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Telomere shortening and aortic plaque progression in Apoliprotein E knockout mice after pulmonary exposure to candle light combustion particles
Abstract
Particles from burning candles contribute to the overall indoor exposure to particulate matter (PM). However, little is known about the effects of indoor sources of particles on cardiovascular disease endpoints. This study investigated the effect of pulmonary exposure to particles from combustion of candles and progression of atherosclerosis. Telomere shortening was assessed in tissues due to its relationship to risk of cardiovascular diseases. The particles were collected from burning candles and used for toxicological studies in cultured endothelial cells and apolipoprotein E (ApoE) knockout mice. Three hours exposure to particles increased the production of reactive oxygen species in endothelial cells, whereas there was no effect on cytotoxicity. Intratracheal instillation of particles (0.5 or 5 mg/kg) once a week for 5 weeks in ApoE-/- mice was associated with an accelerated progression of atherosclerosis in aorta and telomere shortening in the lung and spleen, whereas there was no effect on inflammation in the lungs (i.e. cell numbers), cell damage (i.e. lactate dehydrogenase) and lung barrier damage (i.e. protein concentration) as measured in bronchoalveolar lavage fluid. The results indicate that particles from burning candles are hazardous and this indoor emission source is an important contribution to the health risk of exposure to PM.
... However, the mechanisms remained unclear. Biomolecular studies were carried out in vitro and in vivo studies that showed the connection between pollutant exposure and its pathology related parameters including oxidative stress and inflammation as shown in Table 7. Telomere length shortening was observed in the majority of studies, which was found in NHBE, COPD-DHBE, A549 cells, and HUVECs following exposure to PM (Damiao Gouveia et al., 2018;Leclercq et al., 2016;Leclercq et al., 2017;Ma et al., 2020). However, a tendency toward increased telomere length was also observed, though without statistical significance (Fougere et al., 2018). ...
... This trend of an increase in telomere length shown in white blood cells might be caused by a brief exposure which allowed limitation of the division cycle and different stages of white blood cells (Fougere et al., 2018;Lin et al., 2010). Most studies also showed that more frequently repeated incidence and a higher amount of exposure had more effects on telomere length shortening (Damiao Gouveia et al., 2018;Fougere et al., 2018;Leclercq et al., 2016;Leclercq et al., 2017;Ma et al., 2020). Interestingly, telomerase activity was found to increase after a short time of exposure to air pollutants of up to 72 h, but decreased after prolonged exposure to air pollutants for up to 2 weeks (Buchner et al., 2013;Fougere et al., 2018;Leclercq et al., 2016;Leclercq et al., 2017). ...
... due to genomic instability from short-time exposure whether the telomere length had changed or not (Fougere et al., 2018;Leclercq et al., 2016;Leclercq et al., 2017). Markers of oxidative stress were mostly increased while a variety of DNA methylation has been reported by various studies (Buchner et al., 2013;Damiao Gouveia et al., 2018;Fougere et al., 2018;Leclercq et al., 2016;Leclercq et al., 2017;Ma et al., 2020). The effects of the exposure to air pollutants on DNA methylation were dependent on specific types of methylation as shown in Table 7. Contrary to most cytotoxicity markers, superoxide dismutase was reported to increase then slightly decrease, while adenosine triphosphate and total antioxidant status decreased after being exposed to air pollutants (Leclercq et al., 2016). ...
Air pollution remains the major environmental problem globally. There is extensive evidence showing that the variety of air pollutants from environmental and occupational exposures cause adverse effects to our health. The clinical symptoms of those effects may present at a late stage, so surveillance is difficult to manage. Several biomarkers have been used for the early detection of health issues following exposure to air pollution, including the use of telomere length which indicates cellular senescence in response to oxidative stress. Oxidative stress is one of the most plausible mechanisms associated with exposure to air pollutants. Some specific contexts including age groups, gender, ethnicity, occupations, and health conditions, showed significant alterations in telomere length after exposure to air pollutants. Several reports demonstrated both negative and positive associations between telomere length and air pollution, the studies using different concentrations and exposure times to air pollution on the study of telomere lengths. Surprisingly, some studies reported that low levels of exposure to air pollutants (lower than regulated levels) caused the alterations in telomere length. Those findings suggest that telomere length could be one of most practical biomarkers in air pollution surveillance. Therefore, this review aimed to summarize and discuss the relationship between telomere length and exposure to air pollution. The knowledge from this review will be beneficial for the planning of public health to reduce health problems in the general population, particularly in vulnerable people, who still live in areas with high air pollution.
... Interestingly, observations from epidemiological studies indicate an inverse association between longterm exposure to black carbon and other forms of particulate matter in ambient air and telomere length in blood leukocytes (22,23). We have previously shown that 5 weeks of pulmonary exposure to particles from burning candles were associated with telomere shortening in the lungs and spleen of mice (24). Telomere shortening is involved in cellular senescence and ageing-related illnesses, including cardiovascular diseases, cancer and liver diseases (25,26). ...
... In general, there are relatively few studies on the association between exposure to environmental agents and telomere dynamics in animal models (60). We have found an inverse association between pulmonary exposure by intratracheal instillation to particles from candle lights and telomere length in the lungs and liver of apolipoprotein E knockout mice (24). Another study showed that male rats had shorter telomeres in testes after oral exposure to benzo[a]pyrene (1, 5 or 10 mg/kg) every other day for 4 weeks (61). ...
Vegetable carbon (E153) and titanium dioxide (E171) are widely used as black and white food colour additives. The aim of this study was to assess gastrointestinal tight junction and systemic genotoxic effects in rats following exposure to E153 and E171 for 10 weeks by oral gavage once a week. The expression of tight junction proteins was assessed in intestinal tissues. Levels of DNA strand breaks, oxidatively damaged DNA and telomere length were assessed in secondary organs. Hydrodynamic suspensions of E153 and E173 indicated mean particles sizes of 230 and 270 nm, respectively, and only E153 gave rise to intracellular production of reactive oxygen species in colon epithelial (Caco-2) cells. Rats exposed to E153 (6.4 mg/kg/week) or E171 (500 mg/kg/week) had decreased gene expression of the tight junction protein TJP1 (P < 0.05). E153 (6.4 mg/kg/week) also decreased OCLN (P < 0.05) in the colon and occludin protein expression in the small intestine (P < 0.05). Furthermore, E153 or E171 exposed rats had shorter telomeres in the lung (P < 0.05). Plasma from particle-exposed rats also produced telomere shortening in cultured lung epithelial cells. There were unaltered levels of oxidatively damaged DNA in the liver and lung and no changes in the DNA repair activity of oxidatively damaged DNA in the lung. Altogether, these results indicate that intragastric exposure to E153 and E171 is associated with reduced tight junction protein expression in the intestinal barrier and telomere length shortening in the lung in rats.
... 14 Experimental animal studies showed that exposure to candle emissions leads to similar health effects as those found with ambient air pollution and diesel exhaust particles: pulmonary inflammation, 16 impaired endothelial function, 17 shortening of telomere lengths in the lungs and spleen, and progression of atherosclerotic plaques in the aorta. 18 Human exposure studies found that candle emissions caused a transient decrease in lung function 19 and cognitive function, 20 as well as increases in arterial stiffness and high-frequency heart rate variability. 21 However, epidemiological studies on long-term at-home candle use are scarce. ...
Burning candles at home emit small particles and gases that pollute indoor air. Exposure to fine particles in outdoor air has been convincingly linked to cardiovascular and respiratory events, while the associations with fine and ultrafine particles from candle burning remain unexplored. We examined the association between the use of candles and incident cardiovascular and respiratory events. We collected data on 6757 participants of the Copenhagen Aging and Midlife Biobank cohort recruited in 2009 and followed them up for the first hospital contact for incident cardiovascular and respiratory events until 2018. We investigated an association between the self-reported frequency of candle use in wintertime and cardiovascular and respiratory events, using Cox regression models adjusting for potential confounders. During follow-up, 1462 and 834 were admitted for cardiovascular and respiratory events, respectively. We found null associations between candle use and a hospital contact due to cardiovascular and respiratory events, with hazard ratios (HRs) and 95% confidence intervals (CI) of 0.97 (95% CI: 0.84, 1.11) and 0.98 (95% CI: 0.81, 1.18), respectively, among those using candles >4 times/week compared with <1 time/week. For cause-specific cardiovascular diseases, HRs were 1.10 (95% CI: 0.85, 1.43) for ischemic heart disease and 1.18 (95% CI: 0.77, 1.81) for myocardial infarction. For chronic obstructive pulmonary disease, HR was 1.26 (95% CI: 0.81, 1.97). We found no statistically significant associations between candle use and the risk of cardiovascular and respiratory events. Studies with improved exposure assessments are warranted.
... 14 Animal studies conducted on mice exposed to candle soot particles are associated with cytotoxicity and inflammation in the lungs 15 as well as telomere shortening in the lung and spleen, a marker for the risk of developing cardiovascular diseases. 16 In addition to being a major pollutant in indoor air, candle soot from various types of stressed burning has attracted a huge interest as a cheap emerging technology to produce functional nanomaterials with unique properties such as high hydrophobicity. 17 Candle emissions were found to be the primary source to the daily residential exposure to ultrafine particle number concentrations in a study of Danish homes. ...
