Publications by authors named "Johan Øvrevik"

51 Publications

Biological effects of combustion-derived particles from different biomass sources on human bronchial epithelial cells.

Toxicol In Vitro 2021 May 5;75:105190. Epub 2021 May 5.

Section of Pollution and Noise, Department of Environmental Health, Norwegian Institute of Public Health, PO Box 4404, Nydalen, N-0403 Oslo, Norway. Electronic address:

Combustion-derived particles (CDPs), in particular from traffic, are regarded as a central contributor for adverse health effects linked to air pollution. Recently, also biomass burning has been recognized as an important source for CDPs. Here, the effects of CDPs (PM) originating from burning of pellet, charcoal and wood on key processes associated to lung carcinogenesis were explored. Human bronchial epithelial cells (HBEC3-KT) were exposed to 2.5 μg/cm of CDPs for 24 h and biological effects were examined in terms of cytotoxicity, inflammation, epithelial to mesenchymal transition (EMT)-related effects, DNA damage and genotoxicity. Reduced cell migration, inflammation and modulation of various PM-associated genes were observed mainly after exposure to wood and pellet. In contrast, only particles from pellet burning induced alteration in cell proliferation and DNA damage, which resulted in cell cycle alterations. Charcoal instead, appeared in general less effective in inducing pro-carcinogenic effects. These results illustrate differences in the toxicological profile due to the CDPs source. The different chemical compounds adsorbed on CDPs seemed to be central for particle properties, leading to an activation of various cellular signaling pathways involved in early steps of cancer progression.
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http://dx.doi.org/10.1016/j.tiv.2021.105190DOI Listing
May 2021

Respirable stone particles differ in their ability to induce cytotoxicity and pro-inflammatory responses in cell models of the human airways.

Part Fibre Toxicol 2021 May 6;18(1):18. Epub 2021 May 6.

Section of Air Pollution and Noise, Department of Environmental Health, Domain of Infectious Disease Control and Environmental Health, Norwegian Institute of Public Health, PO Box 4404, Nydalen, N-0403, Oslo, Norway.

Background: Respirable stone- and mineral particles may be a major constituent in occupational and ambient air pollution and represent a possible health hazard. However, with exception of quartz and asbestos, little is known about the toxic properties of mineral particles. In the present study, the pro-inflammatory and cytotoxic responses to six stone particle samples of different composition and with diameter below 10 μm were assessed in human bronchial epithelial cells (HBEC3-KT), THP-1 macrophages and a HBEC3-KT/THP-1 co-culture. Moreover, particle-induced lysis of human erythrocytes was assessed to determine the ability of the particles to lyse biological membranes. Finally, the role of the NLRP3 inflammasome was assessed using a NLRP3-specific inhibitor and detection of ASC oligomers and cleaved caspase-1 and IL-1β. A reference sample of pure α-quartz was included for comparison.

Results: Several stone particle samples induced a concentration-dependent increase in cytotoxicity and secretion of the pro-inflammatory cytokines CXCL8, IL-1α, IL-1β and TNFα. In HBEC3-KT, quartzite and anorthosite were the most cytotoxic stone particle samples and induced the highest levels of cytokines. Quartzite and anorthosite were also the most cytotoxic samples in THP-1 macrophages, while anorthosite and hornfels induced the highest cytokine responses. In comparison, few significant differences between particle samples were detected in the co-culture. Adjusting responses for differences in surface area concentrations did not fully account for the differences between particle samples. Moreover, the stone particles had low hemolytic potential, indicating that the effects were not driven by membrane lysis. Pre-incubation with a NLRP3-specific inhibitor reduced stone particle-induced cytokine responses in THP-1 macrophages, but not in HBEC3-KT cells, suggesting that the effects are mediated through different mechanisms in epithelial cells and macrophages. Particle exposure also induced an increase in ASC oligomers and cleaved caspase-1 and IL-1β in THP-1 macrophages, confirming the involvement of the NLRP3 inflammasome.

Conclusions: The present study indicates that stone particles induce cytotoxicity and pro-inflammatory responses in human bronchial epithelial cells and macrophages, acting through NLRP3-independent and -dependent mechanisms, respectively. Moreover, some particle samples induced cytotoxicity and cytokine release to a similar or greater extent than α-quartz. Thus, these minerals warrant further attention in future research.
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http://dx.doi.org/10.1186/s12989-021-00409-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8101231PMC
May 2021

Can air pollution increase the risk of COVID-19?

Tidsskr Nor Laegeforen 2020 12 14;140(18). Epub 2020 Dec 14.

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http://dx.doi.org/10.4045/tidsskr.20.0843DOI Listing
December 2020

Potential role of polycyclic aromatic hydrocarbons in air pollution-induced non-malignant respiratory diseases.

Respir Res 2020 Nov 13;21(1):299. Epub 2020 Nov 13.

Section of Air Pollution and Noise, Department of Environmental Health, Norwegian Institute of Public Health, Skøyen, PO Box 222, 0213, Oslo, Norway.

Epidemiological studies have found strong associations between air pollution and respiratory effects including development and/or exacerbation of asthma and chronic obstructive pulmonary disease (COPD) as well as increased occurrence of respiratory infections and lung cancer. It has become increasingly clear that also polycyclic aromatic hydrocarbons (PAHs) may affect processes linked to non-malignant diseases in the airways. The aim of the present paper was to review epidemiological studies on associations between gas phase and particle-bound PAHs in ambient air and non-malignant respiratory diseases or closely related physiological processes, to assess whether PAH-exposure may explain some of the effects associated with air pollution. Based on experimental in vivo and in vitro studies, we also explore possible mechanisms for how different PAHs may contribute to such events. Epidemiological studies show strongest evidence for an association between PAHs and asthma development and respiratory function in children. This is supported by studies on prenatal and postnatal exposure. Exposure to PAHs in adults seems to be linked to respiratory functions, exacerbation of asthma and increased morbidity/mortality of obstructive lung diseases. However, available studies are few and weak. Notably, the PAHs measured in plasma/urine also represent other exposure routes than inhalation. Furthermore, the role of PAHs measured in air is difficult to disentangle from that of other air pollution components originating from combustion processes. Experimental studies show that PAHs may trigger various processes linked to non-malignant respiratory diseases. Physiological- and pathological responses include redox imbalance, oxidative stress, inflammation both from the innate and adaptive immune systems, smooth muscle constriction, epithelial- and endothelial dysfunction and dysregulated lung development. Such biological responses may at the molecular level be initiated by PAH-binding to the aryl hydrocarbon receptor (AhR), but possibly also through interactions with beta-adrenergic receptors. In addition, reactive PAH metabolites or reactive oxygen species (ROS) may interfere directly with ion transporters and enzymes involved in signal transduction. Overall, the reviewed literature shows that respiratory effects of PAH-exposure in ambient air may extend beyond lung cancer. The relative importance of the specific PAHs ability to induce disease may differ between the biological endpoint in question.
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http://dx.doi.org/10.1186/s12931-020-01563-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666487PMC
November 2020

Pro-inflammatory effects of crystalline- and nano-sized non-crystalline silica particles in a 3D alveolar model.

Part Fibre Toxicol 2020 04 21;17(1):13. Epub 2020 Apr 21.

