Peter Møller

University of Copenhagen, København, Capital Region, Denmark

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Publications (163)645.73 Total impact

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    ABSTRACT: Background The liver has a crucial role in metabolic homeostasis as well as being the principal detoxification centre of the body, removing xenobiotics and waste products which could potentially include some nanomaterials (NM). With the ever increasing public and occupational exposure associated with accumulative production of nanomaterials, there is an urgent need to consider the possibility of detrimental health consequences of engineered NM exposure. It has been shown that exposure via inhalation, intratracheal instillation or ingestion can result in NM translocation to the liver. Traditional in vitro or ex vivo hepatic nanotoxicology models are often limiting and/or troublesome (i.e. reduced metabolism enzymes, lacking important cell populations, unstable with very high variability, etc.).Methods In order to rectify these issues and for the very first time we have utilised a 3D human liver microtissue model to investigate the toxicological effects associated with a single or multiple exposure of a panel of engineered NMs (Ag, ZnO, MWCNT and a positively charged TiO2).ResultsHere we demonstrate that the repeated exposure of the NMs is more damaging to the liver tissue as in comparison to a single exposure with the adverse effects more significant following treatment with the Ag and ZnO as compared with the TiO2 and MWCNT NMs (in terms of cytotoxicity, cytokine secretion, lipid peroxidation and genotoxicity).Conclusions Overall, this study demonstrates that the human microtissue model utilised herein is an excellent candidate for replacement of traditional in vitro single cell hepatic models and further progression of liver nanotoxicology.
    Particle and Fibre Toxicology 10/2014; 11(1):56. · 9.18 Impact Factor
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    ABSTRACT: This cross-sectional study investigated the relationship between exposure to airborne indoor and outdoor particulate matter (PM) and cardiovascular and respiratory health in a population-based sample of 58 residences in Copenhagen, Denmark. Over a 2-day period indoor particle number concentrations (PNC, 10-300nm) and PM2.5 (aerodynamic diameter<2.5μm) were monitored for each of the residences in the living room, and outdoor PNC (10-280nm), PM2.5 and PM10 (aerodynamic diameter<10μm) were monitored at an urban background station in Copenhagen. In the morning, after the 2-day monitoring period, we measured microvascular function (MVF) and lung function and collected blood samples for biomarkers related to inflammation, in 78 middle-aged residents. Bacteria, endotoxin and fungi were analyzed in material from electrostatic dust fall collectors placed in the residences for 4weeks. Data were analyzed using linear regression with the generalized estimating equation approach. Statistically significant associations were found between indoor PNC, dominated by indoor use of candles, and lower lung function, the prediabetic marker HbA1c and systemic inflammatory markers observed as changes in leukocyte differential count and expression of adhesion markers on monocytes, whereas C-reactive protein was significantly associated with indoor PM2.5. The presence of indoor endotoxin was associated with lower lung function and expression of adhesion markers on monocytes. An inverse association between outdoor PNC and MVF was also statistically significant. The study suggests that PNC in the outdoor environment may be associated with decreased MVF, while PNC, mainly driven by candle burning, and bioaerosols in the indoor environment may have a negative effect on lung function and markers of systemic inflammation and diabetes.
    Environment international. 09/2014; 73C:372-381.
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    ABSTRACT: The development of products containing carbon nanotubes (CNTs) is a major achievement of nanotechnology, although concerns regarding risk of toxic effects linger if the hazards associated with these materials are not thoroughly investigated. Exposure to CNTs has been associated with depletion of antioxidants, increased intracellular production of reactive oxygen species and pro-inflammatory signaling in cultured cells with primary function in the immune system as well as epithelial, endothelial and stromal cells. Pre-treatment with antioxidants has been shown to attenuate these effects, indicating a dependency of oxidative stress on cellular responses to CNT exposure. CNT-mediated oxidative stress in cell cultures has been associated with elevated levels of lipid peroxidation products and oxidatively damaged DNA. Investigations of oxidative stress endpoints in animal studies have utilized pulmonary, gastrointestinal, intravenous and intraperitoneal exposure routes, documenting elevated levels of lipid peroxidation products and oxidatively damaged DNA nucleobases especially in the lungs and liver, which to some extent occur concomitantly with altered levels of components in the antioxidant defense system (glutathione, superoxide dismutase or catalase). CNTs are biopersistent high aspect ratio materials, and some are rigid with lengths that lead to frustrated phagocytosis and pleural accumulation. There is accumulating evidence showing that pulmonary exposure to CNTs is associated with fibrosis and neoplastic changes in the lungs, and cardiovascular disease. As oxidative stress and inflammation responses are implicated in the development of these diseases, converging lines of evidence indicate that exposure to CNTs is associated with increased risk of cardiopulmonary diseases through generation of a pro-inflammatory and pro-oxidant milieu in the lungs.