Burning candles release a variety of pollutants to indoor air, some of which are of concern for human health. We studied emissions of particles and gases from the stressed burning of five types of pillar candles with different wax and wick compositions. The stressed burning was introduced by controlled fluctuating air velocities in a 21.6 m3 laboratory chamber. The aerosol physicochemical properties were measured both in well‐mixed chamber air and directly above the candle flame with online and offline techniques. All candles showed different emission profiles over time with high repeatability among replicates. The particle mass emissions from stressed burning for all candle types were dominated by soot (black carbon; BC). The wax and wick composition strongly influenced emissions of BC, PM2.5, and particle‐phase polycyclic aromatic hydrocarbons (PAHs), and to lower degree ultrafine particles, inorganic and organic carbon fraction of PM, but did not influence NOx, formaldehyde, and gas‐phase PAHs. Measurements directly above the flame showed empirical evidence of short‐lived strong emission peaks of soot particles. The results show the importance of including the entire burn time of candles in exposure assessments, as their emissions can vary strongly over time. Preventing stressed burning of candles can reduce exposure to pollutants in indoor air.
... In humans, urokinase is known to be increased in the BALF of humans with asthma (43), suggesting that in our study the increase in BALF urokinase levels may contribute to the increase in airway responsiveness. Decreased APOE levels in other animal models has been shown to increase susceptibility to cardiovascular and pulmonary injury (44,45), especially after pulmonary environmental and occupational exposures (46)(47)(48). Furthermore, one study investigating the relationship between APOE and urokinase showed that decreased levels of urokinase lead to increased levels of ApoE, suggesting urokinase plays a role in regulating ApoE levels (49). ...
Human genome-wide association studies (GWAS) have identified over 270 loci associated with pulmonary function; however, follow-up studies to determine causal genes at these loci are few. Single nucleotide polymorphisms (SNPs) in low-density lipoprotein receptor-related protein 1 (LRP1) are associated with human pulmonary function in GWAS. Using murine models, we investigated the effect of genetic disruption of the Lrp1 gene in smooth muscle cells on pulmonary function in naïve animals and after exposure to bacterial lipopolysaccharide (LPS) or house dust mite extract (HDME). Disruption of Lrp1 in smooth muscle cells leads to an increase in tissue resistance, elastance, and tissue elastance at baseline. Further, disruption of Lrp1 in smooth muscle increases airway responsiveness as measured by increased total lung resistance and airway resistance after methacholine. Immune cell counts in bronchoalveolar lavage fluid were increased in animals with Lrp1 disruption. The difference in airway responsiveness by genotype observed in naïve animals was not observed following LPS or HDME exposure. To further explore the mechanisms contributing to changes in pulmonary function, we identified several ligands dysregulated with Lrp1 disruption in smooth muscle cells. These data suggest that dysregulation of LRP1 in smooth muscle cells affects baseline pulmonary function and airway responsiveness and helps establish LRP1 as the causal gene at this GWAS locus.
... The first observational evidence stems from molecular epidemiology studies that have shown inverse associations between concentrations of particles in ambient air and telomere length in leukocytes (Hou et al., 2012;McCracken et al., 2010;Ward-Caviness et al., 2016). Studies in animal models have also indicated that exposure to particles is associated with telomere shortening in lungs of mice and rats (Damiao Gouveia et al., 2018;Jensen et al., 2019). In vitro studies have shown that exposure to air pollution particles decreased telomere length in human bronchial epithelial cells (Leclercq et al., 2016(Leclercq et al., , 2017. ...
Particulate matter (PM) from combustion processes has been associated with oxidative stress to DNA, whereas effects related to telomere dysfunction are less investigated. We collected air-borne PM from a passenger cabin of a diesel-propelled train and at a training facility for smoke diving exercises. Effects on oxidative stress biomarkers, genotoxicity measured by the comet assay and telomere length in PM-exposed A549 cells were compared with the genotoxicity and telomere length in peripheral blood mononuclear cells (PBMCs) from human volunteers exposed to the same aerosol source. Although elevated levels of DNA strand breaks and oxidatively damaged DNA in terms of Fpg-sensitive sites were observed in PBMCs from exposed humans, the PM collected at same locations did not cause genotoxicity in the comet assay in A549 cells. Nevertheless, A549 cells displayed telomere length shortening after four weeks exposure to PM. This is in line with slightly shorter telomere length in PBMCs from exposed humans, although it was not statistically significant. In conclusion, the results indicate that genotoxic potency measured by the comet assay of PM in A549 cells may not predict genotoxicity in exposed humans, whereas telomere length measurements may be a novel indicator of genotoxic stress in cell cultures and humans.
We spend most of our time indoors; however, little is known about the effects of exposure to aerosol particles indoors. We aimed to determine differences in relative toxicity and physicochemical properties of PM2.5 collected simultaneously indoors (PM2.5 INDOOR) and outdoors (PM2.5 OUTDOOR) in 15 occupied homes in southern Sweden. Collected particles were extracted from filters, pooled (indoor and outdoor separately), and characterized for chemical composition and endotoxins before being tested for toxicity in mice via intratracheal instillation. Various endpoints including lung inflammation, genotoxicity, and acute‐phase response in lung and liver were assessed 1, 3, and 28 days post‐exposure. Chemical composition of particles used in toxicological assessment was compared to particles analyzed without extraction. Time‐resolved particle mass and number concentrations were monitored. PM2.5 INDOOR showed higher relative concentrations (μg mg−1) of metals, PAHs, and endotoxins compared to PM2.5 OUTDOOR. These differences may be linked to PM2.5 INDOOR causing significantly higher lung inflammation and lung acute‐phase response 1 day post‐exposure compared to PM2.5 OUTDOOR and vehicle controls, respectively. None of the tested materials caused genotoxicity. PM2.5 INDOOR displayed higher relative toxicity than PM2.5 OUTDOOR under the studied conditions, that is, wintertime with reduced air exchange rates, high influence of indoor sources, and relatively low outdoor concentrations of PM. Reducing PM2.5 INDOOR exposure requires reduction of both infiltration from outdoors and indoor‐generated particles.
Exposure to particulate matter (PM) has been associated with DNA damage, but the relationships between PM, telomere length and cellular senescence remain unclear. This study aimed to investigate the effects and potential mechanisms of PM on telomere length and cellular senescence in human lung epithelial cells. Human lung epithelial A549 cells were exposed to PM for 24 h. Cell viability and cytotoxicity were measured by the WST-1 assay and the lactate dehydrogenase release, respectively. Cellular uptake of PM was observed using transmission electron microscopy. Telomere length was measured using qPCR and expressed as T/S ratio. Cell cycle progression was analyzed by flow cytometry. Expression of human telomerase reverse transcriptase (hTERT) and cell cycle regulators was measured using mRNA by qPCR and protein levels by Western blot. Cellular senescence was determined by the expression of senescence-associated β-galactosidase (SA-β-Gal) with fluorescent microscopy and flow cytometry. Exposed to PM at the concentration of 200 μg/ml decreased cell viability and increased LDH levels in culture medium. Remarkably increased uptake of PM, shortening of telomere length, induction of G0/G1 phase arrest, and increased expression of senescence hallmarks were observed after exposure to PM in A549 cells. PM exposure induced upregulation of p21 and downregulation of proliferating cell nuclear antigen (PCNA) and hTERT expression, but no significant change in p53 expression, in A549 cells. Overall, exposure to PM may downregulate hTERT and PCNA through p53-independent induction of p21 expression, leading to telomere shortening, G0/G1 arrest and the onset of cellular senescence in human lung epithelial cells.
Evidences on the association of air pollutants and semen quality were limited and mechanism-based biomarkers were sparse. We enrolled 423 men at a fertility clinic in Shijiazhuang, China to evaluate associations between air pollutants and semen quality parameters including the conventional ones, sperm mitochondrial DNA copy number (mtDNAcn), sperm telomere length (STL) and seminal spermatogenic cells. PM2.5, PM10, CO, SO2, NO2 and O3 exposure during lag0-90, lag0-9, lag10-14 and lag70-90 days were evaluated with ordinary Kringing model. The exposure-response correlations were analyzed with multiple linear regression models. CO, PM2.5 and PM10 were adversely associated with conventional semen parameters including sperm count, motility and morphology. Besides, CO was positively associated with seminal primary spermatocyte (lag70-90, 0.49; 0.14, 0.85) and mtDNAcn (lag0-90, 0.37; 0.12, 0.62, lag10-14, 0.31; 0.12, 0.49), negatively associated with STL (lag0-9, -0.30; -0.57, -0.03). PM2.5 was positively associated with mtDNAcn (0.50; 0.24, 0.75 and 0.38; 0.02, 0.75 for lag0-90 and lag70-90) while negatively associated with STL (lag70-90, -0.49; -0.96, -0.01). PM10 and NO2 were positively associated with mtDNAcn. Our findings indicate CO and PM might impair semen quality testicularly and post-testicularly while seminal spermatogenic cell, STL and mtDNAcn change indicate necessity for more attention on these mechanisms.
Inflammation and oxidative stress are considered the main drivers of vasomotor dysfunction and progression of atherosclerosis after inhalation of particulate matter. In addition, new studies have shown that particle exposure can induce the level of bioactive mediators in serum, driving vascular- and systemic toxicity. We aimed to investigate if pulmonary inflammation would accelerate nanoparticle-induced atherosclerotic plaque progression in Apolipoprotein E knockout (ApoE-/-) mice. ApoE -/- mice were exposed to vehicle, 8.53 or 25.6 μg nanosized carbon black (CB) alone or spiked with LPS (0.2 μg/mouse/exposure; once a week for 10 weeks). Inflammation was determined by counting cells in bronchoalveolar lavage fluid. Serum Amyloid A3 (Saa3) expression and glutathione status were determined in lung tissue. Plaque progression was assessed in the aorta and the brachiocephalic artery. The effect of vasoactive mediators in plasma of exposed ApoE-/- mice was assessed in aorta rings isolated from naïve C57BL/6 mice. Pulmonary exposure to CB and/or LPS resulted in pulmonary inflammation with a robust influx of neutrophils. The CB exposure did not promote plaque progression in aorta or BCA. Incubation with 0.5% plasma extracted from CB-exposed ApoE-/- mice caused vasoconstriction in aorta rings isolated from naïve mice; this effect was abolished by the treatment with the serotonin receptor antagonist Ketanserin. In conclusion, repeated pulmonary exposure to nanosized CB and LPS caused lung inflammation without progression of atherosclerosis in ApoE-/- mice. Nevertheless, plasma extracted from mice exposed to nanosized CB induced vasoconstriction in aortas of naïve wild-type mice, an effect possibly related to increased plasma serotonin.