Section of Air Pollution and Noise, Department of Environment and Health, Norwegian Institute of Public Health, PO Box 4404 Nydalen, N-0403, Oslo, Norway.

Background: Silica nanoparticles (SiNPs) are among the most widely manufactured and used nanoparticles. Concerns about potential health effects of SiNPs have therefore risen. Using a 3D tri-culture model of the alveolar lung barrier we examined effects of exposure to SiNPs (Si10) and crystalline silica (quartz; Min-U-Sil) in the apical compartment consisting of human alveolar epithelial A549 cells and THP-1-derived macrophages, as well as in the basolateral compartment with Ea.hy926 endothelial cells. Inflammation-related responses were measured by ELISA and gene expression.

Results: Exposure to both Si10 and Min-U-Sil induced gene expression and release of CXCL8, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), interleukin-1α (IL-1α) and interleukin-1β (IL-1β) in a concentration-dependent manner. Cytokine/chemokine expression and protein levels were highest in the apical compartment. Si10 and Min-U-Sil also induced expression of adhesion molecules ICAM-1 and E-selectin in the apical compartment. In the basolateral endothelial compartment we observed marked, but postponed effects on expression of all these genes, but only at the highest particle concentrations. Geneexpressions of heme oxygenase-1 (HO-1) and the metalloproteases (MMP-1 and MMP-9) were less affected. The IL-1 receptor antagonist (IL-1RA), markedly reduced effects of Si10 and Min-U-Sil exposures on gene expression of cytokines and adhesion molecules, as well as cytokine-release in both compartments.

Conclusions: Si10 and Min-U-Sil induced gene expression and release of pro-inflammatory cytokines/adhesion molecules at both the epithelial/macrophage and endothelial side of a 3D tri-culture. Responses in the basolateral endothelial cells were only induced at high concentrations, and seemed to be mediated by IL-1α/β released from the apical epithelial cells and macrophages.
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http://dx.doi.org/10.1186/s12989-020-00345-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7175518PMC
April 2020

Characterization and pro-inflammatory potential of indoor mold particles.

Indoor Air 2020 07 18;30(4):662-681. Epub 2020 Mar 18.

Group of Occupational Toxicology, STAMI National Institute of Occupational Health, Oslo, Norway.

A number of epidemiological studies find an association between indoor air dampness and respiratory health effects. This is often suggested to be linked to enhanced mold growth. However, the role of mold is obviously difficult to disentangle from other dampness-related exposure including microbes as well as non-biological particles and chemical pollutants. The association may partly be due to visible mycelial growth and a characteristic musty smell of mold. Thus, the potential role of mold exposure should be further explored by evaluating information from experimental studies elucidating possible mechanistic links. Such studies show that exposure to spores and hyphal fragments may act as allergens and pro-inflammatory mediators and that they may damage airways by the production of toxins, enzymes, and volatile organic compounds. In the present review, we hypothesize that continuous exposure to mold particles may result in chronic low-grade pro-inflammatory responses contributing to respiratory diseases. We summarize some of the main methods for detection and characterization of fungal aerosols and highlight in vitro research elucidating how molds may induce toxicity and pro-inflammatory reactions in human cell models relevant for airway exposure. Data suggest that the fraction of fungal hyphal fragments in indoor air is much higher than that of airborne spores, and the hyphal fragments often have a higher pro-inflammatory potential. Thus, hyphal fragments of prevalent mold species with strong pro-inflammatory potential may be particularly relevant candidates for respiratory diseases associated with damp/mold-contaminated indoor air. Future studies linking of indoor air dampness with health effects should assess the toxicity and pro-inflammatory potential of indoor air particulate matter and combined this information with a better characterization of biological components including hyphal fragments from both pathogenic and non-pathogenic mold species. Such studies may increase our understanding of the potential role of mold exposure.
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http://dx.doi.org/10.1111/ina.12656DOI Listing
July 2020

Oxidative Potential Versus Biological Effects: A Review on the Relevance of Cell-Free/Abiotic Assays as Predictors of Toxicity from Airborne Particulate Matter.

Authors:
Johan Øvrevik

Int J Mol Sci 2019 Sep 26;20(19). Epub 2019 Sep 26.

Department of Air Pollution and Noise, Division of Environmental Medicine, Norwegian Institute of Public Health, 0213 Oslo, Norway.

: The oxidative potential (OP) of particulate matter (PM) in cell-free/abiotic systems have been suggested as a possible measure of their biological reactivity and a relevant exposure metric for ambient air PM in epidemiological studies. The present review examined whether the OP of particles correlate with their biological effects, to determine the relevance of these cell-free assays as predictors of particle toxicity. : PubMed, Google Scholar and Web of Science databases were searched to identify relevant studies published up to May 2019. The main inclusion criteria used for the selection of studies were that they should contain (1) multiple PM types or samples, (2) assessment of oxidative potential in cell-free systems and (3) assessment of biological effects in cells, animals or humans. : In total, 50 independent studies were identified assessing both OP and biological effects of ambient air PM or combustion particles such as diesel exhaust and wood smoke particles: 32 in vitro or in vivo studies exploring effects in cells or animals, and 18 clinical or epidemiological studies exploring effects in humans. Of these, 29 studies assessed the association between OP and biological effects by statistical analysis: 10 studies reported that at least one OP measure was statistically significantly associated with all endpoints examined, 12 studies reported that at least one OP measure was significantly associated with at least one effect outcome, while seven studies reported no significant correlation/association between any OP measures and any biological effects. The overall assessment revealed considerable variability in reported association between individual OP assays and specific outcomes, but evidence of positive association between intracellular ROS, oxidative damage and antioxidant response in vitro, and between OP assessed by the dithiothreitol (DDT) assay and asthma/wheeze in humans. There was little support for consistent association between OP and any other outcome assessed, either due to repeated lack of statistical association, variability in reported findings or limited numbers of available studies. : Current assays for OP in cell-free/abiotic systems appear to have limited value in predicting PM toxicity. Clarifying the underlying causes may be important for further advancement in the field.
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http://dx.doi.org/10.3390/ijms20194772DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6801578PMC
September 2019

Potential role of polycyclic aromatic hydrocarbons as mediators of cardiovascular effects from combustion particles.

Environ Health 2019 08 22;18(1):74. Epub 2019 Aug 22.

Department of Air Pollution and Noise, Division of Infection Control and Environmental Health, Norwegian Institute of Public Health, PO Box 222, Skøyen, N-0213, Oslo, Norway.

