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Fine particles, genetic pathways, and markers of inflammation and endothelial dysfunction: Analysis on particulate species and sources
Abstract
Studies have found associations between PM2.5 and cardiovascular events. The role of different components of PM2.5 is not well understood. We used linear mixed-effects models with the adaptive LASSO penalty to select PM2.5 species and source(s), separately, that may be associated with markers of inflammation and endothelial dysfunction, with adjustment for age, obesity, smoking, statin use, diabetes mellitus, temperature, and season as fixed effects in a large longitudinal cohort of elderly men. We also analyzed these associations with source apportionment models and examined genetic pathway-air pollution interactions within three relevant pathways (oxidative stress, metal processing, and endothelial function). We found that independent of PM2.5 mass vanadium (V) was associated with intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). An IQR increase (3.2 ng/m(3)) in 2-day moving average V was associated with a 2.5% (95% CI: 1.2-3.8%) change in ICAM-1 and a 3.9% (95% CI: 2.2-5.7%) change in VCAM-1, respectively. In addition, an oil combustion source rich in V was linked to these adhesion molecules. People with higher allelic risk profiles related to oxidative stress may have greater associations (P-value of interaction=0.11). Our findings suggest that particles derived from oil combustion may be associated with inflammation and endothelial dysfunction, and it is likely that oxidative stress plays a role in the associations.Journal of Exposure Science and Environmental Epidemiology advance online publication, 6 January 2016; doi:10.1038/jes.2015.83.
... We measured daily PM 2.5 , and 14 of its species: ambient UFP concentrations [number of particles (PN)/cm 3 ], black carbon (BC), sodium (Na), iron (Fe), aluminum (Al), silicon (Si), potassium (K), nickel (Ni), vanadium (V), sulfur (S), selenium (Se), lead (Pb), zinc (Zn), and titanium (Ti). We focused on these species as their levels were mostly above detection limits and representative of different PM 2.5 sources (Dai et al., 2016). All exposures were measured at a fixed monitoring site at the ambient air particle monitoring Harvard Supersite, located on the roof of the Countway Library of the Harvard Medical School in downtown Boston, MA and approximately 1 km from the examination center. ...
... Such metals can induce oxidative stress through redox cycling or quenching antioxidant capacity (Valko et al., 2016). PM derived from oil combustion e.g., V may be associated with inflammation and endothelial dysfunction as measured by intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), and it is likely that oxidative stress plays a role in these associations (Dai et al., 2016). Residual oil ash which contains these metals has been shown to be highly toxic in animal and in vitro studies. ...
... Si and Al are mostly from road dust and crustal materials. V and Ni are predominantly from fuel oil combustion (Dai et al., 2016;Bell et al., 2014). Wood burning and local pollution produces K and Cu. ...
Background:
The metabolomic signatures of short- and long-term exposure to PM2.5 have been reported and linked to inflammation and oxidative stress. However, little is known about the relative contribution of the specific PM2.5 species (hence sources) that drive these metabolomic signatures.
Objectives:
We aimed to determine the relative contribution of the different species of PM2.5 exposure to the perturbed metabolic pathways related to changes in the plasma metabolome.
Methods:
We performed mass-spectrometry based metabolomic profiling of plasma samples among men from the Normative Aging Study to identify metabolic pathways associated with PM2.5 species. The exposure windows included short-term (one, seven-, and thirty-day moving average) and long-term (one year moving average). We used linear mixed-effect regression with subject-specific intercepts while simultaneously adjusting for PM2.5, NO2, O3, temperature, relative humidity, and covariates and correcting for multiple testing. We also used independent component analysis (ICA) to examine the relative contribution of patterns of PM2.5 species.
Results:
Between 2000 and 2016, 456 men provided 648 blood samples, in which 1158 metabolites were quantified. We chose 305 metabolites for the short-term and 288 metabolites for the long-term exposure in this analysis that were significantly associated (p-value < 0.01) with PM2.5 to include in our PM2.5 species analysis. On average, men were 75.0 years old and their body mass index was 27.7 kg/m2. Only 3% were current smokers. In the adjusted models, ultrafine particles (UFPs) were the most significant species of short-term PM2.5 exposure followed by nickel, vanadium, potassium, silicon, and aluminum. Black carbon, vanadium, zinc, nickel, iron, copper, and selenium were the significant species of long-term PM2.5 exposure. We identified several metabolic pathways perturbed with PM2.5 species including glycerophospholipid, sphingolipid, and glutathione. These pathways are involved in inflammation, oxidative stress, immunity, and nucleic acid damage and repair. Results were overlapped with the ICA.
Conclusions:
We identified several significant perturbed plasma metabolites and metabolic pathways associated with exposure to PM2.5 species. These species are associated with traffic, fuel oil, and wood smoke. This is the largest study to report a metabolomic signature of PM2.5 species' exposure and the first to use ICA.
... Franchini et al. (2016) and others (Spiezia et al., 2016;Baccarelli et al., 2008) have suggested a link between PM and VTE, while a meta-analysis of studies assessing the association between exposure to air pollutants and venous thrombosis risk found no significant association (Tang et al., 2016). In a few studies, components of PM were found associated with mortality and hospitalizations as well as more specific outcomes, including high blood pressure and activated coagulative conditions causing risk of venous thrombosis (Dai et al., 2016). Both in vitro and in vivo data suggest PM transition metal components, such as Fe, Cu, Ni, and Zn, are proinflammatory factors as reported in Gray' review (Gray et al., 2015). ...