Background:
Telomere length and mitochondrial DNA (mtDNA) content are markers of aging and aging-related diseases. There is inconclusive evidence concerning the mechanistic effects of airborne particulate matter (PM) exposure on biomolecular markers of ageing OBJECTIVE: The present study examines the association between short- and long-term PM exposure with telomere length and mtDNA content in elderly and investigates to what extend this association is mediated by expression of genes playing a role in the telomere-mitochondrial axis of aging.
Methods:
Among 166 non-smoking elderly, we used qPCR to measure telomere length and mtDNA content in leukocytes, and RNA from whole blood to measure expression of SIRT1, TP53, PPARGC1A, PPARGC1B, NRF1 and NFE2L. Associations between PM exposure and markers of aging were estimated using multivariable linear regression models adjusted for gender, age, BMI, socio-economic status, statin use, past smoking status, white blood cell count and percentage of neutrophils. Mediation analysis was performed to explore the role of age-related markers between the association of PM exposure and outcome. Annual PM2.5 exposure was calculated for each participant's home address using a high resolution spatial-temporal interpolation model.
Results:
Annual PM2.5 concentrations ranged from 15 to 23 µg/m(3). A 5 µg/m(3) increment in annual PM2.5 concentration was associated with a relative decrease of 16.8% (95% CI: -26.0%, -7.4%, p=0.0005) in telomere length and a relative decrease of 25.7% (95% CI: -35.2%, -16.2%, p<0.0001) in mtDNA content. Assuming causality, results of the mediation analysis indicated that SIRT1 mediated 19.5% and 22.5% of the estimated effect of PM2.5 exposure on telomere length and mtDNA content, respectively.
Conclusions:
Our findings suggest that the estimated effects of PM2.5 exposure on the telomere-mitochondrial axis of aging may play an important role in chronic health effects of PM2.5.
Apolipoprotein E deficiency (ApoE‑/‑) combined with a high‑fat Western‑type diet (WD) is known to activate the toll‑like receptor (TLR4) pathway and promote atherosclerosis. However, to date, the pathogenic effects of these conditions on the lung have not been extensively studied. Therefore, the present study examined the effects of ApoE‑/‑ and a WD on lung injury and investigated the underlying mechanisms. ApoE‑/‑ and wild‑type mice were fed a WD or normal chow diet for 4, 12 and 24 weeks. Lung inflammation, lung cholesterol content and cytokines profiles in broncho‑alveolar lavage fluid (BALF) were determined. TLR4 and its main downstream molecules were analyzed with western blot analysis. In addition, the role of the TLR4 pathway was further validated using TLR4‑targeted gene silencing. The results showed that ApoE‑/‑ mice developed lung lipidosis following 12 weeks of receiving a WD, as evidenced by an increased lung cholesterol content. Moreover, dependent on the time period of receiving the diet, those mice exhibited pulmonary inflammation, which was manifested by initial leukocyte recruitment (at 4 weeks), by increased alveolar septal thickness and mean linear intercept as well as elevated production of inflammation mediators (at 12 weeks), and by granuloma formation (at 24 weeks). The expression levels of TLR4, myeloid differentiation primary response 88 (MyD88) and nuclear factor kappa B were markedly upregulated in ApoE‑/‑ WD mice at week 12. However, these effects were ameliorated by shRNA‑mediated knockdown of TLR4. By contrast, ApoE‑/‑ ND or wild‑type WD mice exhibited low‑grade or no inflammation and mild lipidosis. The levels of TLR4 and MyD88 in those mice showed only minor changes. In conclusion, ApoE deficiency acts synergistically with a WD to trigger lung lipidosis and inflammation at least in part via TLR4 signaling.
To explore associations of exposure to ambient and indoor air particulate and bio-aerosol pollutants with cardiovascular and respiratory disease markers, we utilized seven repeated measurements from 48 elderly subjects participating in a 4-week home air filtration study. Microvascular function (MVF), lung function, blood leukocyte counts, monocyte adhesion molecule expression, C-reactive protein, Clara cell protein (CC16) and surfactant protein-D (SPD) were examined in relation to exposure preceding each measurement. Exposure assessment included 48-h urban background monitoring of PM10, PM2.5 and particle number concentration (PNC), weekly measurements of PM2.5 in living- and bedroom, 24-h measurements of indoor PNC three times, and bio-aerosol components in settled dust on a 2-week basis. Statistically significant inverse associations included: MVF with outdoor PNC; granulocyte counts with PM2.5; CD31 expression with dust fungi; SPD with dust endotoxin. Significant positive associations included: MVF with dust bacteria; monocyte expression of CD11 with PM2.5 in the bedroom and dust bacteria and endotoxin, CD31 expression with dust serine protease; serum CC16 with dust NAGase. Multiple comparisons demand cautious interpretation of results, which suggest that outdoor PNC have adverse effects on MVF, and outdoor and indoor PM2.5 and bio-aerosols are associated with markers of inflammation and lung cell integrity.
Exposure to ambient air particulate matter (PM) has been linked to decline in pulmonary function and cardiovascular events possibly through inflammation. Little is known about individual exposure to ultrafine particles (UFP) inside and outside modern homes and associated health-related effects.
Associations between vascular and lung function, inflammation markers and exposure in terms of particle number concentration (PNC; d = 10-300 nm) were studied in a cross-sectional design with personal and home indoor monitoring in the Western Copenhagen Area, Denmark. During 48-h, PNC and PM2.5 were monitored in living rooms of 60 homes with 81 non-smoking subjects (30-75 years old), 59 of whom carried personal monitors both when at home and away from home. We measured lung function in terms of the FEV1/FVC ratio, microvascular function (MVF) and pulse amplitude by digital artery tonometry, blood pressure and biomarkers of inflammation including C-reactive protein, and leukocyte counts with subdivision in neutrophils, eosinophils, monocytes, and lymphocytes in blood.
PNC from personal and stationary home monitoring showed weak correlation (r = 0.15, p = 0.24). Personal UFP exposure away from home was significantly inversely associated with MVF (1.3% decline per interquartile range, 95% confidence interval: 0.1-2.5%) and pulse amplitude and positively associated with leukocyte and neutrophil counts. The leukocyte and neutrophil counts were also positively and pulse amplitude negatively associated with total personal PNC. Indoor PNC and PM2.5 showed positive association with blood pressure and inverse association with eosinophil counts.
The inverse association between personal exposure away from home and MVF is consistent with adverse health effects of UFP from sources outside the home and might be related to increased inflammation indicated by leukocyte counts, whereas UFP from sources in the home could have less effect.
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.
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.
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.
Diesel exhaust particulate (DEP), a major component of urban air pollution, has been linked to atherogenesis and precipitation of myocardial infarction. We hypothesized that DEP exposure would increase and destabilise atherosclerotic lesions in apolipoprotein E deficient (ApoE-/-) mice.
ApoE-/- mice were fed a 'Western diet' (8 weeks) to induce 'complex' atherosclerotic plaques, with parallel experiments in normal chow fed wild-type mice. During the last 4 weeks of feeding, mice received twice weekly instillation (oropharyngeal aspiration) of 35 muL DEP (1 mg/mL, SRM-2975) or vehicle (saline). Atherosclerotic burden was assessed by en-face staining of the thoracic aorta and histological examination of the brachiocephalic artery.
Brachiocephalic atherosclerotic plaques were larger in ApoE-/- mice treated with DEP (59+/-10%) than in controls (32+/-7%; P = 0.017). In addition, DEP-treated mice had more plaques per section of artery (2.4+/-0.2 vs 1.8+/-0.2; P = 0.048) and buried fibrous layers (1.2+/-0.2 vs 0.4+/-0.1; P = 0.028). These changes were associated with lung inflammation and increased antioxidant gene expression in the liver, but not with changes in endothelial function, plasma lipids or systemic inflammation.
Increased atherosclerosis is caused by the particulate component of diesel exhaust producing advanced plaques with a potentially more vulnerable phenotype. These results are consistent with the suggestion that removal of the particulate component would reduce the adverse cardiovascular effects of diesel exhaust.
BACKGROUND: Telomere length reflects biological age and is inversely associated with risk of cardiovascular disease (CVD). Ambient air pollution is associated with CVD, but its effect on telomere length is unknown. OBJECTIVE: We investigated whether ambient black carbon (BC), a marker for traffic-related particles, is associated with telomere length in the Normative Aging Study (NAS). METHODS: Among 165 never-smoking men from the NAS, leukocyte telomere length (LTL) was measured repeatedly approximately every 3 years from 1999 through 2006 using quantitative real-time polymerase chain reaction (qRT-PCR). BC concentration at their residences during the year before each LTL measurement was estimated based on a spatiotemporal model calibrated with BC measurements from 82 locations within the study area. RESULTS: The median [interquartile range (IQR)] annual moving-average BC concentration was 0.32 (0.20-0.45) mu g/m(3). LTL, expressed as population-standardized ratio of telomere repeat to single-copy gene copy numbers, had a geometric mean (geometric SD) of 1.25 (1.42). We used linear mixed-effects models including random subject intercepts and adjusted for several potential confounders. We used inverse probability of response weighting to adjust for potential selection bias due to loss to follow-up. An IQR increase in annual BC (0.25 mu g/m(3)) was associated with a 7.6% decrease (95% confidence interval, -12.8 to -2.1) in LTL. We found evidence of effect modification, with a stronger association among subjects >= 75 years of age compared with younger participants (p = 0.050) and statin medications appearing protective of the effects of BC on LTL (p = 0.050). CONCLUSIONS: Telomere attrition, linked to biological aging, may be associated with long-term exposures to airborne particles, particularly those rich in BC, which are primarily related to automobile traffic.