    Archive für Toxikologie 09/2014; · 5.22 Impact Factor
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    ABSTRACT: Increased levels of oxidatively damaged DNA have been documented in studies of metal, metal oxide, carbon-based and ceramic engineered nanomaterials (ENMs). In particular, 8-oxo-7,8-dihydroguanine-2'-deoxyguanosine (8-oxodG) is widely assessed as a DNA nucleobase oxidation product, measured by chromatographic assays, antibody-based methods or the comet assay with DNA repair enzymes. However, spurious oxidation of DNA has been a problem in certain studies applying chromatographic assays, yielding high baseline levels of 8-oxodG. Antibody-based assays detect high 8-oxodG baseline levels, related to cross-reactivity with other molecules in cells. This review provides an overview of efforts to reliably detect oxidatively damaged DNA and a critical assessment of the published studies on DNA damage levels. Animal studies with high baseline levels of oxidatively damaged DNA are more likely to show positive associations between airway exposure to ENMs and oxidized DNA in lung tissue than studies showing acceptable baseline levels (odds ratio = 12.1, 95% confidence interval: 1.2–124). Nevertheless, reliable studies indicate that intratracheal instillation of nanosized carbon black is associated with increased levels of oxidatively damaged DNA in lung tissue. Oral exposure to nanosized carbon black, TiO2, carbon nanotubes and ZnO is associated with elevated levels of oxidatively damaged DNA in tissues. These observations are supported by cell culture studies showing concentration-dependent associations between ENM exposure and oxidatively damaged DNA measured by the comet assay. Cell culture studies show relatively high variation in the ability of ENMs to oxidatively damage DNA; hence, it is currently impossible to group ENMs according to their DNA damaging potential. Environ. Mol. Mutagen., 2014. © 2014 Wiley Periodicals, Inc.
    Environmental and Molecular Mutagenesis 09/2014; · 3.71 Impact Factor
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    ABSTRACT: Thorough characterization of particle size distribution in suspension is required for valid in vitro and in vivo toxicological bioassays. Several analytical techniques are available with dynamic light scattering and Nanoparticle Tracking Analysis (NTA) being the most popular. Differences in dispersion procedures and NTA software settings might give rise to inter-investigator and day-to-day variation. We investigated the variation in particle size obtained by eight investigators who determined the particle size in four samples by the Nanosight NTA system. Each investigator analyzed the samples in triplicates on three different days. The samples were carbon black Printex 90, two differently sized TiO2 particles and latex polystyrene beads. The mean and mode particle size was obtained with a precision in the range of 10–20 and 2–30 nm on each side of the central estimate, respectively. The investigators were generally able to distinguish between the four coded samples, and we observed inter-investigator variation that could be explained by the software. There was relatively low interday variation as compared to intra-day variation. The most experienced investigators showed the lowest variation in size determination which indicates that training is essential when using NTA. Development of standard reference conditions of benchmark particles in suspension is warranted for better comparison of characterizations between investigators and laboratories. For the NTA size determination, the mean size of nanoparticles was the value with the lowest difference between investigators.
    Advanced Science. 09/2014; 6(9).
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    ABSTRACT: This study investigated toxicity of nanocarriers comprised of cationic polymer and lipid components often used in gene and drug delivery, formulated as cationic micelles and liposomes. Rats were injected intravenously with 10, 25 or 100mg/kg and sacrificed after 24 or 48hours, or 24hours after the last of three intravenous injections of 100mg/kg every other day. Histological evaluation of liver, lung and spleen, clinical chemistry parameters, and hematology indicated little effect of treatment. DNA strand breaks were increased in the lung and spleen. Further, in the dose response study we found unaltered expression levels of genes in the antioxidant response (HMOX1) and repair of oxidized nucleobases (OGG1), whereas expression levels of cytokines (IL6, CXCL2 and CCL2) were elevated in lung, spleen or liver. The results indicate that assessment of genotoxicity and gene expression add information on toxicity of nanocarriers, which is not obtained by histology and hematology.