... We present the studies included in this systematic review in Table 1 ( Bae et al., 2010;Bonzini et al., 2012;Wu et al., 2012;Meng et al., 2013;Niu et al., 2013;Strak et al., 2013;Tarantini et al., 2013;Cantone et al., 2014;Spiezia et al., 2014Spiezia et al., , 2016Hampel et al., 2015;Dai et al., 2016;Pavanello et al., 2016). ...
... These studies included one study conducted on children (Bae et al., 2010), two studies on young adults (19-26 years) (Wu et al., 2012;Strak et al., 2013), three studies on older adults (> 60 years) (Hampel et al., 2015.;Niu et al., 2013;Dai et al., 2016) including the Dai's study carried out only on women, and finally 6 studies conducted on healthy foundry and steel workers (Bonzini et al., 2012;Tarantini et al., 2013;Cantone et al., 2014;Spiezia et al., 2014Spiezia et al., , 2016Pavanello et al., 2016)The results of this review support the hypothesis that exposure to some inhalable metals, as elemental compounds in PM, cause changes or activation of a number of human prothrombotic hemostatic biomarkers versus a hypercoagulative prothrombotic status. Hampel et al. (2008Hampel et al. ( -2011 investigated the association between long-term exposure to elemental components of PM and inflammatory blood markers (CRP and fibrinogen) as part of the European ESCAPE and TRANSPHORM multi-center projects. ...
Environmental pollution is an important modifiable determinant for preventing cardiovascular diseases. Acute exposure to air pollution is linked to severe adverse cardiovascular events, including venous thromboembolism risk. The adverse health effects seem to arise from blood-borne metals and transition metal components from exposure to particulate matter that, when breathed, passes through the lungs into the heart and the blood stream. Pollution affects health via mechanisms including oxidative stress and inflammation, and metals may have a detrimental effect on both the blood cells, particularly platelets, and circulation. Some evidences demonstrates atherotrombotic consequences of acute and chronic exposure to air pollution, but few studies have examined exposure effects on the prothrombotic biomarkers leading to venous thromboembolism. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology, we performed a systematic review (14 papers) of the past twelve years, focusing on the relationship between inhalable airborne metal exposures and coagulative biomarker disorders leading to lower limb venous thromboembolisms, e.g., deep vein thrombosis. Results support the hypothesis that exposure to inhalable metals, as elemental compounds in particulate matter, cause changes or activation of a number of human prothrombotic hemostatic biomarkers.
... More than half of the studies identified were conducted in the US, and the majority were studies of a single city. Study types included cohort, time series, and case-crossover studies, and associations were estimated with both subclinical health outcomes, such as inflammatory biomarkers [20,21], and clinical health outcomes including asthma symptoms [22], birth outcomes [23,24], hospitalizations [25•, 26], and mortality [27, 28•, 29]. Overwhelmingly, PMF was the most popular source apportionment method, possibly because it can be implemented using software provided by the US EPA (https://www.epa.gov/air-research/positive-matrixfactorization-model-environmental-data-analyses). ...
... • Requires assumption that some sources have no impact on health [20] incorporate source uncertainties when estimating associations between source-specific PM 2.5 and pediatric asthma emergency department visits. The Bayesian ensemble method estimates source concentrations using a weighted average of source apportionment methods, where the weights are assumed to have random error. ...
... However, this approach estimates one health effect for traffic pollution and it does not aim to disentangle and separately estimate health effects associated with vehicle exhaust and brake dust. Alternatively, Dai et al. [20] used the adaptive LASSO to select those sources most associated with inflammatory biomarkers and endothelial dysfunction. ...
Purpose of review:
Estimating health effects associated with source-specific exposure is important for better understanding how pollution impacts health and for developing policies to better protect public health. Although epidemiologic studies of sources can be informative, these studies are challenging to conduct because source-specific exposures (e.g., particulate matter from vehicles) often are not directly observed and must be estimated. We reviewed recent studies that estimated associations between pollution sources and health to identify methodological developments designed to address important challenges.
Recent findings:
Notable advances in epidemiologic studies of sources include approaches for (1) propagating uncertainty in source estimation into health effect estimates, (2) assessing regional and seasonal variability in emissions sources and source-specific health effects, and (3) addressing potential confounding in estimated health effects. Novel methodological approaches to address challenges in studies of pollution sources, particularly evaluation of source-specific health effects, are important for determining how source-specific exposure impacts health.
... As shown in Figure 1, 8113 potentially relevant articles were selected from four databases through keyword retrieval, and then 18 studies with a total of 9611 participants were eventually included in this meta-analysis through strict exclusion and inclusion criteria [15,21,[32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47], including 14 studies for ICAM-1, 13 studies for VCAM-1, 6 studies for ET-1, and 4 studies for E-selectin. The quality of the included studies was evaluated via the EPHHP, and the quality of the studies remained generally good or moderate (Table S3). ...
... Forest plots[15,21,[32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47] of pooled percent changes (%) and 95% confidence intervals (CIs) in the biomarkers of endothelial function in association with a 10 µg/m 3 increase in short-term exposure to PM 2.5 . ...