A current paradigm states that monocytes circulate freely and patrol blood vessels but differentiate irreversibly into dendritic
cells (DCs) or macrophages upon tissue entry. Here we show that bona fide undifferentiated monocytes reside in the spleen
and outnumber their equivalents in circulation. The reservoir monocytes assemble in clusters in the cords of the subcapsular
red pulp and are distinct from macrophages and DCs. In response to ischemic myocardial injury, splenic monocytes increase
their motility, exit the spleen en masse, accumulate in injured tissue, and participate in wound healing. These observations
uncover a role for the spleen as a site for storage and rapid deployment of monocytes and identify splenic monocytes as a
resource that the body exploits to regulate inflammation.
There is growing evidence that exposure to small size particulate matter increases the risk of developing cardiovascular disease.
We investigated plaque progression and vasodilatory function in apolipoprotein E knockout (ApoE(-/-)) mice exposed to TiO(2). ApoE(-/-) mice were intratracheally instilled (0.5 mg/kg bodyweight) with rutile fine TiO2 (fTiO2, 288 nm), photocatalytic 92/8 anatase/rutile TiO(2) (pTiO(2), 12 nm), or rutile nano TiO(2) (nTiO(2), 21.6 nm) at 26 and 2 hours before measurement of vasodilatory function in aorta segments mounted in myographs. The progression of atherosclerotic plaques in aorta was assessed in mice exposed to nanosized TiO(2) (0.5 mg/kg bodyweight) once a week for 4 weeks. We measured mRNA levels of Mcp-1, Mip-2, Vcam-1, Icam-1 and Vegf in lung tissue to assess pulmonary inflammation and vascular function. TiO(2)-induced alterations in nitric oxide (NO) production were assessed in human umbilical vein endothelial cells (HUVECs).
The exposure to nTiO(2) was associated with a modest increase in plaque progression in aorta, whereas there were unaltered vasodilatory function and expression levels of Mcp-1, Mip-2, Vcam-1, Icam-1 and Vegf in lung tissue. The ApoE(-/-) mice exposed to fine and photocatalytic TiO(2) had unaltered vasodilatory function and lung tissue inflammatory gene expression. The unaltered NO-dependent vasodilatory function was supported by observations in HUVECs where the NO production was only increased by exposure to nTiO(2).
Repeated exposure to nanosized TiO(2) particles was associated with modest plaque progression in ApoE(-/-) mice. There were no associations between the pulmonary TiO(2) exposure and inflammation or vasodilatory dysfunction.
Telomere length reflects biological age and is inversely associated with risk of cardiovascular disease (CVD). Ambient air pollution is associated with CVD, but its effect on telomere length is unknown.
We investigated whether ambient black carbon (BC), a marker for traffic-related particles, is associated with telomere length in the Normative Aging Study (NAS).
Among 165 never-smoking men from the NAS, leukocyte telomere length (LTL) was measured repeatedly approximately every 3 years from 1999 through 2006 using quantitative real-time polymerase chain reaction (qRT-PCR). BC concentration at their residences during the year before each LTL measurement was estimated based on a spatiotemporal model calibrated with BC measurements from 82 locations within the study area.
The median [interquartile range (IQR)] annual moving-average BC concentration was 0.32 (0.20-0.45) microg/m3. LTL, expressed as population-standardized ratio of telomere repeat to single-copy gene copy numbers, had a geometric mean (geometric SD) of 1.25 (1.42). We used linear mixed-effects models including random subject intercepts and adjusted for several potential confounders. We used inverse probability of response weighting to adjust for potential selection bias due to loss to follow-up. An IQR increase in annual BC (0.25 microg/m3) was associated with a 7.6% decrease (95% confidence interval, -12.8 to -2.1) in LTL. We found evidence of effect modification, with a stronger association among subjects > or = 75 years of age compared with younger participants (p = 0.050) and statin medications appearing protective of the effects of BC on LTL (p = 0.050).
Telomere attrition, linked to biological aging, may be associated with long-term exposures to airborne particles, particularly those rich in BC, which are primarily related to automobile traffic.
Particulate matter, such as diesel exhaust particles (DEPs), modulate adaptive immune responses in the lung; however, their mechanism of action remains largely unclear. Pulmonary dendritic cells (DCs) are crucial mediators in regulating immune responses. We hypothesized that the immunomodulatory effects of DEPs are caused by alteration of DC function. To test this, we instilled mice with DEPs and examined the pulmonary DC recruitment and maturation, their migration to the mediastinal lymph node (MLN), and the subsequent T cell response. We demonstrated that exposure to DEPs increased DC numbers in the bronchoalveolar lavage and the lungs and that DEPs increased the maturation status of these DCs. DEP exposure also enhanced the DC migration to the MLN. Moreover, we showed that DEPs themselves were transported to the MLN in a CCR7- and DC-dependent manner. This resulted in an enhanced T cell recruitment and effector differentiation in the MLN. These data suggest that DEP inhalation modulates immune responses in the lung via stimulation of DC function.
Hypercholesterolemia is increasingly considered the basis for not only cardiovascular pathologies but also several complications affecting other organs such as lungs. In this study, we examined the effect of hypercholesterolemia on lung integrity using a mouse model (ApoE(-/-)) of high-fat (HF) diet-induced atherosclerosis. A 12-week HF diet regimen induced systemic production of TNF-alpha, IFN-gamma, GMC-SF, RANTES, IL-1alpha, IL-2 and IL-12 with TNF-alpha as the predominant cytokine in ApoE(-/-) mice. Concomitantly, TNF-alpha, IFN-gamma and MIP-1alpha were detected in brochoalveolar lavage (BAL) fluids of these mice, coinciding with lung inflammation consisting primarily of monocytes/macrophages. Such lung inflammation correlated with marked collagen deposition and an increase in matrix metalloproteinase-9 activity in ApoE(-/-)mice without mucus production. Although TGF-beta1 was undetectable in the BAL fluid of ApoE(-/-) mice on HF diet, it showed a much wider tissue distribution compared with that of control animals. Direct exposure of smooth muscle cells to oxidized-LDL, in vitro, induced a time-dependent expression of TNF-alpha. Direct intratracheal TNF-alpha-administration induced a lung inflammation pattern in wild-type mice that was strikingly similar to that induced by HF diet in ApoE(-/-) mice. TNF-alpha administration induced expression of several factors known to be critically involved in lung remodeling, such as MCP-1, IL-1beta, TGF-beta1, adhesion molecules, collagen type-I and TNF-alpha itself in the lungs of treated mice. These results suggest that hypercholesterolemia may promote chronic inflammatory conditions in lungs that are conducive to lung remodeling potentially through TNF-alpha-mediated processes.
Atherosclerosis and heart failure are major causes of morbidity and mortality in Western countries. Recent studies are suggesting involvement of telomere biology in the development and progression of age-associated conditions, including hypertension, atherosclerosis, and heart failure. Whether any of these reported associations are based on causal relationships remains to be elucidated. The construction of telomerase-deficient (telomerase RNA component, TERC(-/-)) mice might provide a potential instrumental model to study the involvement of telomere biology in cardiovascular disease. Here, we review the current available information from all studies performed in TERC(-/-) mice providing information on the cardiovascular phenotypic characteristics. Although this mouse model has proven its value in the understanding of the role of telomere biology in cancer, stem cell, and basic telomere research, only few studies were specifically designed to answer cardiovascular-related questions. The TERC(-/-) mice provide exciting opportunities to expand our knowledge of telomere biology in cardiovascular disease and the potential identification of novel targets of treatment.
Telomere shortening and telomerase activation in human somatic cells have been implicated in cell immortalization and cellular senescence. To further study the role of telomerase in immortalization, we assayed telomere length and telomerase activity in primary mouse fibroblasts, in spontaneously immortalized cell clones, and in mouse tissues. In the primary cell cultures, telomere length decreased with increased cell doublings and telomerase activity was not detected. In contrast, in spontaneously immortalized clones, telomeres were maintained at a stable length and telomerase activity was present. To determine if telomere shortening occurs in vivo, we assayed for telomerase and telomere length in tissues from mice of different ages. Telomere length was similar among different tissues within a newborn mouse, whereas telomere length differed between tissues in an adult mouse. These findings suggest that there is tissue-specific regulation of mouse telomerase during development and aging in vivo. In contrast to human tissues, most mouse tissues had active telomerase. The presence of telomerase in these tissues may reflect the ease of immortalization of primary mouse cells relative to human cells in culture.