    Nanomedicine : nanotechnology, biology, and medicine. 08/2014;
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    ABSTRACT: Gold nanoparticles (AuNPs) are relevant in nanomedicine for drug delivery in the vascular system, where endothelial cells are first point of contact. We investigated the uptake of 80 nm AuNPs in primary human umbilical vein endothelial cells (HUVECs) by flow cytometry, 3D confocal microscopy, nano-scale 3D-imaging using focused ion beam - scanning electron microscopy (FIB/SEM), and single particle inductively coupled plasma - mass spectrometry (spICP-MS). HUVECs were cultured for 3 or 24 h in medium with AuNPs in a concentration range of 1.25 – 10 µg/ml. There was a concentration-dependent increase of AuNP inside cells measured by flow cytometry, spICP-MS and 3D confocal microscopy. The latter also showed that AuNPs were located in the cytosol. This was supported by FIB/SEM, showing that AuNPs were located in membrane enclosures in the cytoplasm as single particles or agglomerates of 2-3 or more particles. Pre-treatment with chlorpromazine inhibited the AuNP uptake in HUVECs, indicating that internalisation occurred mainly by clathrin-mediated endocytosis. Cell activation by exposure to tumour necrosis factor or lipopolysaccharide had slight and no effect on the uptake of AuNPs, respectively. The AuNP exposure did not influence cell cytotoxicity, whereas the intracellular reactive oxygen species production was slightly increased. In conclusion, uptake of AuNPs by endothelial cells can be addressed quantitatively by several methods with high throughput and/or high specificity. Uptake of AuNPs in HUVECs occurred by mainly clathrin-mediated endocytosis and trafficking to membrane enclosures in the form of single and agglomerates of 2-3 particles.
    Toxicol. Res. 08/2014;
  • Peter Møller, Jens Lykkesfeldt
    Nanomedicine (London, England). 07/2014; 9(10):1441-3.
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    ABSTRACT: Exposure to particles from combustion of wood is associated with respiratory symptoms, whereas there is limited knowledge about systemic effects. We investigated effects on systemic inflammation, oxidative stress and DNA damage in humans who lived in a reconstructed Viking Age house, with indoor combustion of wood for heating and cooking. The subjects were exposed to high indoor concentrations of PM2.5 (700-3,600 µg/m(3) ), CO (10.7-15.3 ppm) and NO2 (140-154 µg/m(3) ) during a 1-week stay. Nevertheless, there were unaltered levels of genotoxicity, determined as DNA strand breaks and formamidopyrimidine DNA glycosylase and oxoguanine DNA glycosylase 1 sensitive sites in peripheral blood mononuclear cells. There were also unaltered expression levels of OGG1, HMOX1, CCL2, IL8, and TNF levels in leukocytes. In serum, there were unaltered levels of C-reactive protein, IL6, IL8, TNF, lactate dehydrogenase, cholesterol, triglycerides, and high-density lipoproteins. The wood smoke exposure was associated with decreased serum levels of sICAM-1, and a tendency to decreased sVCAM-1 levels. There was a minor increase in the levels of circulating monocytes expressing CD31, whereas there were unaltered expression levels of CD11b, CD49d, and CD62L on monocytes after the stay in the house. In conclusion, even a high inhalation exposure to wood smoke was associated with limited systemic effects on markers of oxidative stress, DNA damage, inflammation, and monocyte activation. Environ. Mol. Mutagen. 2014. © 2014 Wiley Periodicals, Inc.
    Environmental and Molecular Mutagenesis 06/2014; · 3.71 Impact Factor
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    ABSTRACT: This study investigated the levels of DNA strand breaks and formamidopyrimidine DNA glycosylase (FPG) sensitive sites, as assessed by the comet assay, in peripheral blood mononuclear cells (PBMC) from healthy women from five different countries in Europe. The laboratory in each country (referred to as 'centre') collected and cryopreserved PBMC samples from three donors, using a standardised cell isolation protocol. The samples were analysed in 13 different laboratories for DNA damage, which is measured by the comet assay. The study aim was to assess variation in DNA damage in PBMC samples that were collected in the same way and processed using the same blood isolation procedure. The inter-laboratory variation was the prominent contributor to the overall variation. The inter-laboratory coefficient of variation decreased for both DNA strand breaks (from 68 to 26%) and FPG sensitive sites (from 57 to 12%) by standardisation of the primary comet assay endpoint with calibration curve samples. The level of DNA strand breaks in the samples from two of the centres (0.56-0.61 lesions/10(6) bp) was significantly higher compared with the other three centres (0.41-0.45 lesions/10(6) bp). In contrast, there was no difference between the levels of FPG sensitive sites in PBMC samples from healthy donors in the different centres (0.41-0.52 lesion/10(6) bp).