Air pollution is the most important environmental risk factor for disease and premature death, and exposure to combustion particles from vehicles is a major contributor. Human epidemiological studies combined with experimental studies strongly suggest that exposure to combustion particles may enhance the risk of cardiovascular disease (CVD), including atherosclerosis, hypertension, thrombosis and myocardial infarction.In this review we hypothesize that adhered organic chemicals like polycyclic aromatic hydrocarbons (PAHs), contribute to development or exacerbation of CVD from combustion particles exposure. We summarize present knowledge from existing human epidemiological and clinical studies as well as experimental studies in animals and relevant in vitro studies. The available evidence suggests that organic compounds attached to these particles are significant triggers of CVD. Furthermore, their effects seem to be mediated at least in part by the aryl hydrocarbon receptor (AhR). The mechanisms include AhR-induced changes in gene expression as well as formation of reactive oxygen species (ROS) and/or reactive electrophilic metabolites. This is in accordance with a role of PAHs, as they seem to be the major chemical group on combustion particles, which bind AhR and/or is metabolically activated by CYP-enzymes. In some experimental models however, it seems as PAHs may induce an inflammatory atherosclerotic plaque phenotype irrespective of DNA- and/or AhR-ligand binding properties. Thus, various components and several signalling mechanisms/pathways are likely involved in CVD induced by combustion particles.We still need to expand our knowledge about the role of PAHs in CVD and in particular the relative importance of the different PAH species. This warrants further studies as enhanced knowledge on this issue may amend risk assessment of CVD caused by combustion particles and selection of efficient measures to reduce the health effects of particular matters (PM).
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http://dx.doi.org/10.1186/s12940-019-0514-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6704565PMC
August 2019

Combustion Particle-Induced Changes in Calcium Homeostasis: A Contributing Factor to Vascular Disease?

Cardiovasc Toxicol 2019 06;19(3):198-209

Department of Air Pollution and Noise, Division of Infection Control, Environment and Health, Norwegian Institute of Public Health, PO Box 4404, Nydalen, 0403, Oslo, Norway.

Air pollution is the leading environmental risk factor for disease and premature death in the world. This is mainly due to exposure to urban air particle matter (PM), in particular, fine and ultrafine combustion-derived particles (CDP) from traffic-related air pollution. PM and CDP, including particles from diesel exhaust (DEP), and cigarette smoke have been linked to various cardiovascular diseases (CVDs) including atherosclerosis, but the underlying cellular mechanisms remain unclear. Moreover, CDP typically consist of carbon cores with a complex mixture of organic chemicals such as polycyclic aromatic hydrocarbons (PAHs) adhered. The relative contribution of the carbon core and adhered soluble components to cardiovascular effects of CDP is still a matter of discussion. In the present review, we summarize evidence showing that CDP affects intracellular calcium regulation, and argue that CDP-induced impairment of normal calcium control may be a critical cellular event through which CDP exposure contributes to development or exacerbation of cardiovascular disease. Furthermore, we highlight in vitro research suggesting that adhered organic chemicals such as PAHs may be key drivers of these responses. CDP, extractable organic material from CDP (CDP-EOM), and PAHs may increase intracellular calcium levels by interacting with calcium channels like transient receptor potential (TRP) channels, and receptors such as G protein-coupled receptors (GPCR; e.g., beta-adrenergic receptors [βAR] and protease-activated receptor 2 [PAR-2]) and the aryl hydrocarbon receptor (AhR). Clarifying a possible role of calcium signaling and mechanisms involved may increase our understanding of how air pollution contributes to CVD.
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http://dx.doi.org/10.1007/s12012-019-09518-9DOI Listing
June 2019

Pro-Inflammatory Responses in Human Bronchial Epithelial Cells Induced by Spores and Hyphal Fragments of Common Damp Indoor Molds.

Int J Environ Res Public Health 2019 03 26;16(6). Epub 2019 Mar 26.

Department of Air Pollution and Noise, Division of Infection Control and Environment and Health, Norwegian Institute of Public Health, P.O. Box 4404 Nydalen, N-0403 Oslo, Norway.

Damp indoor environments contaminated with different mold species may contribute to the development and exacerbation of respiratory illnesses. Human bronchial epithelial BEAS-2B cells were exposed to X-ray treated spores and hyphal fragments from pure cultures of , , and . Hyphal fragments of and induced expression and release of the pro-inflammatory cytokine interleukin (IL)-6 and the chemokine IL-8, while none of the other hyphal preparations had effects. Hyphal fragments from and also increased the expression of IL-1α, IL-1β and tumor necrosis factor (TNF)-α, but these cytokines were not released. X-ray treated spores had little or no inflammatory potential. Attenuating Toll-like receptor (TLR)-2 by blocking antibodies strongly reduced the and hyphae-induced IL-6 and IL-8 release, whereas TLR4 antagonist treatment was without effects. Untreated spores formed hyphae and triggered expression of pro-inflammatory genes with similarities to the effects of hyphal fragments. In conclusion, while X-ray treated spores induced no pro-inflammatory responses, hyphal fragments of and enhanced a TLR2-dependent expression and release of IL-6 and IL-8.
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http://dx.doi.org/10.3390/ijerph16061085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466608PMC
March 2019

Concentration-dependent cytokine responses of silica nanoparticles and role of ROS in human lung epithelial cells.

Basic Clin Pharmacol Toxicol 2019 Sep 2;125(3):304-314. Epub 2019 Apr 2.

Department of Air Pollution and Noise, Norwegian Institute of Public Health, Oslo, Norway.

Reactive oxygen species (ROS) is regarded as a critical denominator in nanoparticle toxicology and inflammation. Previously, we have shown that silica nanoparticles sized 50 nm (Si50) induce release of CXCL8 and IL-6 from BEAS-2B cells, via mechanisms involving NFκB, p38 MAP kinase and TGF-α-activated EGF receptor. In the present study, the role of ROS-mediated mechanisms in the concentration-dependent Si50 induction of CXCL8 and IL-6 responses was examined. Si50 (200 µg/mL) induced a time-dependent ROS formation and a postponed increase in expression of haem oxygenase (HO-1) mRNA and protein. Pre-treatment with the ROS inhibitors N-acetyl cysteine (NAC) and diphenyleneiodonium (DPI) partially attenuated CXCL8 and IL-6 responses to 200 µg/mL, but not to 100 µg/mL Si50. The release of TGF-α induced by Si50 (200 µg/mL) was significantly reduced by NAC, but not by DPI nor siRNA against NADPH oxidase DUOX-1 (siDUOX-1). Furthermore, siDUOX-1 reduced Si50-induced CXCL8, but not IL-6. Both p38 and p65 phosphorylations were inhibited by siDUOX-1, but for NAC only p65 phosphorylation reached a significant reduction. Neither NAC nor DPI reduced Si50-induced CXCL8 and IL-6 gene expressions. In conclusion, Si50-induced CXCL8 and IL-6 involved both ROS-dependent and ROS-independent mechanisms. Notably, the role of ROS seemed restricted to effects of higher concentrations of Si50 and not mediated via the gene expression.
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http://dx.doi.org/10.1111/bcpt.13221DOI Listing
September 2019

Lung effects of 7- and 28-day inhalation exposure of rats to emissions from 1st and 2nd generation biodiesel fuels with and without particle filter - The FuelHealth project.

Environ Toxicol Pharmacol 2019 Apr 18;67:8-20. Epub 2019 Jan 18.