Telomerase, a ribonucleoprotein enzyme, has been found in immortalized but not in most somatic adult human tissues, and thus emerged as a novel target for cancer chemotherapy. However, its usefulness could still be limited by normal tissue toxicity. This study compares enzyme activity in tissues and tumours in conventional in vivo models and human biopsy material, specifically normal human liver, with a view to determining the therapeutic potential of anti-telomerase therapy. The telomeric repeat amplification protocol (TRAP assay) was used to measure enzyme activity and levels were semiquantified by assaying equal concentrations of cellular protein. Telomerase activity was high in the murine embryonic stem cell line CGR8.8, WRL 68 human embryo liver cells, testis, ovary and liver of adult mouse and rat. Low activity was detected in normal human liver, marmoset and pig liver. Very low enzyme activity was seen in mouse, rat and marmoset bone marrow, brain or skin; no activity could be detected in mammalian lung and heart. On the contrary, all 30 human and murine malignant tissues studied showed high to moderate enzyme levels. However, activity found in murine liver was often higher than in tumour, e.g. in the transplantable adenocarcinoma of the colon MAC16. Our findings indicate that telomerase is present not only in murine but also in other normal mammalian tissues such as liver, and that this activity might result from the presence of somatic stem cells. In view of this, the role of telomerase as a potential selective target for therapy needs further investigation. Furthermore, the understanding of regulatory pathways of this enzyme and the selection of screening models will be critical.
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Exposure to ultrafine particles (UFPs) from vehicle exhaust has been related to risk of cardiovascular and pulmonary disease and cancer, even though exposure assessment is difficult. We studied personal exposure in terms of number concentrations of UFPs in the breathing zone, using portable instruments in six 18-hr periods in 15 healthy nonsmoking subjects. Exposure contrasts of outdoor pollution were achieved by bicycling in traffic for 5 days and in the laboratory for 1 day. Oxidative DNA damage was assessed as strand breaks and oxidized purines in mononuclear cells isolated from venous blood the morning after exposure measurement. Cumulated outdoor and cumulated indoor exposures to UFPs each were independent significant predictors of the level of purine oxidation in DNA but not of strand breaks. Ambient air concentrations of particulate matter with an aerodynamic diameter of < or = 10 microm (PM10), nitrous oxide, nitrogen dioxide, carbon monoxide, and/or number concentration of UFPs at urban background or busy street monitoring stations was not a significant predictor of DNA damage, although personal UFP exposure was correlated with urban background concentrations of CO and NO2, particularly during bicycling in traffic. The results indicate that biologic effects of UFPs occur at modest exposure, such as that occurring in traffic, which supports the relationship of UFPs and the adverse health effects of air pollution.
The contribution of diesel exhaust to atmospheric pollution is a major concern for public health, especially in terms of occurrence of lung cancers. The present study aimed at addressing the toxic effects of a repeated exposure to these emissions in an animal study performed under strictly controlled conditions. Rats were repeatedly exposed to the exhaust of diesel engine. Parameters such as the presence of a particle filter or the use of gasoil containing rapeseed methyl ester were investigated. Various biological parameters were monitored in the lungs to assess the toxic and genotoxic effects of the exposure. First, a transcriptomic analysis showed that some pathways related to DNA repair and cell cycle were affected to a limited extent by diesel but even less by biodiesel. In agreement with occurrence of a limited genotoxic stress in the lungs of diesel-exposed animals, small induction of γ-H2AX and acrolein adducts was observed but not of bulky adducts and 8-oxodGuo. Unexpected results were obtained in the study of the effect of the particle filter. Indeed, exhausts collected downstream of the particle filter led to a slightly higher induction of a series of genes than those collected upstream. This result was in agreement with the formation of acrolein adducts and γH2AX. On the contrary, induction of oxidative stress remained very limited since only SOD was found to be induced and only when rats were exposed to biodiesel exhaust collected upstream of the particle filter. Parameters related to telomeres were identical in all groups. In summary, our results point to a limited accumulation of damage in lungs following repeated exposure to diesel exhausts when modern engines and relevant fuels are used. Yet, a few significant effects are still observed, mostly after the particle filter, suggesting a remaining toxicity associated with the gaseous or nano-particular phases.
Even though clinical, epidemiological and toxicological studies have progressively provided a better knowledge of the underlying mechanisms by which air pollution-derived particulate matter (PM) exerts its harmful health effects, further in vitro studies on relevant cell systems are still needed. Hence, aiming of getting closer to the human in vivo conditions, primary human bronchial epithelial cells derived from normal subjects (NHBE) or sensitive chronic obstructive pulmonary disease (COPD)-diseased patients (DHBE) were differentiated at the air-liquid interface. Thereafter, they were repeatedly exposed to air pollution-derived PM2.5 to study the occurrence of some relevant genetic and/or epigenetic endpoints. Concentration-, exposure- and season-dependent increases of OH-B[a]P metabolites in NHBE, and to a lesser extent, COPD-DHBE cells were reported; however, there were more tetra-OH-B[a]P and 8-OHdG DNA adducts in COPD-DHBE cells. No increase in primary DNA strand break nor chromosomal aberration was observed in repeatedly exposed cells. Telomere length and telomerase activity were modified in a concentration- and exposure-dependent manner in NHBE and particularly COPD-DHBE cells. There were a global DNA hypomethylation, a P16 gene promoter hypermethylation, and a decreasing DNA methyltransferase activity in NHBE and notably COPD-DHBE cells repeatedly exposed. Changes in site-specific methylation, acetylation, and phosphorylation of histone H3 (i.e., H3K4me3, H3K9ac, H3K27ac, and H3S10ph) and related enzyme activities occurred in a concentration- and exposure-dependent manner in all the repeatedly exposed cells. Collectively, these results highlighted the key role played by genetic and even epigenetic events in NHBE and particularly sensitive COPD-DHBE cells repeatedly exposed to air pollution-derived PM2.5 and their different responsiveness. While these specific epigenetic changes have been already described in COPD and even lung cancer phenotypes, our findings supported that, together with genetic events, these epigenetic events could dramatically contribute to the shift from healthy to diseased phenotypes following repeated exposure to relatively low doses of air pollution-derived PM2.5.
Candle burning produces a large amount of particles that contribute substantially to the exposure to indoor particulate matter. The exposures to various types of combustion particles, such as diesel exhaust particles, have been associated with increased risk of lung cancer by mechanisms that involve oxidative stress, inflammation and genotoxicity. The aim of this study was to compare pulmonary effects of candle light combustion particles (CP) with two benchmark diesel exhaust particles (A-DEP and SRM2975). Intratracheal (i.t.) instillation of CP (5 mg/kg bodyweight) in C57BL/6n mice produced a significant influx of alveolar macrophages and polymorphonuclear leukocytes and increased concentrations of proteins and lactate dehydrogenase activity in bronchoalveolar fluid. Lower levels of these markers of inflammation and cytotoxicity were observed after i.t. instillation of the same dose of A-DEP or SRM2975. The i.t. instillation of CP did not generate oxidative damage to DNA in lung tissue, measured as DNA strand breaks and human 8-oxoguanine glycosylase-sensitive sites by the comet assay. The lack of genotoxic response was confirmed in lung epithelial (A549) cells, although the exposure to CP increased intracellular levels of reactive oxygen species. In conclusion, pulmonary exposure to particles from burning candles is associated with inflammation and cytotoxicity in the lungs.
It has long been presumed impossible to measure telomeres in vertebrate DNA by PCR amplification with oligonucleotide primers designed to hybridize to the TTAGGG and CCCTAA repeats, because only primer dimer-derived products are expected. Here we present a primer pair that eliminates this problem, allowing simple and rapid measurement of telomeres in a closed tube, fluorescence-based assay. This assay will facilitate investigations of the biology of telomeres and the roles they play in the molecular pathophysiology of diseases and aging.
While the knowledge of the underlying mechanisms by which air pollution-derived particulate matter (PM) exerts its harmful health effects is still incomplete, detailed in vitro studies are highly needed. With the aim of getting closer to the human in vivo conditions and better integrating a number of factors related to pre-existing chronic pulmonary inflammatory, we sought to develop primary cultures of normal human bronchial epithelial (NHBE) cells and chronic obstructive pulmonary disease (COPD)-diseased human bronchial epithelial (DHBE) cells, grown at the air-liquid interface. Pan-cytokeratin and MUC5AC immunostaining confirmed the specific cell-types of both these healthy and diseased cell models and showed they are closed to human bronchial epithelia. Thereafter, healthy and diseased cells were repeatedly exposed to air pollution-derived PM4 at the non-cytotoxic concentration of 5 μg/cm(2). The differences between the oxidative and inflammatory states in non-exposed NHBE and COPD-DHBE cells indicated that diseased cells conserved their specific physiopathological characteristics. Increases in both oxidative damage and cytokine secretion were reported in repeatedly exposed NHBE cells and particularly in COPD-DHBE cells. Diseased cells repeatedly exposed had lower capacities to metabolize the organic chemicals-coated onto the air-pollution-derived PM4, such as benzo[a]pyrene (B[a]P), but showed higher sensibility to the formation of OH-B[a]P DNA adducts, because their diseased state possibly affected their defenses. Differential profiles of epigenetic hallmarks (i.e., global DNA hypomethylation, P16 promoter hypermethylation, telomere length shortening, telomerase activation, and histone H3 modifications) occurred in repeatedly exposed NHBE and particularly in COPD-DHBE cells. Taken together, these results closely supported the highest responsiveness of COPD-DHBE cells to a repeated exposure to air pollution-derived PM4. The use of these innovative in vitro exposure systems such as NHBE and COPD-DHBE cells could therefore be consider as a very useful and powerful promising tool in the field of the respiratory toxicology, taking into account sensitive individuals.
