[Show abstract][Hide abstract] 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;
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] ABSTRACT: Established causes of diabetes do not fully explain the epidemic. High level arsenic exposure has been implicated in diabetes risk but the effect of low-level arsenic exposure in drinking water remains unclear.
Environmental Health Perspectives 06/2014; · 7.26 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In urban environments airborne particles are continuously emitted, followed by atmospheric aging. Also particles emitted elsewhere, transported by winds, contribute to the urban aerosol. We studied the effective density (mass-mobility relationship) and mixing state with respect to the density of particles in central Copenhagen, at wintertime. The results are related to particle origin, morphology, and aging. Using a Differential Mobility Analyzer-Aerosol Particle Mass Analyzer (DMA-APM) we showed that particles in the diameter range 50-400 nm were of two groups: porous soot aggregates and more dense particles. Both groups were present at each size in varying proportions. Two types of temporal variability in the relative number fraction of the two groups were found: soot correlated with intense traffic in a diel pattern, and the dense particles increased during episodes with long range transport from polluted continental areas. The effective density of each group was relatively stable over time, especially of the soot aggregates, which had effective densities similar to those observed in laboratory studies of fresh diesel exhaust emissions. When heated to 300 C the soot aggregate volatile mass fraction was ~10%. For the dense particles, the volatile mass fraction varied from ~80% to nearly 100%.
[Show abstract][Hide abstract] 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).
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] ABSTRACT: Whole-grain intake has been reported to be associated with a lower risk of several lifestyle-related diseases such as type 2 diabetes, CVD and some types of cancers. As measurement errors in self-reported whole-grain intake assessments can be substantial, dietary biomarkers are relevant to be used as complementary tools for dietary intake assessment. Alkylresorcinols (AR) are phenolic lipids found almost exclusively in whole-grain wheat and rye products among the commonly consumed foods and are considered as valid biomarkers of the intake of these products. In the present study, we analysed the plasma concentrations of five AR homologues in 2845 participants from ten European countries from a nested case-control study in the European Prospective Investigation into Cancer and Nutrition. High concentrations of plasma total AR were found in participants from Scandinavia and Central Europe and lower concentrations in those from the Mediterranean countries. The geometric mean plasma total AR concentrations were between 35 and 41 nmol/l in samples drawn from fasting participants in the Central European and Scandinavian countries and below 23 nmol/l in those of participants from the Mediterranean countries. The whole-grain source (wheat or rye) could be determined using the ratio of two of the homologues. The main source was wheat in Greece, Italy, the Netherlands and the UK, whereas rye was also consumed in considerable amounts in Germany, Denmark and Sweden. The present study demonstrates a considerable variation in the plasma concentrations of total AR and concentrations of AR homologues across ten European countries, reflecting both quantitative and qualitative differences in the intake of whole-grain wheat and rye.
The British journal of nutrition 02/2014; · 3.45 Impact Factor
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] ABSTRACT: Exposure to ultrafine particles (UFP) has been linked to cardiovascular and lung diseases. Combustion of jet fuel and diesel powered handling equipment emit UFP resulting in potentially high exposure levels among employees working at airports. High levels of UFP have been reported at several airports, especially on the apron, but knowledge on individual exposure profiles among different occupational groups working at an airport is lacking.
PLoS ONE 01/2014; 9(9):e106671. · 3.73 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Exposure to airborne particulate matter in homes is associated with the risk of cardiovascular diseases and respiratory problems. Due to the extended time people spend at home, reducing the particle concentration in homes may be a means to reduce the risk of cardiovascular diseases and respiratory problems. Use of particle filtration units (PFU's) might be an effective way for rapid removal of indoor PM.
In a randomised cross-over design, the custom built PFU's ran for two weeks in each of two modes: with or without the inclusion of a HEPA filter.
We assessed the association between the concentration levels of particulate matter and building characteristics; and the use of PFU as a way to effectively reduce the levels of PM2.5 indoors.
The results obtained from the study have shown that a small room area, wooden floor material, or the use of gas for cooking is strongly associated with high PM2.5 mass concentrations. Furthermore, the winter period and a location farther from a trafficked street were associated with increased PM2.5 mass. Overall, the use of PFU led to a decrease in the concentrations of PM2.5 of 54.5% (median value).
We assessed the PFU particle-removal efficiency by using the amount of infiltrated air, size of the controlled room and filtration effectiveness.
Building and Environment 01/2014; 73:55–63. · 2.43 Impact Factor
[Show abstract][Hide abstract] 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. · 3.73 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Exposure to particulate air pollution increases respiratory and cardiovascular morbidity and mortality, especially in elderly, possibly through inflammation and vascular dysfunction.
We examined potential beneficial effects of indoor air filtration in the homes of elderly, including people taking vasoactive drugs.Forty-eight nonsmoking subjects (51 to 81 years) in 27 homes were included in this randomized, double-blind, crossover intervention study with consecutive two-week periods with or without the inclusion of a high-efficiency particle air filter in re-circulating custom built units in their living room and bedroom. We measured blood pressure, microvascular and lung function and collected blood samples for hematological, inflammation monocyte surface and lung cell damage markers before and at day 2, 7 and 14 during each exposure scenario.
The particle filters reduced the median concentration of PM2.5 from approximately 8 to 4 mug/m3 and the particle number concentration from 7669 to 5352 particles/cm3. No statistically significant effects of filtration as category were observed on microvascular and lung function or the biomarkers of systemic inflammation among all subjects, or in the subgroups taking (n = 11) or not taking vasoactive drugs (n = 37). However, the filtration efficacy was variable and microvascular function was within 2 days significantly increased with the actual PM2.5 decrease in the bedroom, especially among 25 subjects not taking any drugs.
Substantial exposure contrasts in the bedroom and no confounding by drugs appear required for improved microvascular function by air filtration, whereas no other beneficial effect was found in this elderly population.
Environmental Health 12/2013; 12(1):116. · 2.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Few studies have investigated the association between whole-grain intake and colorectal cancer. Because whole-grain intake estimation might be prone to measurement errors, more objective measures (eg, biomarkers) could assist in investigating such associations.
The association between alkylresorcinols, biomarkers of whole-grain rye and wheat intake, and colorectal cancer incidence were investigated using prediagnostic plasma samples from colorectal cancer case patients and matched control subjects nested within the European Prospective Investigation into Cancer and Nutrition. We included 1372 incident colorectal cancer case patients and 1372 individual matched control subjects and calculated the incidence rate ratios (IRRs) for overall and anatomical subsites of colorectal cancer using conditional logistic regression adjusted for potential confounders. Regional differences (Scandinavia, the Mediterranean, Central Europe) were also explored.
High plasma total alkylresorcinol concentration was associated with lower incidence of distal colon cancer; the adjusted incidence rate ratio of distal colon cancer for the highest vs lowest quartile of plasma total alkylresorcinols was 0.48 (95% confidence interval [CI] = 0.28 to 0.83). An inverse association between plasma total alkylresorcinol concentrations and colon cancer was found for Scandinavian participants (IRR per doubling = 0.83; 95% CI = 0.70 to 0.98). However, plasma total alkylresorcinol concentrations were not associated with overall colorectal cancer, proximal colon cancer, or rectal cancer. Plasma alkylresorcinols concentrations were associated with colon and distal colon cancer only in Central Europe and Scandinavia (ie, areas where alkylresorcinol levels were higher).
High concentrations of plasma alkylresorcinols were associated with a lower incidence of distal colon cancer but not with overall colorectal cancer, proximal colon cancer, and rectal cancer.