Division for Infection Control and Environmental Health, Norwegian Institute of Public Health, Norway. Electronic address:

Increased use of 1st and 2nd generation biofuels raises concerns about health effects of new emissions. We analyzed cellular and molecular lung effects in Fisher 344 rats exposed to diesel engine exhaust emissions (DEE) from a Euro 5-classified diesel engine running on B7: petrodiesel fuel containing 7% fatty acid methyl esters (FAME), or SHB20 (synthetic hydrocarbon biofuel): petrodiesel fuel containing 7% FAME and 13% hydrogenated vegetable oil. The Fisher 344 rats were exposed for 7 consecutive days (6 h/day) or 28 days (6 h/day, 5 days/week), both with and without diesel particle filter (DPF) treatment of the exhaust in whole body exposure chambers (n = 7/treatment). Histological analysis and analysis of cytokines and immune cell numbers in bronchoalveolar lavage fluid (BALF) did not reveal adverse pulmonary effects after exposure to DEE from B7 or SHB20 fuel. Significantly different gene expression levels for B7 compared to SHB20 indicate disturbed redox signaling (Cat, Hmox1), beta-adrenergic signaling (Adrb2) and xenobiotic metabolism (Cyp1a1). Exhaust filtration induced higher expression of redox genes (Cat, Gpx2) and the chemokine gene Cxcl7 compared to non-filtered exhaust. Exposure time (7 versus 28 days) also resulted in different patterns of lung gene expression. No genotoxic effects in the lungs were observed. Overall, exposure to B7 or SHB20 emissions suggests only minor effects in the lungs.
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http://dx.doi.org/10.1016/j.etap.2019.01.005DOI Listing
April 2019

Gene expression changes in rat brain regions after 7- and 28 days inhalation exposure to exhaust emissions from 1st and 2nd generation biodiesel fuels - The FuelHealth project.

Inhal Toxicol 2018 Jun - Jul;30(7-8):299-312. Epub 2018 Dec 20.

a Division of Infection Control and Environmental Health , Norwegian Institute of Public Health , Oslo , Norway.

While the impact of emissions from combustion of fossil fuel on human health has been extensively studied, current knowledge of exhaust exposure from combustion of biofuels provides limited and inconsistent information about its neurotoxicity. The objective of the present work was to compare the gene expression patterns in rat frontal cortex and hippocampus after exposure to diesel exhaust emissions (DEE) from combustion of two 1st generation fuels, 7% fatty acid methyl esters (FAME) (B7) and 20% FAME (B20), and a 2nd generation 20% FAME/hydrotreated vegetable oil (SHB20: synthetic hydrocarbon biofuel), with and without diesel particulate filter (DPF). The Fisher 344 rats (n = 7/treatment) were exposed to DEE for 7 days (6h/day), and for 28 days (6h/day, 5 days/week) in whole body exposure chambers. The controls were breathing room air. Brain histological examinations did not reveal any adverse exposure-related effects of DEE in frontal cortex or in hippocampus. Gene expression analysis showed that several genes associated with antioxidant defenses and inflammation were statistically differently expressed in DEE exposed animals versus control. In addition, the gene expression changes between the exposure groups were compared, where the observed rank order in frontal cortex was B7 > B20 > SHB20 after 7 days of exposure, and SHB20 > B7 = B20 after 28 days of exposure. In the hippocampus, the rank order was B7 > SHB20 > B20. Effect of DPF treatment was observed for Tnf only. Overall, moderate increases in bio-components in diesel blends do not appear to result in dramatic alterations in gene expression or adverse histopathological effects.
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http://dx.doi.org/10.1080/08958378.2018.1520370DOI Listing
August 2019

Organic chemicals from diesel exhaust particles affects intracellular calcium, inflammation and β-adrenoceptors in endothelial cells.

Toxicol Lett 2019 Mar 29;302:18-27. Epub 2018 Nov 29.

Department of Air Pollution and Noise, Division of Infection Control and Environmental Health, Norwegian Institute of Public Health, Oslo, Norway. Electronic address:

Exposure to diesel exhaust particles (DEP) may contribute to endothelial dysfunction and cardiovascular disease. DEP, extractable organic material from DEP (DEP-EOM) and certain PAHs seem to trigger [Ca] increase as well as inflammation via GPCRs like βARs and PAR-2. In the present study we explored the involvement of βARs and PAR-2 in effects of DEP-EOM on [Ca] and expression of inflammation-associated genes in the endothelial cell-line HMEC-1. We exposed the human microvascular endothelial cell line HMEC-1 to DEP-EOM fractionated by sequential extraction with solvents of increasing polarity: n-hexane (n-Hex-EOM), dichloromethane (DCM-EOM), methanol (Methanol-EOM) and water (Water-EOM). While Methanol-EOM and Water-EOM had no marked effects, n-Hex-EOM and DCM-EOM enhanced [Ca] (2-3 times baseline) and expression of inflammation-associated genes (IL-1α, IL-1β, COX-2 and CXCL8; 2-15 times baseline) in HMEC-1. The expression of βARs (60-80% of baseline) and βAR-inhibitor carazolol suppressed the increase in [Ca] induced by both n-Hex- and DCM-EOM. Carazolol as well as the Ca-channel inhibitor SKF-96365 reduced the DCM-EOM-induced pro-inflammatory gene-expression. Overexpression of βARs increased DCM-EOM-induced [Ca] responses in HEK293 cells, while βAR-overexpression suppressed [Ca] responses from n-Hex-EOM. Furthermore, the PAR-2-inhibitor ENMD-1068 attenuated [Ca] responses to DCM-EOM, but not n-Hex-EOM in HMEC-1. The results suggest that βAR and PAR-2 are partially involved in effects of complex mixtures of chemicals extracted from DEP on calcium signalling and inflammation-associated genes in the HMEC-1 endothelial cell-line.
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http://dx.doi.org/10.1016/j.toxlet.2018.11.009DOI Listing
March 2019

Evidence of selective activation of aryl hydrocarbon receptor nongenomic calcium signaling by pyrene.

Biochem Pharmacol 2018 12 22;158:1-12. Epub 2018 Sep 22.

Department of Air Pollution and Noise, Domain of Infection Control, Environment and Health, Norwegian Institute of Public Health, Oslo, Norway. Electronic address:

In its classical genomic mode of action, the aryl hydrocarbon receptor (AhR) acts as a ligand activated transcription factor regulating expression of target genes such as CYP1A1 and CYP1B1. Some ligands may also trigger more rapid nongenomic responses through AhR, including calcium signaling (Ca). In the present study we observed that pyrene induced a relatively rapid increase in intracellular Ca-concentrations ([Ca]) in human microvascular endothelial cells (HMEC-1) and human embryonic kidney cells (HEK293) that was attenuated by AhR-inhibitor treatment and/or transient AhR knockdown by RNAi. In silico molecular docking based on homology models, suggested that pyrene is not able to bind to the human AhR in the agonist conformation. Instead, pyrene docked in the antagonist conformation of the AhR PAS-B binding pocket, although the interaction differed from antagonists such as GNF-351 and CH223191. Accordingly, pyrene did not induce CYP1A1 or CYP1B1, but suppressed CYP1-expression by benzo[a]pyrene (B[a]P) in HMEC-1 cells, confirming that pyrene act as an antagonist of AhR-induced gene expression. Use of pharmacological inhibitors and Ca-free medium indicated that the pyrene-induced AhR nongenomic [Ca] increase was initiated by Ca-release from intracellular stores followed by a later phase of extracellular Ca-influx, consistent with store operated calcium entry (SOCE). These effects was accompanied by an AhR-dependent reduction in ordered membrane lipid domains, as determined by di-4-ANEPPDHQ staining. Addition of cholesterol inhibited both the pyrene-induced [Ca]-increase and alterations in membrane lipid order. In conclusion, we propose that pyrene binds to AhR, act as an antagonist of the canonical genomic AhR/Arnt/CYP1-pathway, reduces ordered membrane lipid domains, and activates AhR nongenomic Ca-signaling from intracellular stores.
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http://dx.doi.org/10.1016/j.bcp.2018.09.023DOI Listing
December 2018

Milan winter fine particulate matter (wPM2.5) induces IL-6 and IL-8 synthesis in human bronchial BEAS-2B cells, but specifically impairs IL-8 release.