Background: The burden of cardiovascular diseases caused by ambient particulate air pollution is universal. An increasing number of studies have investigated the potential effects of exposure to particulate air pollution on endothelial function, which is one of the important mechanisms for the onset and development of cardiovascular disease. However, no previous study has conducted a summary analysis of the potential effects of particulate air pollution on endothelial function. Objectives: To summarize the evidence for the potential effects of short-term exposure to ambient particulate air pollution on endothelial function based on existing studies. Methods: A systematic literature search on the relationship between ambient particulate air pollution and biomarkers of endothelial function including endothelin-1 (ET-1), E-selectin, intercellular cell adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) was conducted in PubMed, Scopus, EMBASE, and Web of Science up to 20 May 2023. Subsequently, a meta-analysis was conducted using a random effects model. Results: A total of 18 studies were included in this meta-analysis. A 10 μg/m3 increase in short-term exposure to ambient PM2.5 was associated with a 1.55% (95% CI: 0.89%, 2.22%) increase in ICAM-1 and a 1.97% (95% CI: 0.86%, 3.08%) increase in VCAM-1. The associations of ET-1 (0.22%, 95% CI: −4.94%, 5.65%) and E-selectin (3.21%, 95% CI: −0.90% 7.49%) with short-term exposure to ambient PM2.5 were statistically insignificant. Conclusion: Short-term exposure to ambient PM2.5 pollution may significantly increase the levels of typical markers of endothelial function, including ICAM-1 and VCAM-1, suggesting potential endothelial dysfunction following ambient air pollution exposure.
... The role of DNA methylation on numerous genes contributing to stroke such as endothelial function (54,56,57), the cytokine-mediated inflammatory reactions and coagulation [56,57], are another new way of research. Flavonoïds, methyl nutrients, folic acid, vitamin B12, may act on DNA methylation and may have a protective effect on prevention of stroke [58,59]. ...
... The role of DNA methylation on numerous genes contributing to stroke such as endothelial function (54,56,57), the cytokine-mediated inflammatory reactions and coagulation [56,57], are another new way of research. Flavonoïds, methyl nutrients, folic acid, vitamin B12, may act on DNA methylation and may have a protective effect on prevention of stroke [58,59]. ...
Evidence from epidemiological studies has demonstrated that outdoor air pollution is now a well-known major problem of public health, mainly in low and middle income countries. Contrasting with myocardial infarction, there are few data on the association of air pollution and stroke.
Methods:
We propose a narrative literature review of the effects and the underlying biological mechanisms of short- and long-term exposure to air pollutants on stroke risk and mortality, using the following key-words: stroke, cerebrovascular events, ischemic and haemorrhage stroke, transient ischaemic attack, mortality, air pollution and air pollutants.
Results:
Twenty-one papers were selected. Air pollution, of which whose small particulate matter are the most toxic, contributes to about one-third of the global burden of stroke. We can identify vulnerable patients with classical neuro-vascular risk factors or a prior history of stroke or transient ischemic attack or persons living in low-income countries. Biological mechanisms of this new morbid association are discussed.
Conclusion:
Air pollution should be recognized as a silent killer inducing stroke whose mortality rates remain elevated by its role as a new modifiable neurovascular risk factor, needing public health policies.
... 75 The consequence is that blood DNA hypo-methylation could serve as a biomarker of atherosclerosis and neurodegeneration, 19,36 and be used to identify persons at risk. 76 Several studies have investigated the role of DNA methylation on numerous genes expressing biomarkers involved in mechanisms that contribute to stroke, such as coagulation, the systemic cytokine-mediated inflammatory response and endothelial function, 77,78 and to neurodegeneration. 19,36 DNA hypo-methylation also alters the toll-like receptor 2 mediated immune response. ...
... 5,32 Neighborhood deprivation is also found to be associated with a greater susceptibility to air pollution depending on the pollutant mixture and the closer proximity of such neighborhoods to roadways or factories. 10,11,22,49,77 Interestingly, a stronger association between stroke and NO 2 and PM10 was observed in low-income countries than in high-income countries, 12,19,22,36,78 suggesting a modulating role of socio-demographic factors in these relationships. ...
Background
Outdoor air pollution is now a well-known risk factor for morbidity and mortality, and is increasingly being identified as a major risk factor for stroke.
Methods
A narrative literature review of the effects of short and long-term exposure to air pollution on stroke and dementia risk and cognitive functioning.
Results
Ten papers on stroke and 17 on dementia were selected. Air pollution, and in particular small particulate matter, contributes to about one-third of the global stroke burden and about one-fifth of the global burden of dementia. It particularly affects vulnerable patients with other vascular risk factors or a prior history of stroke in low- and medium-income countries. New pathophysiological mechanisms of the cause-effect associations are suggested.
Conclusion
Air pollution should be considered as a new modifiable cerebrovascular and neurodegenerative risk factor. This massive worldwide public health problem requires environmental health policies able to reduce air pollution and thus the stroke and dementia burden.
... It has been hypothesized that exposure to PM might induce a low-grade systemic inflammatory response that leads to an increased risk of CVD, and previous studies have suggested that exposure to PM is associated with elevated levels of systemic inflammatory markers Dai et al. 2016;Delfino et al. 2009;Riediker et al. 2004;Ruckerl et al. 2007;Schwartz 2001), the potential predictors of susceptibility to CVD (Blake and Ridker 2002;Saadeddin et al. 2002;Tousoulis et al. 2007). However, the results have been inconsistent, and recently a growing number of studies have reported null associations (Brauner et al. 2008;Forbes et al. 2009;Mirowsky et al. 2015;Rudez et al. 2009), especially for C-reactive protein (CRP), a widely known acute phase protein produced by the liver in response to proinflammatory cytokines. ...