    Mutagenesis 04/2014; · 3.50 Impact Factor
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    ABSTRACT: AimTo examine associations of DNA damage, cardiovascular risk factors, and physical performance with vitality, in middle aged men. We also sought to elucidate underlying factors of physical performance by comparing physical performance parameters to DNA damage parameters and cardiovascular risk factors.Methods We studied 2487 participants from the Metropolit Cohort of 11,532 men born in 1953 in the Copenhagen Metropolitan area. The vitality level was estimated using the SF-36 vitality scale. Cardiovascular risk factors were determined by body mass index (BMI) and hematological biochemistry tests obtained from non-fasting participants. DNA damage parameters were measured in peripheral blood mononuclear cells (PBMCs) from as many participants as possible from a representative subset of 207 participants.ResultsVitality was inversely associated with spontaneous DNA breaks (measured by comet assay) (P = 0.046) and BMI (P = 0.002), and positively associated with all of the physical performance parameters (all P < 0.001). Also, we found several associations between physical performance parameters and cardiovascular risk factors. In addition, the load of short telomeres was inversely associated with maximum jump force (P = 0.018), with lowered significance after exclusion of either arthritis sufferers (P = 0.035) or smokers (P = 0.031).Conclusion Here we show that self-reported vitality is associated with DNA breaks, BMI and objective (measured) physical performance in a cohort of middle aged men. Several other associations in this study verify clinical observations in medical practice. In addition, the load of short telomeres may be linked to peak performance in certain musculoskeletal activities.This article is protected by copyright. All rights reserved.
    Acta Physiologica 04/2014; · 4.38 Impact Factor
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    ABSTRACT: Accumulating evidences indicate that pulmonary exposure to carbon nanotubes is associated with increased risk of lung diseases, whereas the effect on the vascular system is less studied. We investigated vascular effects of two types of multi-walled carbon nanotubes (MWCNT) in apolipoprotein E(-/-) mice, wild type mice and cultured cells. The ApoE(-/-) mice had accelerated plaque progression in aorta after five intracheal instillations of MWCNT (25.6 µg/mouse weekly for five weeks). The exposure was associated with pulmonary inflammation, lipid peroxidation and increased expression of inflammatory, oxidative stress, DNA repair and vascular activation response genes. The level of oxidatively damaged DNA in lung tissue was unaltered, probably due to increased DNA repair capacities. Despite upregulation of inflammatory genes in the liver, effects on systemic cytokines and lipid peroxidation were minimal. The exposure to MWCNTs in cultured human endothelial cells increased the expression of vascular adhesion molecules (ICAM1 and VCAM1). In co-cultures there was increased adhesion of monocytes to endothelial cells after exposure to MWCNT. The exposure to both types of MWCNT was also associated with increased lipid accumulation in monocytic-derived foam cells, which was dependent on concomitant oxidative stress since the antioxidant N-acetylcysteine inhibited the lipid accumulation. Collectively our results indicate that exposure to MWCNT is associated with accelerated progression of atherosclerosis, which could be related to both increased adherence of monocytes onto the endothelium and oxidative stress-mediated transformation of monocytes to foam cells.
    Toxicological Sciences 01/2014; · 4.33 Impact Factor
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    Peter Møller, Steffen Loft
    Frontiers in Genetics 01/2014; 5:292.
  • Frontiers in Genetics 01/2014; 5:217.
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    Environment International. 01/2014; 73:372–381.