Toxicol In Vitro 2018 Oct 23;52:365-373. Epub 2018 Jul 23.

Division for Infection Control and Environmental Health, Norwegian Institute of Public Health, Oslo N-0403, Norway.

Inflammatory responses have an important role in the onset of many lung diseases associated with urban airborne particulate matter (PM). Here we investigate effects and mechanisms linked to PM-induced expression and release of two main interleukins, IL-6 and IL-8, in human bronchial epithelial BEAS-2B cells. The cells were exposed to well characterized Milan city PM, winter PM2.5 (wPM2.5) and summer PM10 (sPM10), representing combustion and non-combustion sources, respectively. Both wPM2.5 and sPM10 increased mRNA-synthesis and intracellular protein levels of IL-6 and IL-8. Exposure to sPM10 also resulted in continuous and time-dependent increases in release of IL-6 and IL-8 for up to 48 h. By comparison, in wPM2.5-exposed cells IL-8 release was not significantly augmented, while extracellular IL-6 levels were increased but remained constant beyond 24 h exposure. Moreover, wPM2.5 also reduced the lipopolysaccharide (LPS)-increased release of IL-8. No cytotoxicity or significant adsorption of cytokines to wPM2.5 were observed. Immunofluorescence microscopy revealed an accumulation of IL-8 in intracellular vesicles and alterations in actin filament organization in wPM2.5 exposed cells, suggesting that the trafficking of vesicles carrying interleukins to the plasma membrane might be inhibited. Thus, wPM2.5 appeared to impair cytokine release in BEAS-2B cells, in particular of IL-8, possibly by damaging cytoskeletal function involved in protein secretion.
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http://dx.doi.org/10.1016/j.tiv.2018.07.016DOI Listing
October 2018

Lipophilic components of diesel exhaust particles induce pro-inflammatory responses in human endothelial cells through AhR dependent pathway(s).

Part Fibre Toxicol 2018 05 11;15(1):21. Epub 2018 May 11.

Department of Air Pollution and Noise, Domain of Infection Control, Environment and Health, Norwegian Institute of Public Health, PO Box 4404, Nydalen, N-0403, Oslo, Norway.

Background: Exposure to traffic-derived particulate matter (PM), such as diesel exhaust particles (DEP), is a leading environmental cause of cardiovascular disease (CVD), and may contribute to endothelial dysfunction and development of atherosclerosis. It is still debated how DEP and other inhaled PM can contribute to CVD. However, organic chemicals (OC) adhered to the particle surface, are considered central to many of the biological effects. In the present study, we have explored the ability of OC from DEP to reach the endothelium and trigger pro-inflammatory reactions, a central step on the path to atherosclerosis.

Results: Exposure-relevant concentrations of DEP (0.12 μg/cm) applied on the epithelial side of an alveolar 3D tri-culture, rapidly induced pro-inflammatory and aryl hydrocarbon receptor (AhR)-regulated genes in the basolateral endothelial cells. These effects seem to be due to soluble lipophilic constituents rather than particle translocation. Extractable organic material of DEP (DEP-EOM) was next fractionated with increasing polarity, chemically characterized, and examined for direct effects on pro-inflammatory and AhR-regulated genes in human microvascular endothelial (HMEC-1) cells and primary human endothelial cells (PHEC) from four healthy donors. Exposure-relevant concentrations of lipophilic DEP-EOM (0.15 μg/cm) induced low to moderate increases in IL-1α, IL-1β, COX2 and MMP-1 gene expression, and the MMP-1 secretion was increased. By contrast, the more polar EOM had negligible effects, even at higher concentrations. Use of pharmacological inhibitors indicated that AhR and protease-activated receptor-2 (PAR-2) were central in regulation of EOM-induced gene expression. Some effects also seemed to be attributed to redox-responses, at least at the highest exposure concentrations tested. Although the most lipophilic EOM, that contained the majority of PAHs and aliphatics, had the clearest low-concentration effects, there was no straight-forward link between chemical composition and biological effects.

Conclusion: Lipophilic and semi-lipophilic chemicals seemed to detach from DEP, translocate through alveolar epithelial cells and trigger pro-inflammatory reactions in endothelial cells at exposure-relevant concentrations. These effects appeared to be triggered by AhR agonists, and involve PAR-2 signaling.
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http://dx.doi.org/10.1186/s12989-018-0257-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5948689PMC
May 2018

Lipophilic Chemicals from Diesel Exhaust Particles Trigger Calcium Response in Human Endothelial Cells via Aryl Hydrocarbon Receptor Non-Genomic Signalling.

Int J Mol Sci 2018 May 10;19(5). Epub 2018 May 10.

Department of Air Pollution and Noise, Division of Infection Control and Environmental Health, Norwegian Institute of Public Health, N-0403 Oslo, Norway.

Exposure to diesel exhaust particles (DEPs) affects endothelial function and may contribute to the development of atherosclerosis and vasomotor dysfunction. As intracellular calcium concentration [Ca] is considered important in myoendothelial signalling, we explored the effects of extractable organic matter from DEPs (DEP-EOM) on [Ca] and membrane microstructure in endothelial cells. DEP-EOM of increasing polarity was obtained by pressurized sequential extraction of DEPs with -hexane (-Hex-EOM), dichloromethane (DCM-EOM), methanol, and water. Chemical analysis revealed that the majority of organic matter was extracted by the -Hex- and DCM-EOM, with polycyclic aromatic hydrocarbons primarily occurring in -Hex-EOM. The concentration of calcium was measured in human microvascular endothelial cells (HMEC-1) using micro-spectrofluorometry. The lipophilic -Hex-EOM and DCM-EOM, but not the more polar methanol- and water-soluble extracts, induced rapid [Ca] increases in HMEC-1. -Hex-EOM triggered [Ca] increase from intracellular stores, followed by extracellular calcium influx consistent with store operated calcium entry (SOCE). By contrast, the less lipophilic DCM-EOM triggered [Ca] increase via extracellular influx alone, resembling receptor operated calcium entry (ROCE). Both extracts increased [Ca] via aryl hydrocarbon receptor (AhR) non-genomic signalling, verified by pharmacological inhibition and RNA-interference. Moreover, DCM-EOM appeared to induce an AhR-dependent reduction in the global plasma membrane order, as visualized by confocal fluorescence microscopy. DCM-EOM-triggered [Ca] increase and membrane alterations were attenuated by the membrane stabilizing lipid cholesterol. In conclusion, lipophilic constituents of DEPs extracted by -hexane and DCM seem to induce rapid AhR-dependent [Ca] increase in HMEC-1 endothelial cells, possibly involving both ROCE and SOCE-mediated mechanisms. The semi-lipophilic fraction extracted by DCM also caused an AhR-dependent reduction in global membrane order, which appeared to be connected to the [Ca] increase.
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http://dx.doi.org/10.3390/ijms19051429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5983734PMC
May 2018

Early life exposure to air pollution particulate matter (PM) as risk factor for attention deficit/hyperactivity disorder (ADHD): Need for novel strategies for mechanisms and causalities.