One type of carbon nanotubes (CNTs) (MWCNT-7, from Mitsui) has been classified as probably carcinogenic to humans, however insufficient data does not warrant the same classification for other types of CNTs. Experimental data indicate that CNT exposure can result in oxidative stress and DNA damage in cultured cells, whereas these materials appear to induce low or no mutagenicity. Therefore, the present study aimed to investigate whether in vitro exposure of cultured airway epithelial cells (A549) to multi-walled CNTs (MWCNTs) could increase the DNA repair activity of oxidatively damaged DNA and drive the cells toward replicative senescence, assessed by attrition of telomeres. To investigate this, H2O2 and KBrO3 were used to induce DNA damage in the cells and the effect of pre-exposure to MWCNT tested for a change in repair activity inside the cells or in the extract of treated cells. The effect of MWCNT exposure on telomere length was investigated for concentration and time response. We report a significantly increased repair activity in A549 cells exposed to MWCNTs compared to non-exposed cells, suggesting that DNA repair activity may be influenced by exposure to MWCNTs. The telomere length was decreased at times longer than 24h, but this decrease was not concentration dependent. The results suggest that the seemingly low mutagenicity of CNTs in cultured cells may be associated with an increased DNA repair activity and a replicative senescence, which may counteract the manifestation of DNA lesions to mutations.
Exposure to particulate matter (PM) from traffic vehicles is hazardous to the vascular system, leading to clinical manifestations and mortality due to ischemic heart disease. By analogy, nanomaterials may also be associated with the same outcomes. Here, the effects of exposure to PM from ambient air, diesel exhaust and certain nanomaterials on atherosclerosis and vasomotor function in animals have been assessed. The majority of studies have used pulmonary exposure by inhalation or instillation, although there are some studies on non-pulmonary routes such as the gastrointestinal tract. Airway exposure to air pollution particles and nanomaterials is associated with similar effects on atherosclerosis progression, augmented vasoconstriction and blunted vasorelaxation responses in arteries, whereas exposure to diesel exhaust is associated with lower responses. At present, there is no convincing evidence of dose-dependent effects across studies. Oxidative stress and inflammation have been observed in the arterial wall of PM-exposed animals with vasomotor dysfunction or plaque progression. From the data, it is evident that pulmonary and systemic inflammation does not seem to be necessary for these vascular effects to occur. Furthermore, there is inconsistent evidence with regard to altered plasma lipid profile and systemic inflammation as a key step in vasomotor dysfunction and progression of atherosclerosis in PM-exposed animals. In summary, the results show that certain nanomaterials, including TiO2, carbon black and carbon nanotubes, have similar hazards to the vascular system as combustion-derived PM.
Engineered nanomaterials (NMs) offer great technological advantages but their risks to human health are still not fully understood. An increasing body of evidence suggests that some NMs are capable of distributing from the site of exposure to a number of secondary organs. The research into the toxicity posed by the NMs in these secondary organs is expanding due to the realisation that some materials may reach and accumulate in these target sites. The translocation to secondary organs includes, but is not limited to, the hepatic, central nervous, cardiovascular and renal systems. Current data indicates that pulmonary exposure is associated with low (inhalation route–0.00001–1% of total applied dose–24 h) translocation of virtually insoluble NMs such as iridium, carbon black, gold and polystyrene, while slightly higher translocation has been observed for NMs with either slow (e.g. silver, cerium dioxide and quantum dots) or fast (e.g. zinc oxide) solubility. The translocation of NMs following intratracheal, intranasal and pharyngeal aspiration is higher (up to 10% of administered dose), however the relevance of these routes for risk assessment is questionable. Uptake of the materials from the gastrointestinal tract seems to follow the same pattern as inhalation translocation, whereas the dermal uptake of NMs is generally reported to be low. The toxicological effects in secondary organs include oxidative stress, inflammation, cytotoxicity and dysfunction of cellular and physiological processes. For toxicological and risk evaluation, further information on the toxicokinetics and persistence of NMs is crucial. The overall aim of this review is to outline the data currently available in the literature on the biokinetics, accumulation, toxicity and eventual fate of NMs in order to assess the potential risks posed by NMs to secondary organs.
-Telomeres are repetitive, gene-poor regions that cap the ends of DNA and help maintain chromosomal integrity. Their shortening is caused by inflammation and oxidative stress within the cellular environment and ultimately leads to cellular senescence. Shortened leukocyte telomere length (LTL) is hypothesized to be a novel biomarker for age and age-related diseases, yet reports on its association with cardio-metabolic outcomes in the literature are conflicting.
-MEDLINE (1966-present), and EMBASE (1980-present) were last searched on September 9(th) 2013. Reference lists of retrieved citations were hand searched for relevant studies. No restrictions were placed on sample size, language, or publication type or date. 15 Cohort and 12 case-control studies reporting the association between LTL and stroke, myocardial infarction, and type 2 diabetes were independently selected for inclusion by two reviewers. Data extraction and risk of bias assessment were completed independently by two reviewers using pre-defined criteria. Studies were pooled using the generic inverse variance method and both fixed and random effects models. A 1-standard deviation decrease in LTL was significantly associated with stroke (OR=1.21, 95% CI=1.06-1.37; I(2)=61%), myocardial infarction (OR=1.24, 95% CI=1.04-1.47; I(2)=68%), and type 2 diabetes (OR=1.37, 95% CI=1.10-1.72; I(2)=91%). Stratification by measurement technique, study design, study size, and ethnicity explained heterogeneity in certain cardio-metabolic outcomes.
-Shortened LTL demonstrates a significant association with stroke, myocardial infarction, and type 2 diabetes. Larger, well-designed studies are needed to confirm these findings and explore sources of heterogeneity.
Background:
Biomass smoke at higher concentrations is associated with respiratory symptoms and, after years of exposure, increased risk of respiratory disorders in adults, but its effects on cardiovascular diseases are not well characterized, particularly compared with other pollution sources like tobacco smoke or traffic.
Methods:
We conducted a cross-sectional study and enrolled 25 women living in rural Sichuan, China. We measured integrated 24-h personal exposure to fine particulate matter (PM2.5) and black carbon, and measured PM2.5 and black carbon in their kitchens. We assessed participants' brachial and central blood pressure and arterial stiffness using pulse wave analysis, and analyzed dried blood spot and buccal cell samples for C-reactive protein and relative telomere length. We also evaluated the difference in these physiological and biomarker measures between individuals with high (≥median) versus low (<median) PM2.5 exposure using multivariate regression.
Results:
Geometric mean 24-h PM2.5 and black carbon exposures were 61 µg/m(3) (95% CI: 48, 78) and 3.2 µg/m(3) (95% CI: 2.3, 4.5), respectively. Average kitchen PM2.5 and black carbon concentrations were only moderately correlated with personal exposures (PM2.5: r=0.41; black carbon: r=0.63), although they had similar means. Women in the high and low exposure groups were similar in age, obesity, socioeconomic status, salt intake, and physical activity. Women in the high PM2.5 exposure group had higher mean brachial systolic blood pressure (SBP; difference=4.6 mmHg, 95% CI -7.8, 16.9), central SBP (difference=3.1 mmHg, 95% CI: -8.4, 14.5), central pulse pressure (difference=4.1 mmHg; 95% CI: -4.2, 12.4), and augmentation index (difference=2.8%, 95% CI: -1.6, 7.2). High exposed women had 43% shorter telomere length (95% CI: -113, 28) than that of women in the low exposure group. There were no differences in pulse wave velocity or C-reactive protein between the two exposure groups. None of the results was statistically significant.
Conclusions:
Our results suggest that it is feasible to measure markers of vascular function and biomarkers of inflammation and oxidative stress in field studies of biomass smoke. Although many of the associations were in the expected direction, larger studies would be needed to establish the effects.
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.
Exposure to particles has been suggested to generate hepatosteatosis by oxidative stress mechanisms. We investigated lipid accumulation in cultured human hepatocytes (HepG2) and rat liver after exposure to four different carbon-based particles. HepG2 cells were exposed to particles for 3h and subsequently incubated for another 18h to manifest lipid accumulation. In an animal model of metabolic syndrome we investigated the association between intake of carbon black (CB, 14nm) particles and hepatic lipid accumulation, inflammation and gene expression of Srebp-1, Fasn and Scd-1 involved in lipid synthesis. There was a concentration-dependent increase in intracellular lipid content after exposure to CB in HepG2 cells, which was only observed after co-exposure to oleic/palmitic acid. Similar results were observed in HepG2 cells after exposure to diesel exhaust particles, fullerenes C60 or pristine single-walled carbon nanotubes. All four types of particles also generated oxidatively damaged DNA, assessed as formamidopyrimidine DNA glycosylase (FPG) sensitive sites, in HepG2 cells after 3h exposure. The animal model of metabolic syndrome showed increased lipid load in the liver after one oral exposure to 6.4mg/kg of CB in lean Zucker rats. This was not associated with increased iNOS staining in the liver, indicating that the oral CB exposure was associated with hepatic steatosis rather than steatohepatitis. The lipid accumulation did not seem to be related to increased lipogenesis because there were unaltered expression levels in both the HepG2 cells and rat livers. Collectively, exposure to particles is associated with oxidative stress and steatosis in hepatocytes.
Particle number (PN) concentrations (10 - 300 nm in size) were continuously measured over a period of ~45 hours in 56 residences of non-smokers in Copenhagen, Denmark. The highest concentrations were measured when occupants were present and awake (geometric mean, GM: 22.3 × 10^3 cm-3), the lowest when the homes were vacant (GM: 6.1 × 10^3 cm-3) or the occupants were asleep (GM: 5.1 × 10^3 cm-3). Diary entries regarding occupancy and particle related activities were used to identify source events and apportion the daily integrated exposure among sources. Source events clearly resulted in increased PN concentrations and decreased average particle diameter. For a given event, elevated particle concentrations persisted for several hours after the emission of fresh particles ceased. The residential daily integrated PN exposure in the 56 homes ranged between 37 × 10^3 and 6.0 × 10^6 particles per cm3•h/day (GM: 3.3 × 10^5 cm-3•h/day). On average, ~90% of this exposure occurred outside of the period from midnight to 6 AM. Source events, especially candle burning, cooking, toasting and unknown activities, were responsible on average for ~65% of the residential integrated exposure (51% without the unknown activities). Candle burning occurred in half of the homes where, on average, it was responsible for almost 60% of the integrated exposure.