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    ABSTRACT: Exposure to nanoparticles (NPs) may cause vascular effects including endothelial dysfunction and foam cell formation, with oxidative stress and inflammation as supposed central mechanisms. We investigated oxidative stress, endothelial dysfunction and lipid accumulation caused by nano-sized carbon black (CB) exposure in cultured human umbilical vein endothelial cells (HUVECs), THP-1 (monocytes) and THP-1 derived macrophages (THP-1a). The proliferation of HUVECs or co-cultures of HUVECs and THP-1 cells were unaffected by CB exposure, whereas there was increased cytotoxicity, assessed by the LDH and WST-1 assays, especially in THP-1 and THP-1a cells. The CB exposure decreased the glutathione (GSH) content in THP-1 and THP-1a cells, whereas GSH was increased in HUVECs. The reactive oxygen species (ROS) production was increased in all cell types after CB exposure. A reduction of the intracellular GSH concentration by buthionine sulfoximine (BSO) pre-treatment further increased the CB-induced ROS production in THP-1 cells and HUVECs. The expression of adhesion molecules ICAM-1 and VCAM-1, but not adhesion of THP-1 to HUVECs or culture dishes, was elevated by CB exposure, whereas these effects were unaffected by BSO pre-treatment. qRT-PCR showed increased VCAM1 expression, but no change in GCLM and HMOX1 expression in CB-exposed HUVECs. Pre-exposure to CB induced lipid accumulation in THP-1a cells, which was not affected by the presence of the antioxidant N-acetylcysteine. In addition, the concentrations of CB to induce lipid accumulation were lower than the concentrations to promote intracellular ROS production in THP-1a cells. In conclusion, exposure to nano-sized CB induced endothelial dysfunction and foam cell formation, which was not dependent on intracellular ROS production.
    PLoS ONE 01/2014; 9(9):e106711. · 3.53 Impact Factor
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    ABSTRACT: Generation of oxidatively damaged DNA by particulate matter (PM) is hypothesized to occur via production of reactive oxygen species (ROS) and inflammation. We investigated this hypothesis by comparing ROS production, inflammation and oxidatively damaged DNA in different experimental systems investigating air pollution particles. There is substantial evidence indicating that exposure to air pollution particles was associated with elevated levels of oxidatively damaged nucleobases in circulating blood cells and urine from humans, which is supported by observations of elevated levels of genotoxicity in cultured cells exposed to similar PM. Inflammation is most pronounced in cultured cells and animal models, whereas an elevated level of oxidatively damaged DNA is more pronounced than inflammation in humans. There is non-congruent data showing corresponding variability in effect related to PM sampled at different locations (spatial variability), times (temporal variability) or particle size fraction across different experimental systems of acellular conditions, cultured cells, animals and humans. Nevertheless, there is substantial variation in the genotoxic, inflammation and oxidative stress potential of PM sampled at different locations or times. Small air pollution particles did not appear more hazardous than larger particles, which is consistent with the notion that constituents such as metals and organic compounds also are important determinants for PM-generated oxidative stress and inflammation. In addition, the results indicate that PM-mediated ROS production is involved in the generation of inflammation and activated inflammatory cells can increase their ROS production. The observations indicate that air pollution particles generate oxidatively damaged DNA by promoting a milieu of oxidative stress and inflammation.
    Mutation Research/Reviews in Mutation Research. 01/2014;

Publication Stats

4k Citations
645.73 Total Impact Points

Institutions

  • 2002–2014
    • University of Copenhagen
      • Department of Public Health
      København, Capital Region, Denmark
  • 2001–2014
    • IT University of Copenhagen
      København, Capital Region, Denmark
  • 2013
    • Maastricht University
      • Department of Toxicology
      Maastricht, Provincie Limburg, Netherlands
  • 2008–2013
    • University of Milan
      • • Department of Food, Enviromental and Nutritional Sciences DEFENS
      • • Department of Food Science and Microbiology DISTAM
      Milano, Lombardy, Italy
    • Technical University of Denmark
      København, Capital Region, Denmark
  • 2008–2012
    • Imperial College London
      • Department of Epidemiology and Biostatistics
      London, ENG, United Kingdom
  • 2011
    • The University of Edinburgh
      Edinburgh, Scotland, United Kingdom
  • 2007–2011
    • National Research Centre for the Working Environment
      København, Capital Region, Denmark
  • 2009
    • Nicolaus Copernicus University
      • Department of Clinical Biochemistry
      Toruń, Kujawsko-Pomorskie, Poland
  • 1996–2008
    • National Institute of Public Health, Denmark
      København, Capital Region, Denmark
  • 2005
    • University of Abomey-Calavi
      • Laboratory of Biochemistry and Molecular Biology (LBBM)
      Cotonou, Departement du Littoral, Benin
  • 2000
    • Aarhus University
      • Department of Environmental and Occupational Medicine
      Aarhus, Central Jutland, Denmark