Toxicol Appl Pharmacol 2018 09 14;354:196-214. Epub 2018 Mar 14.

Department of Toxicology and Risk Assessment, Norwegian Institute of Public Health, Oslo, Norway.

Epidemiological studies have demonstrated that air pollution particulate matter (PM) and adsorbed toxicants (organic compounds and trace metals) may affect child development already in utero. Recent studies have also indicated that PM may be a risk factor for neurodevelopmental disorders (NDDs). A pattern of increasing prevalence of attention deficit/hyperactivity disorder (ADHD) has been suggested to partly be linked to environmental pollutants exposure, including PM. Epidemiological studies suggest associations between pre- or postnatal exposure to air pollution components and ADHD symptoms. However, many studies are cross-sectional without possibility to reveal causality. Cohort studies are often small with poor exposure characterization, and confounded by traffic noise and socioeconomic factors, possibly overestimating the study associations. Furthermore, the mechanistic knowledge how exposure to PM during early brain development may contribute to increased risk of ADHD symptoms or cognitive deficits is limited. The closure of this knowledge gap requires the combined use of well-designed longitudinal cohort studies, supported by mechanistic in vitro studies. As ADHD has profound consequences for the children affected and their families, the identification of preventable risk factors such as air pollution exposure should be of high priority.
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http://dx.doi.org/10.1016/j.taap.2018.03.015DOI Listing
September 2018

Diagnosis, monitoring and prevention of exposure-related non-communicable diseases in the living and working environment: DiMoPEx-project is designed to determine the impacts of environmental exposure on human health.

J Occup Med Toxicol 2018 5;13. Epub 2018 Feb 5.

20Center for Human Genetics, University of Leuven, Leuven, Belgium.

The WHO has ranked environmental hazardous exposures in the living and working environment among the top risk factors for chronic disease mortality. Worldwide, about 40 million people die each year from noncommunicable diseases (NCDs) including cancer, diabetes, and chronic cardiovascular, neurological and lung diseases. The exposure to ambient pollution in the living and working environment is exacerbated by individual susceptibilities and lifestyle-driven factors to produce complex and complicated NCD etiologies. Research addressing the links between environmental exposure and disease prevalence is key for prevention of the pandemic increase in NCD morbidity and mortality. However, the long latency, the chronic course of some diseases and the necessity to address cumulative exposures over very long periods does mean that it is often difficult to identify causal environmental exposures. EU-funded COST Action DiMoPEx is developing new concepts for a better understanding of health-environment (including gene-environment) interactions in the etiology of NCDs. The overarching idea is to teach and train scientists and physicians to learn how to include efficient and valid exposure assessments in their research and in their clinical practice in current and future cooperative projects. DiMoPEx partners have identified some of the emerging research needs, which include the lack of evidence-based exposure data and the need for human-equivalent animal models mirroring human lifespan and low-dose cumulative exposures. Utilizing an interdisciplinary approach incorporating seven working groups, DiMoPEx will focus on aspects of air pollution with particulate matter including dust and fibers and on exposure to low doses of solvents and sensitizing agents. Biomarkers of early exposure and their associated effects as indicators of disease-derived information will be tested and standardized within individual projects. Risks arising from some NCDs, like pneumoconioses, cancers and allergies, are predictable and preventable. Consequently, preventative action could lead to decreasing disease morbidity and mortality for many of the NCDs that are of major public concern. DiMoPEx plans to catalyze and stimulate interaction of scientists with policy-makers in attacking these exposure-related diseases.
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http://dx.doi.org/10.1186/s12995-018-0186-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5800006PMC
February 2018

Do Carpets Impair Indoor Air Quality and Cause Adverse Health Outcomes: A Review.

Int J Environ Res Public Health 2018 01 23;15(2). Epub 2018 Jan 23.

The Norwegian Labour Inspection Authority, P.O. Box 4720 Sluppen, 7468 Trondheim, Norway.

Several earlier studies have shown the presence of more dust and allergens in carpets compared with non-carpeted floors. At the same time, adverse effects of carpeted floors on perceived indoor air quality as well as worsening of symptoms in individuals with asthma and allergies were reported. Avoiding extensive carpet use in offices, schools, kindergartens and bedrooms has therefore been recommended by several health authorities. More recently, carpet producers have argued that former assessments were obsolete and that modern rugs are unproblematic, even for those with asthma and allergies. To investigate whether the recommendation to be cautious with the use of carpets is still valid, or whether there are new data supporting that carpet flooring do not present a problem for indoor air quality and health, we have reviewed the literature on this matter. We have not found updated peer reviewed evidence that carpeted floor is unproblematic for the indoor environment. On the contrary, also more recent data support that carpets may act as a repository for pollutants which may become resuspended upon activity in the carpeted area. Also, the use of carpets is still linked to perception of reduced indoor air quality as well as adverse health effects as previously reported. To our knowledge, there are no publications that report on deposition of pollutants and adverse health outcomes associated with modern rugs. However, due to the three-dimensional structure of carpets, any carpet will to some extent act like a sink. Thus, continued caution should still be exercised when considering the use of wall-to-wall carpeted floors in schools, kindergartens and offices, as well as in children's bedrooms unless special needs indicate that carpets are preferable.
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http://dx.doi.org/10.3390/ijerph15020184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5858259PMC
January 2018

Dampness and Moisture Problems in Norwegian Homes.

Int J Environ Res Public Health 2017 10 17;14(10). Epub 2017 Oct 17.

Domain of Infection Control and Environmental Health, Norwegian Institute of Public Health, P.O. Box 4404 Nydalen, N-0403 Oslo, Norway.

The occurrence of dampness and mold in the indoor environment is associated with respiratory-related disease outcomes. Thus, it is pertinent to know the magnitude of such indoor environment problems to be able to estimate the potential health impact in the population. In the present study, the moisture damage in 10,112 Norwegian dwellings was recorded based on building inspection reports. The levels of moisture damage were graded based on a condition class (CC), where CC0 is immaculate and CC1 acceptable (actions not required), while CC2 and CC3 indicate increased levels of damage that requires action. Of the 10,112 dwellings investigated, 3125 had verified moisture or mold damage. This amounts to 31% of the surveyed dwellings. Of these, 27% had CC2 as the worst grade, whereas 4% had CC3 as the worst grade level. The room types and building structures most prone to moisture damage were (in rank order) crawl spaces, basements, un-insulated attics, cooling rooms, and bathrooms. The high proportion of homes with moisture damage indicate a possible risk for respiratory diseases in a relatively large number of individuals, even if only the more extensive moisture damages and those located in rooms where occupants spend the majority of their time would have a significant influence on adverse health effects.
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http://dx.doi.org/10.3390/ijerph14101241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5664742PMC
October 2017

Genotoxic potential of diesel exhaust particles from the combustion of first- and second-generation biodiesel fuels-the FuelHealth project.

Environ Sci Pollut Res Int 2017 Nov 9;24(31):24223-24234. Epub 2017 Sep 9.

Department of Radiobiology and Immunology, Institute of Biology, Jan Kochanowski University, 15 Swietokrzyska Str, 25-406, Kielce, Poland.