A high volume electrostatic field-sampler was developed for collection of fine particles, which easily can be recovered for subsequent sample characterisation and bioassays. The sampler was based on a commercial office air cleaner and consisted of a prefilter followed by electrostatic collection plates operating at 2.7kV. The sampler performance was characterised for 26nm to 5.4μm-size particles in urban street air. The collection efficiency reached a maximum (60–70%) between 0.2 and 0.8μm and dropped to ∼25% at 30nm and 2.5μm, respectively. After extraction in water, the particle loss was
Cellular senescence, defined as arrest during the cell cycle (G0), is involved in the complex process of the biological ageing of tissues, organs, and organisms. Senescence is driven by many factors including oxidative stress, the DNA damage and repair response, inflammation, mitogenic signals, and telomere shortening. Telomeres are shortened by each cell division until a critical length is reached and dysfunction ensues. DNA-repair pathways are then recruited and cells enter senescence, losing their capacity to proliferate. In addition to cell division, factors causing telomere shortening include DNA damage, inflammation, and oxidative stress. Both cardiovascular risk factors and common cardiovascular diseases, such as atherosclerosis, heart failure, and hypertension, are associated with short leucocyte telomeres, but causality remains undetermined. Telomere length does not satisfy strict criteria for being a biomarker of ageing, but adds predictive power to that of chronological age, and can be considered a marker of cardiovascular ageing. The 'senescence-associated secretory phenotype' of senescent cells exerts a wide range of autocrine and paracrine activities aimed at tissue repair, but which also fuel degenerative and proliferative alterations that contribute to cardiovascular disease. In this Review, the relationship between telomere shortening, senescence, and cardiovascular disease is discussed.
Studies in mono-culture of cells have shown that diesel exhaust particles (DEPs) increase the production of reactive oxygen species (ROS) and oxidative stress-related damage to DNA. However, the level of particle-generated genotoxicity may depend on interplay between different cell types, e.g. lung epithelium and immune cells. Macrophages have important immune defence functions by engulfing insoluble foreign materials, including particles, although they might also promote or enhance inflammation. We investigated the effect of co-culturing type II lung epithelial A549 cells with macrophages upon treatment with standard reference DEPs, SRM2975 and SRM1650b. The exposure to DEPs did not affect the colony-forming ability of A549 cells in co-culture with THP-1a cells. The DEPs generated DNA strand breaks and oxidatively damaged DNA, measured using the alkaline comet assay as formamidopyrimidine-DNA glycosylase or oxoguanine DNA glycosylase (hOGG1) sensitive sites, in mono-cultures of A549 or THP-1a and co-cultures of A549 and THP-1a cells. The strongest genotoxic effects were observed in A549 mono-cultures and SRM2975 was more potent than SRM1650b. The ROS production only increased in cells exposed to SRM2975, with strongest concentration-dependent effect in the THP-1a mono-cultures. The basal respiration level in THP-1a cells increased on exposure to SRM1650b and SRM2975 without indication of mitochondrial dysfunction. This is consistent with activation of the cells and there was no direct relationship between levels of respiration and ROS production. In conclusion, exposure of mono-cultured cells to DEPs generated oxidative stress to DNA, whereas co-cultures with macrophages had lower levels of oxidatively damaged DNA than A549 epithelial cells.
The aim of this study is to investigate the physical and chemical properties of particle emissions from candle burning in indoor air. Two representative types of tapered candles were studied during steady burn, sooting burn and smouldering (upon extinction) under controlled conditions in a walk-in stainless steel chamber. Steady burn emits relatively high number emissions of ultrafine particles dominated by either phosphates or alkali nitrates. The likely source of these particles is flame retardant additives to the wick. Sooting burn in addition emits larger particles mainly consisting of agglomerated elemental carbon. This burning mode is associated with the highest mass emission factors. Particles emitted during smouldering upon extinction are dominated by organic matter. A mass closure was illustrated for the total mass concentration, the summed mass concentration from chemical analysis and the size-integrated mass concentration assessed from number distribution measurements using empirically determined effective densities for the three particle types.
Smokers with airflow obstruction have an increased risk of atherosclerosis, but the relationship between the pathogenesis of these diseases is not well understood. To determine whether hypercholesterolemia alters lung inflammation and emphysema formation, we examined the lung phenotype of two hypercholesterolemic murine models of atherosclerosis at baseline and on a high-fat diet. Airspace enlargement developed in the lungs of apolipoprotein E-deficient (Apoe(-/-)) mice exposed to a Western-type diet for 10 wk. An elevated number of macrophages and lymphocytes accompanied by an increase in matrix metalloproteinase-9 (MMP-9) activity and MMP-12 expression was observed in the lungs of Apoe(-/-) mice on a Western-type diet. In contrast, low-density lipoprotein receptor-deficient (Ldlr(-/-)) mice did not exhibit lung destruction or inflammatory changes. Most importantly, we revealed augmented expression of the downstream targets of the Toll-like receptor (TLR) pathway, interleukin-1 receptor-associated kinase 1, and granulocyte colony-stimulating factor, in the lungs of Apoe(-/-) mice fed with a Western-type diet. In addition, we demonstrated overexpression of MMP-9 in Apoe(-/-) macrophages treated with TLR4 ligand, augmented with the addition of oxidized LDL, suggesting that emphysema in these mice results from the activation of the TLR pathway secondary to known abnormal cholesterol efflux. Our findings indicate that, in Apoe(-/-) mice fed with an atherogenic diet, abnormal cholesterol efflux leads to increased systemic inflammation with subsequent lung damage and emphysema formation.
Toxicological effects of wood smoke particles are less investigated than traffic-related combustion particles. We investigated the effect of wood smoke particles, generated by smouldering combustion conditions, on human umbilical endothelial cells (HUVECs) co-cultured with or without monocytic THP-1 cells. Standard reference material (SRM) 2975 diesel exhaust particles were used as benchmark particles. Wood smoke particles at 50 μg/ml or 100 μg/ml caused adhesion of THP-1 monocytes onto HUVECs in co-cultures, whereas SRM2975 had no such effect. Both types of particles from 1 μg/ml increased VCAM-1 expression on HUVECs in mono-cultures. However, only the exposure to wood smoke particles was associated with increased expression of TNF and IL8 mRNA in THP-1 cells. We found no effect on the intracellular production of reactive oxygen species by the fluorescent probe DCFH-DA, whereas especially the wood smoke particles caused increased level of DNA strand breaks and oxidised guanines at concentrations with low cytotoxicity. In conclusion, our results indicate that the adherence of monocytes on endothelial cells in wood smoke particle exposed cultures depend on activation of both cell types.
Our aim was to compare hazards of particles from combustion of biodiesel blends and conventional diesel (D(100)) in old and improved engines. We determined DNA damage in A549 cells, mRNA levels of CCL2 and IL8 in THP-1 cells, and expression of ICAM-1 and VCAM-1 in human umbilical cord endothelial cells (HUVECs). Viability and production of reactive oxygen species (ROS) were investigated in all cell types. We collected particles from combustion of D(100) and 20% (w/w) blends of animal fat or rapeseed oil methyl esters in light-duty vehicle engines complying with Euro2 or Euro4 standards. Particles emitted from the Euro4 engine were smaller in size and more potent than particles emitted from the Euro2 engine with respect to ROS production and DNA damage, but similarly potent concerning cytokine mRNA expression. Particles emitted from combustion of biodiesel blends were larger in size, and less or equally potent than particles emitted from combustion of D(100) concerning ROS production, DNA damage and mRNA of CCL2 and IL8. ICAM-1 and VCAM-1 expression in HUVECs was only increased by D(100) particles from the Euro4 engine. This suggests that particle emissions from biodiesel in equal mass concentration are less toxic than conventional diesel.
Exposure to particulate matter is associated with oxidative stress and risk of cardiovascular diseases. We investigated if vitamin C and desferrioxamine (iron chelator) altered the levels of oxidative stress and expression of cell adhesion molecules upon exposure to diesel exhaust particles (DEP) and carbon black in cultured human umbilical vein endothelial cells (HUVECs). We found that the particles were only slightly cytotoxic in the high concentration ranges. Particle-induced intracellular reactive oxygen species (ROS) production was attenuated by vitamin C administration or iron chelation and particularly when combined (p<0.001). Only desferrioxamine protected the DNA from oxidative damage in terms of strand breaks and formamidopyrimidine DNA glycosylase sensitive sites induced by carbon black (p<0.01). Carbon black and small sized DEP generated from an Euro4 engine increased the surface expression of VCAM-1 and ICAM-1, whereas DEP from an engine representing an old combustion type engine (SRM2975) with larger particles did not affect the expression of cell adhesion molecules. These effects were also attenuated by desferrioxamine but not vitamin C. The study shows that exposure to carbon black and DEP in HUVECs can generate both oxidative stress and expression of cell surface adhesion molecules and that these effects can in part be attenuated by vitamin C and desferrioxamine.