... To date, little information on sICAM-1 is available to make an inference of the potential exposure-response timeline. Similar to our findings, significant associations of short-term (within 3 days) PM 2.5 exposure and sICAM-1 has been found in other populations such as patients with coronary heart disease (Ruckerl et al. 2006), and the elderly who were free of known chronic medical conditions at enrollment (Dai et al. 2016). Seven-day exposure to PM 2.5 (Wilker et al. 2011) as well as median-term (4-12 weeks) exposure to black carbon (BC) , another marker of vehicular-related pollution, have also been associated with elevated sICAM-1 levels. ...
Background:
Previous studies have suggested an association between particulate air pollution and cardiovascular disease, but the mechanism is still unclear.
Objective:
We examined the association between workplace exposure to vehicle-related particles and cardiovascular disease related systemic inflammatory markers, C-reactive protein (hs-CRP), soluble intercellular adhesion molecule-1 (sICAM-1), and interleukin-6 (IL-6) in 137 trucking terminal workers (non-drivers) in the U.S. trucking industry.
Methods:
We visited two large trucking terminals in 2009 and measured vehicle-related elemental carbon (EC), organic carbon (OC), and particulate matter with aerodynamic diameter ≤2.5µm (PM2.5), for 5 days consecutively at the main work areas. Each participant provided a blood sample and completed a health questionnaire during the sampling period. Individual workplace exposure level was calculated by 12-h time weighted moving averages based on work shift. The association between each blood marker and exposure to each pollutant during 0-12, 12-24, 24-36, and 36-48h before the blood draw was examined by multivariable regression analyses.
Results:
In general, OC and EC had a positive association with sICAM-1, especially for exposure periods 12-24 (lag12-24) and 24-36 (lag24-36)h prior to blood draw [β=54.9 (95%CI: 12.3-97.5) for lag12-24 and β=46.5 (95%CI: 21.2-71.8) for lag12-24; change in sICAM-1 (in ng/mL) corresponding to an IQR increase in OC]. A similar pattern was found for EC and PM2.5. We did not find an association between measured pollutants up to 48h before blood draw and hs-CRP or IL-6.
Conclusion:
In this group of healthy workers, short-term exposure to vehicle-related air pollutants may be associated with sICAM-1. Our findings may be dependent on the exposure period studied.
... We also found that SO 4 2− increased diabesity risk, which may be attributed to mechanisms of inflammation, endothelial dysfunction, and oxidative stress. 54 We found that adverse effects of PM 2.5 chemical constituents on diabesity risk were less pronounced in those with a high level of physical activity. This suggests that physical activity may modify the association between PM 2.5 chemical constituents and diabesity risk. ...
... Source contributions represent the mass contribution of each source to the mixture measurements, while source profiles reflect the emission types from a given source. Source contributions are constrained to be non-negative, and the method can incorporate uncertainty measurements related to the data at each point (61)(62)(63)(64). ...
Traditional environmental epidemiology has consistently focused on studying the impact of single exposures on specific health outcomes, considering concurrent exposures as variables to be controlled. However, with the continuous changes in environment, humans are increasingly facing more complex exposures to multi-pollutant mixtures. In this context, accurately assessing the impact of multi-pollutant mixtures on health has become a central concern in current environmental research. Simultaneously, the continuous development and optimization of statistical methods offer robust support for handling large datasets, strengthening the capability to conduct in-depth research on the effects of multiple exposures on health. In order to examine complicated exposure mixtures, we introduce commonly used statistical methods and their developments, such as weighted quantile sum, bayesian kernel machine regression, toxic equivalency analysis, and others. Delineating their applications, advantages, weaknesses, and interpretability of results. It also provides guidance for researchers involved in studying multi-pollutant mixtures, aiding them in selecting appropriate statistical methods and utilizing R software for more accurate and comprehensive assessments of the impact of multi-pollutant mixtures on human health.
... Rights reserved. level, total cholesterol level, and hypertensive status (yes: with self-reporting or SBP/DBP > 120/80, no: without selfreporting or SBP/DBP ≤ 120/80) (Dai et al. 2016;Ding et al. 2016;Kannan et al. 2006;Kasperczyk et al. 2005;Sirivarasai et al. 2013;Wells et al. 2014). ...
Purpose
Several epidemiological studies have linked lead (Pb) exposure to induced oxidative stress and the promotion of inflammatory response. We performed a within-subjects study (repeated measures study) to evaluate the relationship between the concentration of blood lead (B-Pb) and toenail lead (T-Pb) and circulating markers of inflammation.
Methods
We evaluated the associations between B-Pb concentrations and T-Pb concentrations and circulating markers of inflammation, soluble intracellular adhesion molecule-1 (s-ICAM-1), soluble vascular adhesion molecule-1 (s-VCAM-1), and high-sensitivity C-reactive protein (hs-CRP) on 158 traffic enforcers from the Metropolitan Manila Development Authority (MMDA) traffic enforcer’s health study. Linear mixed-effects models with random subject-specific intercepts were fitted to estimate the association between B-Pb and T-Pb exposure and circulating markers of inflammation, adjusting for confounding factors.