Epidemiological data indicate that exposure to diesel exhaust particles (DEPs) from traffic emissions is associated with higher risk of morbidity and mortality related to cardiovascular and pulmonary diseases, accelerated progression of atherosclerotic plaques, and possible lung cancer. While the impact of DEPs from combustion of fossil diesel fuel on human health has been extensively studied, current knowledge of DEPs from combustion of biofuels provides limited and inconsistent information about its mutagenicity and genotoxicity, as well as possible adverse health risks. The objective of the present work was to compare the genotoxicity of DEPs from combustion of two first-generation fuels, 7% fatty acid methyl esters (FAME) (B7) and 20% FAME (B20), and a second-generation 20% FAME/hydrotreated vegetable oil (SHB: synthetic hydrocarbon biofuel) fuel. Our results revealed that particulate engine emissions from each type of biodiesel fuel induced genotoxic effects in BEAS-2B and A549 cells, manifested as the increased levels of single-strand breaks, the increased frequencies of micronuclei, or the deregulated expression of genes involved in DNA damage signaling pathways. We also found that none of the tested DEPs showed the induction of oxidative DNA damage and the gamma-H2AX-detectable double-strand breaks. The most pronounced differences concerning the tested particles were observed for the induction of single-strand breaks, with the greatest genotoxicity being associated with the B7-derived DEPs. The differences in other effects between DEPs from the different biodiesel blend percentage and biodiesel feedstock were also observed, but the magnitude of these variations was limited.
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http://dx.doi.org/10.1007/s11356-017-9995-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5655577PMC
November 2017

No adverse lung effects of 7- and 28-day inhalation exposure of rats to emissions from petrodiesel fuel containing 20% rapeseed methyl esters (B20) with and without particulate filter - the FuelHealth project.

Inhal Toxicol 2017 04 17;29(5):206-218. Epub 2017 Jul 17.

a Division for Infection Control and Environmental Health , Norwegian Institute of Public Health , Oslo , Norway.

Increased use of biofuels raises concerns about health effects of new emissions. We analyzed relative lung health effects, on Fisher 344 rats, of diesel engine exhausts emissions (DEE) from a Euro 5-classified diesel engine running on petrodiesel fuel containing 20% rapeseed methyl esters (B20) with and without diesel particulate filter (DPF). One group of animals was exposed to DEE for 7 days (6 h/day), and another group for 28 days (6 h/day, 5 days/week), both with and without DPF. The animals (n = 7/treatment) were exposed in whole body exposure chambers. Animals breathing clean air were used as controls. Genotoxic effects of the lungs by the Comet assay, histological examination of lung tissue, bronchoalveolar lavage fluid (BALF) markers of pulmonary injury, and mRNA markers of inflammation and oxidative stress were analyzed. Our results showed that a minor number of genes related to inflammation were slightly differently expressed in the exposed animals compared to control. Histological analysis also revealed only minor effects on inflammatory tissue markers in the lungs, and this was supported by flow cytometry and ELISA analysis of cytokines in BALF. No exposure-related indications of genotoxicity were observed. Overall, exposure to DEE with or without DPF technology produced no adverse effects in the endpoints analyzed in the rat lung tissue or the BALF. Overall, exposure to DEE from a modern Euro 5 light vehicle engine run on B20 fuel with or without DPF technology produced no adverse effects in the endpoints analyzed in the rat lung tissue or the BALF.
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http://dx.doi.org/10.1080/08958378.2017.1339149DOI Listing
April 2017

A comparative analysis of in vitro toxicity of diesel exhaust particles from combustion of 1st- and 2nd-generation biodiesel fuels in relation to their physicochemical properties-the FuelHealth project.

Environ Sci Pollut Res Int 2017 Aug 3;24(23):19357-19374. Epub 2017 Jul 3.

Center for Radiobiology and Biological Dosimetry, Institute of Nuclear Chemistry and Technology, 16 Dorodna Str., 03-195, Warsaw, Poland.

Biodiesels represent more carbon-neutral fuels and are introduced at an increasing extent to reduce emission of greenhouse gases. However, the potential impact of different types and blend concentrations of biodiesel on the toxicity of diesel engine emissions are still relatively scarce and to some extent contradictory. The objective of the present work was to compare the toxicity of diesel exhaust particles (DEP) from combustion of two 1st-generation fuels: 7% fatty acid methyl esters (FAME; B7) and 20% FAME (B20) and a 2nd-generation 20% FAME/HVO (synthetic hydrocarbon biofuel (SHB)) fuel. Our findings indicate that particulate emissions of each type of biodiesel fuel induce cytotoxic effects in BEAS-2B and A549 cells, manifested as cell death (apoptosis or necrosis), decreased protein concentrations, intracellular ROS production, as well as increased expression of antioxidant genes and genes coding for DNA damage-response proteins. The different biodiesel blend percentages and biodiesel feedstocks led to marked differences in chemical composition of the emitted DEP. The different DEPs also displayed statistically significant differences in cytotoxicity in A549 and BEAS-2B cells, but the magnitude of these variations was limited. Overall, it seems that increasing biodiesel blend concentrations from the current 7 to 20% FAME, or substituting 1st-generation FAME biodiesel with 2nd-generation HVO biodiesel (at least below 20% blends), affects the in vitro toxicity of the emitted DEP to some extent, but the biological significance of this may be moderate.
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http://dx.doi.org/10.1007/s11356-017-9561-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5556143PMC
August 2017

Proinflammatory effects of diesel exhaust particles from moderate blend concentrations of 1st and 2nd generation biodiesel in BEAS-2B bronchial epithelial cells-The FuelHealth project.

Environ Toxicol Pharmacol 2017 Jun 5;52:138-142. Epub 2017 Apr 5.

Division for Infection Control and Environmental Health, Norwegian Institute of Public Health, Oslo, Norway. Electronic address:

Biodiesel fuel fuels are introduced at an increasing extent as a more carbon-neutral alternative to reduce CO-emissions, compared to conventional diesel fuel. In the present study we have investigated the impact of increasing the use of 1st generation fatty acid methyl ester (FAME) biodiesel from current 7% blend (B7) to 20% blend (B20), or by increasing the biodiesel content by adding 2nd generation hydrotreated vegetable oil (HVO) based biodiesel (SHB; Synthetic Hydrocarbon Biofuel) on toxicity of diesel exhaust particles (DEP) in an in vitro system. Human bronchial epithelial BEAS-2B cells were exposed for 4 and 20h to DEP from B7, B20 and SHB at different concentrations, and examined for effects on gene expression of interleukin 6 (IL-6), CXCL8 (IL-8), CYP1A1 and heme oxygenase-1 (HO-1). The results show that both B20 and SHB were more potent inducers of IL-6 expression compared to B7. Only B20 induced statistically significant increases in CXCL8 expression. By comparison the rank order of potency to induce CYP1A1 was SHB>B7>B20. No statistically significant difference were observed form HO-1 expression, suggesting that the differences in cytokine responses were not due to oxidative stress. The results show that even moderate increases in biodiesel blends, from 7% to 20%, may increase the proinflammatory potential of emitted DEP in BEAS-2B cells. This effect was observed for both addition of 1st generation FAME and 2nd generation HVO biodiesel.
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http://dx.doi.org/10.1016/j.etap.2017.04.004DOI Listing
June 2017

Triggering Mechanisms and Inflammatory Effects of Combustion Exhaust Particles with Implication for Carcinogenesis.