The development and use of nanoparticles have alerted toxicologists and regulators to issues of safety testing. By analogy with ambient air particles, it can be expected that small doses are associated with a small increase in risk of cardiovascular diseases, possibly through oxidative stress and inflammatory pathways. We have assessed the effect of exposure to particulate matter on progression of atherosclerosis and vasomotor function in humans, animals, and ex vivo experimental systems. The type of particles that have been tested in these systems encompass TiO(2), carbon black, fullerene C(60), single-walled carbon nanotubes, ambient air particles, and diesel exhaust particles. Exposure to ambient air particles is associated with accelerated progression of atherosclerosis and vasomotor dysfunction in both healthy and susceptible animal models and humans at risk of developing cardiovascular diseases. The vasomotor dysfunction includes increased vasoconstriction as well as reduced endothelium-dependent vasodilatation; endothelium-independent vasodilatation is often unaffected indicating mainly endothelial dysfunction. Pulmonary exposure to TiO(2), carbon black, and engineered nanoparticles generate vasomotor dysfunction; the effect size is similar to that generated by combustion-derived particles, although the effect could depend on the exposure period and the administered dose, route, and mode. The relative risk associated with exposure to nanoparticles may be small compared to some traditional risk factors for cardiovascular diseases, but superimposed on these and possible exposure to large parts of the population it is a significant public health concern. Overall, assessment of vasomotor dysfunction and progression of atherosclerosis are promising tools for understanding the effects of particulate matter.
Combustion of biomass and wood for residential heating and/or cooking contributes substantially to both ambient air and indoor levels of particulate matter (PM). Toxicological characterization of ambient air PM, especially related to traffic, is well advanced, whereas the toxicology of wood smoke PM (WSPM) is poorly assessed. We assessed a wide spectrum of toxicity end points in human A549 lung epithelial and THP-1 monocytic cell lines comparing WSPM from high or low oxygen combustion and ambient PM collected in a village with many operating wood stoves and from a rural background area. In both cell types, all extensively characterized PM samples (1.25-100 μg/mL) induced dose-dependent formation of reactive oxygen species and DNA damage in terms of strand breaks and formamidopyrimidine DNA glycosylase sites assessed by the comet assay with WSPM being most potent. The WSPM contained more polycyclic aromatic hydrocarbons (PAH), less soluble metals, and expectedly also had a smaller particle size than PM collected from ambient air. All four types of PM combined increased the levels of 8-oxo-7,8-dihydro-2'-deoxyguanosine dose-dependently in A549 cells, whereas there was no change in the levels of etheno-adducts or bulky DNA adducts. Furthermore, mRNA expression of the proinflammatory genes monocyte chemoattractant protein-1, interleukin-8, and tumor necrosis factor-α as well as the oxidative stress gene heme oxygenase-1 was upregulated in the THP-1 cells especially by WSPM and ambient PM sampled from the wood stove area. Expression of oxoguanine glycosylase 1, lymphocyte function-associated antigen-1, and interleukin-6 did not change. We conclude that WSPM has small particle size, high level of PAH, low level of water-soluble metals, and produces high levels of free radicals, DNA damage as well as inflammatory and oxidative stress response gene expression in cultured human cells.
In 2004, the first American Heart Association scientific statement on "Air Pollution and Cardiovascular Disease" concluded that exposure to particulate matter (PM) air pollution contributes to cardiovascular morbidity and mortality. In the interim, numerous studies have expanded our understanding of this association and further elucidated the physiological and molecular mechanisms involved. The main objective of this updated American Heart Association scientific statement is to provide a comprehensive review of the new evidence linking PM exposure with cardiovascular disease, with a specific focus on highlighting the clinical implications for researchers and healthcare providers. The writing group also sought to provide expert consensus opinions on many aspects of the current state of science and updated suggestions for areas of future research. On the basis of the findings of this review, several new conclusions were reached, including the following: Exposure to PM <2.5 microm in diameter (PM(2.5)) over a few hours to weeks can trigger cardiovascular disease-related mortality and nonfatal events; longer-term exposure (eg, a few years) increases the risk for cardiovascular mortality to an even greater extent than exposures over a few days and reduces life expectancy within more highly exposed segments of the population by several months to a few years; reductions in PM levels are associated with decreases in cardiovascular mortality within a time frame as short as a few years; and many credible pathological mechanisms have been elucidated that lend biological plausibility to these findings. It is the opinion of the writing group that the overall evidence is consistent with a causal relationship between PM(2.5) exposure and cardiovascular morbidity and mortality. This body of evidence has grown and been strengthened substantially since the first American Heart Association scientific statement was published. Finally, PM(2.5) exposure is deemed a modifiable factor that contributes to cardiovascular morbidity and mortality.
Personal exposure to ultrafine particles (UFP) can occur while people are cooking, driving, smoking, operating small appliances such as hair dryers, or eating out in restaurants. These exposures can often be higher than outdoor concentrations. For 3 years, portable monitors were employed in homes, cars, and restaurants. More than 300 measurement periods in several homes were documented, along with 25 h of driving two cars, and 22 visits to restaurants. Cooking on gas or electric stoves and electric toaster ovens was a major source of UFP, with peak personal exposures often exceeding 100,000 particles/cm³ and estimated emission rates in the neighborhood of 10¹² particles/min. Other common sources of high UFP exposures were cigarettes, a vented gas clothes dryer, an air popcorn popper, candles, an electric mixer, a toaster, a hair dryer, a curling iron, and a steam iron. Relatively low indoor UFP emissions were noted for a fireplace, several space heaters, and a laser printer. Driving resulted in moderate exposures averaging about 30,000 particles/cm³ in each of two cars driven on 17 trips on major highways on the East and West Coasts. Most of the restaurants visited maintained consistently high levels of 50,000-200,000 particles/cm³ for the entire length of the meal. The indoor/outdoor ratios of size-resolved UFP were much lower than for PM₂.₅ or PM₁₀, suggesting that outdoor UFP have difficulty in penetrating a home. This in turn implies that outdoor concentrations of UFP have only a moderate effect on personal exposures if indoor sources are present. A time-weighted scenario suggests that for typical suburban nonsmoker lifestyles, indoor sources provide about 47% and outdoor sources about 36% of total daily UFP exposure and in-vehicle exposures add the remainder (17%). However, the effect of one smoker in the home results in an overwhelming increase in the importance of indoor sources (77% of the total).
The genomes of prokaryotes and eukaryotic organelles are usually circular as are most plasmids and viral genomes. In contrast, the nuclear genomes of eukaryotes are organized on linear chromosomes, which require mechanisms to protect and replicate DNA ends. Eukaryotes navigate these problems with the advent of telomeres, protective nucleoprotein complexes at the ends of linear chromosomes, and telomerase, the enzyme that maintains the DNA in these structures. Mammalian telomeres contain a specific protein complex, shelterin, that functions to protect chromosome ends from all aspects of the DNA damage response and regulates telomere maintenance by telomerase. Recent experiments, discussed here, have revealed how shelterin represses the ATM and ATR kinase signaling pathways and hides chromosome ends from nonhomologous end joining and homology-directed repair.
By imposing a replicative defect in most somatic cells, gradual telomere attrition during aging is thought to progressively impair cellular function and viability and may contribute to age-related disease. Immune cells play important roles in all phases of atherosclerosis, a multifactorial disease that prevails within the elderly. Because shorter telomeres have been found in circulating blood leukocytes of human patients with advanced coronary atherosclerosis, it has been suggested that telomere shortening may predispose the organism to atheroma development. In this study, we assessed the impact of telomere attrition on atherogenesis induced by dietary cholesterol in apolipoprotein E (apoE)-deficient mice, a well-established model of experimental atherosclerosis that recapitulates important aspects of the human disease. Our study shows that late-generation mice doubly deficient in apoE and telomerase RNA experience telomere attrition and a substantial reduction of atherosclerosis compared with control mice with intact telomerase, in spite of sustained hypercholesterolemia in response to the atherogenic diet. Short telomeres impaired the proliferation of both lymphocytes and macrophages, an important step in atherosclerosis development. Therefore, telomere exhaustion resulting in replicative immunosenescence may serve as a mechanism for restricting atheroma progression.
Unlabelled:
Humans and their activities are known to generate considerable amounts of particulate matter indoors. Some of the activities are cooking, smoking and cleaning. In this study 13 different particle sources were for the first time examined in a 32 m3 full-scale chamber with an air change rate of 1.7 +/- 0.1/h. Two different instruments, a condensation particle counter (CPC) and an optical particle counter (OPC) were used to quantitatively determine ultrafine and fine particle emissions, respectively. The CPC measures particles from 0.02 microm to larger than 1.0 microm. The OPC was adjusted to measure particle concentrations in eight fractions between 0.3 and 1.0 microm. The sources were cigarette side-stream smoke, pure wax candles, scented candles, a vacuum cleaner, an air-freshener spray, a flat iron (with and without steam) on a cotton sheet, electric radiators, an electric stove, a gas stove, and frying meat. The cigarette burning, frying meat, air freshener spray and gas stove showed a particle size distribution that changed over time towards larger particles. In most of the experiments the maximum concentration was reached within a few minutes. Typically, the increase of the particle concentration immediately after activation of the source was more rapid than the decay of the concentration observed after deactivation of the source. The highest observed concentration of ultrafine particles was approximately 241,000 particles/cm3 and originated from the combustion of pure wax candles. The weakest generation of ultrafine particles (1.17 x 10(7) particles per second) was observed when ironing without steam on a cotton sheet, which resulted in a concentration of 550 particles/cm3 in the chamber air. The highest generation rate (1.47 x 10(10) particles per second) was observed in the radiator test.
Practical implications:
Humans and their activities are known to generate substantial amounts of particulate matter indoors and potentially they can have a strong influence on short-term exposure. In this study a quantitative determination of the emissions of fine and ultrafine particles from different indoor sources was performed. The aim is a better understanding of the origin and fate of indoor particles. The results may be useful for Indoor Air Quality models.