Results
Traffic enforcers were middle-aged men (89.4%) with a mean age (± SD) of 37.1 years ± 8.9 years and had a total of 293 valid markers of inflammation measurements. B-Pb concentration was related to increased hs-CRP levels. A 10% increase in B-Pb was associated with a 5.7% increase in hs-CRP level [95% confidence interval (95% CI): 1.3–10.1]. However, B-Pb was not associated with s-ICAM-1 and s-VCAM-1. Furthermore, no associations were observed between T-Pb and all the circulating markers of inflammation.
Conclusions
Low-level B-Pb may increase hs-CRP among traffic enforcers. Moreover, the study suggests that Pb via the oxidative and inflammation pathways may have an essential role in the development of cardiovascular disease. Furthermore, MMDA and the Department of Labor and Employment can use our study’s findings as evidence to conduct routine screening of blood heavy metals, especially Pb, among MMDA and other traffic enforcers as part of their yearly medical examination.
... As for the relationship between adverse health outcomes and vanadium contained in particulate matter with a diameter of 2.5 (PM 2.5 ), Cakmak et al. [37] reported an association between vanadium in PM 2.5 and an increased risk of respiratory and cardiovascular diseases. Dai et al. [47], who analyzed the differential effects of PM 2.5 species and sources on blood markers of inflammation and endothelial dysfunction in a large longitudinal cohort, found that among the species examined (K, S, Se, Al, Si, Fe, Ni, V, Cu, Zn, and Na) vanadium was associated with increased levels of both intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). Additionally, they noted an association between oil combustion rich in vanadium and ICAM-1 and VCAM-1. ...
Neurodegenerative disorders, which are currently incurable diseases of the nervous system, are a constantly growing social concern. They are progressive and lead to gradual degeneration and/or death of nerve cells, resulting in cognitive deterioration or impaired motor functions. New therapies that would ensure better treatment results and contribute to a significant slowdown in the progression of neurodegenerative syndromes are constantly being sought. Vanadium (V), which is an element with a wide range of impacts on the mammalian organism, is at the forefront among the different metals studied for their potential therapeutic use. On the other hand, it is a well-known environmental and occupational pollutant and can exert adverse effects on human health. As a strong pro-oxidant, it can generate oxidative stress involved in neurodegeneration. Although the detrimental effects of vanadium on the CNS are relatively well recognized, the role of this metal in the pathophysiology of various neurological disorders, at realistic exposure levels in humans, is not yet well characterized. Hence, the main goal of this review is to summarize data on the neurological side effects/neurobehavioral alterations in humans, in relation to vanadium exposure, with the focus on the levels of this metal in biological fluids/brain tissues of subjects with some neurodegenerative syndromes. Data collected in the present review indicate that vanadium cannot be excluded as a factor playing a pivotal role in the etiopathogenesis of neurodegenerative illnesses, and point to the need for additional extensive epidemiological studies that will provide more evidence supporting the relationship between vanadium exposure and neurodegeneration in humans. Simultaneously, the reviewed data, clearly showing the environmental impact of vanadium on health, suggest that more attention should be paid to chronic diseases related to vanadium and to the assessment of the dose–response relationship.
... 142 A study that further investigated the influence of different components of PM 2.5 revealed that independent of PM 2.5 mass vanadium was related to ICAM-1 and VCAM-1. 143 In line, in a panel of 40 healthy adults from China, total PM 2.5 from dust/soil and several crustal and transition metals were shown to be associated with increased endothelin 1 (ET-1) and ICAM-1 and decreased VCAM-1. 144 Furthermore, CO was associated with higher ICAM-1, whereas nitric oxide (NO) was shown to be associated with decreased ICAM-1. ...
During the last two decades, large epidemiological studies have shown that the physical environment, including noise, air pollution or heavy metals, have a considerable impact on human health. It is known that the most common cardiovascular risk factors are all associated with endothelial dysfunction. Vascular tone, circulation of blood cells, inflammation, and platelet activity are some of the most essential functions regulated by the endothelium that suffer negative effects as a consequence of environmental pollution, causing endothelial dysfunction. In this review, we delineate the impact of environmental risk factors in connection to endothelial function. On a mechanistic level, a significant number of studies suggest the involvement of endothelial dysfunction to fundamentally drive the adverse endothelium health effects of the different pollutants. We focus on well-established studies that demonstrate the negative effects on the endothelium, with a focus on air, noise, and heavy metal pollution. This in-depth review on endothelial dysfunction as a consequence of the physical environment aims to contribute to the associated research needs by evaluating current findings from human and animal studies. From a public health perspective, these findings may also help to reinforce efforts promoting the research for adequate promising biomarkers for cardiovascular diseases since endothelial function is considered a hallmark of environmental stressor health effects.
... PM composition is spatially heterogeneous, which might contribute to discrepancies across PM 2.5 studies. Published literature has suggested that some PM 2.5 components may be more harmful than others, and that some population subgroups such as children, elderly or those with comorbidities may be particularly susceptible (Dai et al., 2016;Eeftens et al., 2014;Huang et al., 2019b;Jung et al., 2017;Lippmann et al., 2000). Thus, this study aimed to use a longitudinal birth cohort of children with physician-diagnosed incident asthma to investigate the effect of exposure to PM 2.5 components at birth on morbidity measured by their health services utilization. ...