Basic Clin Pharmacol Toxicol 2017 Sep 15;121 Suppl 3:55-62. Epub 2017 Mar 15.

Department of Air Pollution and Noise, Domain for Infection Control and Environmental Health, Norwegian Institute of Public Health, Oslo, Norway.

A number of biological responses may contribute to the carcinogenic effects of combustion-derived particulate matter (CPM). Here, we focus on mechanisms that trigger CPM-induced pro-inflammatory responses. Inflammation has both genotoxic and non-genotoxic implications and is considered to play a central role in development of various health outcome associated with CPM exposure, including cancer. Chronic, low-grade inflammation may cause DNA damage through a persistent increased level of reactive oxygen species (ROS) produced and released by activated immune cells. Moreover, a number of pro-inflammatory cytokines and chemokines display mitogenic, motogenic, morphogenic and/or angiogenic properties and may therefore contribute to tumour growth and metastasis. The key triggering events involved in activation of pro-inflammatory responses by CPM and soluble CPM components can be categorized into (i) formation of ROS and oxidative stress, (ii) interaction with the lipid layer of cellular membranes, (iii) activation of receptors, ion channels and transporters on the cell surface and (iv) interactions with intracellular molecular targets including receptors such as the aryl hydrocarbon receptor (AhR). In particular, we will elucidate the effects of diesel exhaust particles (DEP) using human lung epithelial cells as a model system.
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http://dx.doi.org/10.1111/bcpt.12746DOI Listing
September 2017

Physico-chemical properties and biological effects of diesel and biomass particles.

Environ Pollut 2016 Aug 15;215:366-375. Epub 2016 May 15.

Polaris Research Centre, Dept. of Earth and Environmental Sciences, University of Milano-Bicocca, Piazza della Scienza, 1, 20126, Milan, Italy.

Diesel combustion and solid biomass burning are the major sources of ultrafine particles (UFP) in urbanized areas. Cardiovascular and pulmonary diseases, including lung cancer, are possible outcomes of combustion particles exposure, but differences in particles properties seem to influence their biological effects. Here the physico-chemical properties and biological effects of diesel and biomass particles, produced under controlled laboratory conditions, have been characterized. Diesel UFP were sampled from a Euro 4 light duty vehicle without DPF fuelled by commercial diesel and run over a chassis dyno. Biomass UFP were collected from a modern automatic 25 kW boiler propelled by prime quality spruce pellet. Transmission electron microscopy (TEM) and scanning electron microscopy (SEM) images of both diesel and biomass samples showed aggregates of soot particles, but in biomass samples ash particles were also present. Chemical characterization showed that metals and PAHs total content was higher in diesel samples compared to biomass ones. Human bronchial epithelial (HBEC3) cells were exposed to particles for up to 2 weeks. Changes in the expression of genes involved in xenobiotic metabolism were observed after exposure to both UFP already after 24 h. However, only diesel particles modulated the expression of genes involved in inflammation, oxidative stress and epithelial-to-mesenchymal transition (EMT), increased the release of inflammatory mediators and caused phenotypical alterations, mostly after two weeks of exposure. These results show that diesel UFP affected cellular processes involved in lung and cardiovascular diseases and cancer. Biomass particles exerted low biological activity compared to diesel UFP. This evidence emphasizes that the study of different emission sources contribution to ambient PM toxicity may have a fundamental role in the development of more effective strategies for air quality improvement.
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http://dx.doi.org/10.1016/j.envpol.2016.05.015DOI Listing
August 2016

Cytokine responses induced by diesel exhaust particles are suppressed by PAR-2 silencing and antioxidant treatment, and driven by polar and non-polar soluble constituents.

Toxicol Lett 2015 Oct 6;238(2):72-82. Epub 2015 Jul 6.

Department of Air Pollution and Noise, Division of Environmental Medicine, Norwegian Institute of Public Health, Norway. Electronic address:

Adsorbed soluble organics seem to be the main drivers of inflammatory responses induced by diesel exhaust particles (DEP). The specific compounds contributing to this process and the cellular mechanisms behind DEP-induced inflammation are not well known. We have assessed pro-inflammatory effects of DEP and various soluble DEP fractions, in human bronchial epithelial cells (BEAS-2B). DEP increased the expression of interleukin (IL)-6 and CXCL8. Silencing of the aryl hydrocarbon receptor (AhR) by siRNA or pretreatment with AhR-antagonists did not attenuate DEP-induced IL-6 and CXCL8 responses. However, the halogenated aromatic hydrocarbon (HAH)-selective AhR antagonist CH223191 caused a considerable reduction in DEP-induced CYP1A1 expression indicating that this response may be due to dioxin or dioxin-like constituents in DEP. Knock-down of protease activated receptor (PAR)-2 attenuated IL-6 responses without affecting CXCL8. Antioxidants did not affect IL-6 expression after 4h DEP-exposure and only partly reduced CXCL8 expression. However, after 24h exposure antioxidant treatment partly suppressed IL-6 protein release and completely blocked CXCL8 release. Furthermore, a heptane-soluble (non-polar) extract of DEP induced both IL-6 and CXCL8 release, whereas a PBS-soluble (highly polar) extract induced only IL-6. Thus, pro-inflammatory responses in DEP-exposed epithelial cells appear to be the result of both reactive oxygen species and receptor signaling, mediated through combinatorial effects between both non-polar and polar constituents adhered to the particle surface.
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http://dx.doi.org/10.1016/j.toxlet.2015.07.002DOI Listing
October 2015

Activation of Proinflammatory Responses in Cells of the Airway Mucosa by Particulate Matter: Oxidant- and Non-Oxidant-Mediated Triggering Mechanisms.

Biomolecules 2015 Jul 2;5(3):1399-440. Epub 2015 Jul 2.

Department of Air Pollution and Noise, Division of Environmental Medicine, Norwegian Institute of Public Health, P.O. Box 4404 Nydalen, N-0403 Oslo, Norway.

Inflammation is considered to play a central role in a diverse range of disease outcomes associated with exposure to various types of inhalable particulates. The initial mechanisms through which particles trigger cellular responses leading to activation of inflammatory responses are crucial to clarify in order to understand what physico-chemical characteristics govern the inflammogenic activity of particulate matter and why some particles are more harmful than others. Recent research suggests that molecular triggering mechanisms involved in activation of proinflammatory genes and onset of inflammatory reactions by particles or soluble particle components can be categorized into direct formation of reactive oxygen species (ROS) with subsequent oxidative stress, interaction with the lipid layer of cellular membranes, activation of cell surface receptors, and direct interactions with intracellular molecular targets. The present review focuses on the immediate effects and responses in cells exposed to particles and central down-stream signaling mechanisms involved in regulation of proinflammatory genes, with special emphasis on the role of oxidant and non-oxidant triggering mechanisms. Importantly, ROS act as a central second-messenger in a variety of signaling pathways. Even non-oxidant mediated triggering mechanisms are therefore also likely to activate downstream redox-regulated events.
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http://dx.doi.org/10.3390/biom5031399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4598757PMC
July 2015