Polycyclic Aromatic Hydrocarbons metabolism   toxicity   MeSH
• Cell Proliferation drug effects   genetics   MeSH
• Receptors, Aryl Hydrocarbon genetics   metabolism   MeSH
• Receptors, Estrogen genetics   metabolism   MeSH
• Genes, Reporter MeSH
• Transfection MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• CYP1A1 protein, human MeSH Browser
• CYP1B1 protein, human MeSH Browser
• Cytochrome P-450 CYP1A1 MeSH
• Cytochrome P-450 CYP1B1 MeSH
• Endocrine Disruptors MeSH
• Polycyclic Aromatic Hydrocarbons MeSH
• Receptors, Aryl Hydrocarbon MeSH
• Receptors, Estrogen MeSH