... En estos años, Schwartz, 57-62 ha publicado el mayor número de investigaciones sobre el impacto de la exposición a contaminantes ambientales en la salud humana; en esta línea, pero en menor grado, se reconoce a Baccarelli. 61,63,64 Ahora bien, los investigadores que han logrado estipular la relación de los contaminantes de manera específica con la obesidad son Rajagopalan 65-70 en primer lugar, le siguen Coull, 71 Overvad, 72 Tjonneland, 73 Andersen, 74 Lurmann, 75 Liu, 76,68 y Sorensen. 76 Se está sugiriendo indagar como alternativa al paradigma hegemónico de la etiología y el tratamiento de la obesidad, a los contaminantes ambientales como disruptores endócrinos, las alteraciones en las funciones neurotransmisoras, los cambios en el epigenoma, la disbiosis de la microbiota intestinal, y los efectos de nutrientes específicos en la función mitocondrial y en las vías de señalización; incluso se está estipulando la relación entre obesidad y asma, proponiéndose tratar a ambas con el mismo fármaco, metformina. ...
Kuhn in 1962 establishes the revolutionary character of science: “new scientific theories are not born by verification or falsification, but by substitution.” The objective of this review was to analyze the ideas and paradigms through which studies on obesity and its relationship with environmental pollutants, diet and epigenetics have passed, in order to illustrate the current situation of this object of study. Articles were managed in December 2020 from the Web of Science. The strategy was Obesity AND (pollution OR contamination) in the Title field, AND (epigenetic* OR obesity OR food OR nutrition OR diet) in the Themes field. 654 articles were obtained: 577 original investigations and 77 reviews. The documents were exported in BibTeXformat to be quantitatively analyzed with the Bibliometrix program. For the qualitative analysis, review articles were selected in whose titles, keywords and/or abstract, carried the word paradigm*, identifying 19 who underwent content analysis. From 1980 to 2020, four periods
were recognized, the first and third are classified as normal science; the second and the fourth, crisis of knowledge or revolution. The evolution of the studies has been differentiated. First, the central theme was environmental pollution and secondarily, obesity. For the second and third period, the epigenetics related to environmental pollution and that associated with obesity are investigated separately and at present, causal relationships between environmental pollutants and obesity, nutrients and epigenetics are hypothesized.
... En estos años, Schwartz, 57-62 ha publicado el mayor número de investigaciones sobre el impacto de la exposición a contaminantes ambientales en la salud humana; en esta línea, pero en menor grado, se reconoce a Baccarelli. 61,63,64 Ahora bien, los investigadores que han logrado estipular la relación de los contaminantes de manera específica con la obesidad son Rajagopalan 65-70 en primer lugar, le siguen Coull, 71 Overvad, 72 Tjonneland, 73 Andersen, 74 Lurmann, 75 Liu, 76,68 y Sorensen. 76 Se está sugiriendo indagar como alternativa al paradigma hegemónico de la etiología y el tratamiento de la obesidad, a los contaminantes ambientales como disruptores endócrinos, las alteraciones en las funciones neurotransmisoras, los cambios en el epigenoma, la disbiosis de la microbiota intestinal, y los efectos de nutrientes específicos en la función mitocondrial y en las vías de señalización; incluso se está estipulando la relación entre obesidad y asma, proponiéndose tratar a ambas con el mismo fármaco, metformina. ...
Kuhn in 1962 establishes the revolutionary character of science: “new scientific theories are not born by verification or falsification, but by substitution.” The objective of this review was to analyze the ideas and paradigms through which studies on obesity and its relationship with environmental pollutants, diet and epigenetics have passed, in order to illustrate the current situation of this object of study. Articles were managed in December 2020 from the Web of Science. The strategy was Obesity AND (pollution OR contamination) in the Title field, AND (epigenetic* OR obesity OR food OR nutrition OR diet) in the Themes field. 654 articles were obtained: 577 original investigations and 77 reviews. The documents were exported in BibTeXformat to be quantitatively analyzed with the Bibliometrix program. For the qualitative analysis, review articles were selected in whose titles, keywords and/or abstract, carried the word paradigm*, identifying 19 who underwent content analysis. From 1980 to 2020, four periods were recognized, the first and third are classified as normal science; the second and the fourth, crisis of knowledge or revolution. The evolution of the studies has been differentiated. First, the central theme was environmental pollution and secondarily, obesity. For the second and third period, the epigenetics related to environmental pollution and that associated with obesity are investigated separately and at present, causal relationships between environmental pollutants and obesity, nutrients and epigenetics are hypothesized.
... Therefore, endothelial dysfunction affects regular blood flow through arteries and predisposes to a pro-coagulant state with platelet aggregation and fibrinolytic impairment leading to atherogenesis. 11 There are also several studies that link PM exposure to endothelial dysfunction mediated by OS. [12][13][14][15][16] Moreover, OS, generated by PM pollution, is also related to the impairment of nitric oxide (NO) that, physiologically, controls vascular smooth muscle cells (VSMCs) that control relaxation of tunica media of the vessel wall. 11 Reduced production and efficacy of NO in vessels is a hallmark of endothelial dysfunction. ...
Raffaele Serra,1– 3 Andrea Abramo,1– 3 Nicola Ielapi,1,4 Salvatore Procopio,5 Pietro Marino3 1Interuniversity Center of Phlebolymphology (CIFL), International Research and Educational Program in Clinical and Experimental Biotechnology, Department of Surgical and Medical Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy; 2Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy; 3Department of Social Sciences, Vitambiente, Catanzaro, Italy; 4Department of Public Health and Infectious Disease, “Sapienza” University of Rome, Rome, Italy; 5Department of Catanzaro District, Laboratory of Physics, Calabria Regional Agency for Environment Protection, Catanzaro, ItalyCorrespondence: Raffaele SerraInteruniversity Center of Phlebolymphology (CIFL), International Research and Educational Program in Clinical and Experimental Biotechnology, Department of Surgical and Medical Sciences, University Magna Graecia of Catanzaro, Viale Europa, Località Germaneto, Catanzaro, 88100, ItalyTel +3909613647380Email rserra@unicz.itAbstract: Peripheral artery disease (PAD) of the lower limbs represents one of the most important clinical conditions among vascular disease and can negatively impact quality of life of affected patients, representing also an important socioeconomic burden. Several risk factors predispose to PAD and its complications. Nevertheless, the role of pollution in this context has not been fully evaluated and this article explored the most updated information on epidemiology and environmental pollution in order to hypothesize the possible contribution of air pollution in the onset of PAD. Pollution is an important problem for the global community and has harmful effects on human health and cardiovascular system, and, specifically, particulate matter 10 (PM10) was found significantly associated with PAD.Keywords: peripheral artery disease, pollution, environment, PM10, risk factors
... PM composition is spatially heterogeneous, which might contribute to discrepancies across PM 2.5 studies. Published literature has suggested that some PM 2.5 components may be more harmful than others, and that some population subgroups such as children, elderly or those with comorbidities may be particularly susceptible [11][12][13][14][15]. Thus, this study aimed to use a 1 J o u r n a l P r e -p r o o f longitudinal birth cohort of children with physician-diagnosed incident asthma to investigate the effect of exposure to PM 2.5 components at birth on morbidity measured by their health services utilization. ...
Owing to their greater outdoor activity and ongoing lung development, children are particularly vulnerable to the harmful effects of exposure to fine particulate matter (PM2.5). However, the effects of PM2.5 components are poorly understood. This study aimed to use a longitudinal birth cohort of children with physician-diagnosed incident asthma to investigate the effect of PM2.5 components at birth on morbidity measured by health services utilization. Of 1,277 Toronto Child Health Evaluation Questionnaire (T-CHEQ) participants, the study population included 362 children diagnosed with asthma who were followed for a mean of 13 years from birth until March 31, 2016, or loss-to-follow-up. Concentrations of PM2.5 and its components were assigned based on participants’ postal codes at birth. Study outcomes included counts of asthma, asthma-related, and all-cause health services use. Poisson regression in single-, two-, and multi-pollutant models was used to estimate rate ratios (RR) per interquartile range (IQR) increase of exposures. Covariates were included in all models to further adjust for potential confounding. The adjusted RR for sulfate (SO4) and all-cause hospitalizations was statistically significant with RR=2.23 (95% confidence interval [CI]: 1.25-3.96) in a multi-pollutant model with nitrogen dioxide (NO2) and ozone (O3). In multi-pollutant models with oxidants, the adjusted RRs for SO4 of all-cause hospitalizations and emergency department (ED) visits were also statistically significant with RR=2.31 (95% CI: 1.32-4.03) and RR=1.39 (95% CI: 1.02-1.90), respectively. While unadjusted single-pollutant RRs for asthma-specific and asthma-related health services use with the SO4 component of PM2.5 were above one, none were statistically significant. This study found significant associations with exposure to SO4 in PM2.5 and all-cause acute care, chiefly for hospitalizations, in children with asthma.
... The GO functional analysis of these five identified loci revealed top ten significant pathways related to the colorectal cancer risk, among which four pathways were involved in vascular function. PM 2.5 exposure induces the overexpression of VEGF and vascular cell adhesion molecule-1 (Dai et al., 2016). A meta-analysis suggested that PM 2.5 exposure increases the VEGF levels in the Canadian population (Sun et al., 2018), while an experimental assay revealed that PM 2.5 disrupts the barrier function of the vascular endothelium in rats, possibly by increasing the vascular endothelial cell permeability (Dai et al., 2017). ...
Background
Fine particulate matter (PM2.5) is suspected to increase the risk of colorectal cancer, but the mechanism remains unknown. We aimed to investigate the association between PM2.5 exposure, genetic variants and colorectal cancer risk in the Prostate, Lung, Colon and Ovarian (PLCO) Cancer Screening trial.
Methods
We included a prospective cohort of 139,534 cancer-free individuals from 10 United States research centers with over ten years of follow-up. We used a Cox regression model to assess the association between PM2.5 exposure and colorectal cancer incidence by calculating the hazard ratio (HR) and 95% confidence interval (CI) with adjustment for potential confounders. The polygenic risk score (PRS) and genome-wide interaction analysis (GWIA) were used to evaluate the multiplicative interaction between PM2.5 exposure and genetic variants in regard to colorectal cancer risk.
Results
After a median of 10.43 years of follow-up, 1,666 participants had been diagnosed with colorectal cancer. PM2.5 exposure was significantly associated with an increased risk of colorectal cancer (HR = 1.27; 95% CI = 1.17–1.37 per 5 μg/m³ increase). Five independent susceptibility loci reached statistical significance at P < 1.22 × 10⁻⁸ in the interaction analysis. Furthermore, a joint interaction was observed between PM2.5 exposure and the PRS based on these five loci with colorectal cancer risk (P = 3.11 × 10⁻²⁹). The Gene Ontology analysis showed that the vascular endothelial growth factor (VEGF) receptor signaling pathway was involved in the biological process of colorectal cancer.
Conclusions
Our large-scale analysis has shown for the first time that long-term PM2.5 exposure potential increases colorectal cancer risk, which might be modified by genetic variants.
... 8 Among these changes, multiple factors such as lack of physical activity, unhealthy lifestyles, working stress, and environmental pollution may contribute to increased obesity and NCDs. 2,9,10 Air pollution, especially particulate matter with an aerodynamic diameter smaller than 10 μm (PM 10 ) or 2.5 μm (PM 2.5 ), has been improving in recent years but in winter is worsening in Beijing. 11 Beijing is a crowded metropolis where traffic emissions account for a large share of PM 2.5 concentration. ...
Background
Few studies have considered the interplay between commuting mode and air pollution on obesity. The aim of this study was to examine whether workplace air pollutants exposure modifying the associations between different commuting mode and obesity.
Methods
A cross-sectional study of workers in Beijing was conducted in 2016. The study sample comprised 10,524 participants aged 18 to 65 years old. Outcomes were defined as overall obesity (BMI≥ 28 kg/m²) and abdominal obesity (WC ≥ 85 cm in men and WC ≥ 80 cm in women). Commuting modes were divided into walking, cycling, bus, subway, and car or taxi. Logistic regression models were used to estimate odds ratios relating commuting mode to overall and abdominal obesity and stratified by gender, controlling for covariates.
Results
The association between commuting mode and obesity was more strongly in men than women. In the fully adjusted models, compared with car or taxi commuters, cycling (men: OR=0.37, 95% CI=0.20 to 0.68) or bus (men: OR=0.58, 95% CI=0.36 to 0.94) counterparts had a lower risk of overall obesity. Compared with car or taxi commuters, walking (men: OR=0.57, 95% CI=0.36 to 0.91), bus (men: OR=0.59, 95% CI=0.39 to 0.89), or subway (men: OR=0.59, 95% CI=0.39 to 0.89) counterparts had a lower risk of abdominal obesity. We observed significant interactions between exposure PM10 and cycling on overall obesity in men. After adjusting for air pollutants, the association between commuting mode and obesity was slightly strengthened.
Conclusion
This study findings indicate that active (walking or cycling) or public (bus or subway) commuting modes were protected factors for overall and abdominal obesity among men. Air pollutants do not obscure the benefits of active or public commuting for obesity. These associations support the policy for increasing active or public commuting as a strategy to reduce the prevalence of obesity.
... Short-and long-term exposure to traffic-related pollutants lead to increases in non-communicable diseases, such as cardiovascular, respiratory (Lin et al., 2018;Brook et al., 2010), and neurological (Dai et al., 2016) diseases, as well as oxidative stress and tissue damage (Reis et al., 2018). Fine particulate matter (PM 2.5 , particles with aerodynamic diameter, d a , smaller than 2.5 mm) has been adopted by the World Health Organisation and by regulatory agencies in various countries as a proxy to the harmful effects of exposure to air pollution. ...
... Air pollution is a complex mixture of particulate and gaseous compounds and is usually measured in health studies as PM 2.5 (fine particulate matter with diameter ≤ 2.5 μm) and PM 10 (coarse particulate matter with diameter ≤ 10 μm). Cardiovascular disease (CVD), including both biomarkers of disease such as blood pressure and inflammatory markers, as well as acute events, such as myocardial infarctions (MI), strokes, and heart failure, have been associated with short-term exposures to air pollution (Chuang et al., 2017;Bind et al., 2016;Li et al., 2017;Dai et al., 2016;Yitshak Sade et al., 2015;Araujo, 2010;Brook et al., 2009;Barnett et al., 2006;D'Ippoliti et al., 2003;Albert and Ridker, 1999;Wellenius et al., 2012). ...
Background:
Although many studies have established significant associations between short-term air pollution and the risk of getting cardiovascular diseases, there is a lack of evidence based on causal distributed lag modeling.
Methods:
Inverse probability weighting (ipw) propensity score models along with conditional logistic outcome regression models based on a case-crossover study design were applied to get the causal unconstrained distributed (lag0-lag5) as well as cumulative lag effect of short-term exposure to PM2.5/Ozone on hospital admissions of acute myocardial infarction (AMI), congestive heart failure (CHF) and ischemic stroke (IS) among New England Medicare participants during 2000-2012. Effect modification by gender, race, secondary diagnosis of Chronic Obstructive Pulmonary Diseases (COPD) and Diabetes (DM) was explored.
Results:
Each 10 μg/m3 increase in lag0-lag5 cumulative PM2.5 exposure was associated with an increase of 4.3% (95% confidence interval: 2.2%, 6.4%, percentage change) in AMI hospital admission rate, an increase of 3.9% (2.4%, 5.5%) in CHF rate and an increase of 2.6% (0.4%, 4.7%) in IS rate. A weakened lagging effect of PM2.5 from lag0 to lag5 could be observed. No cumulative short-term effect of ozone on CVD was found. People with secondary diagnosis of COPD, diabetes, female gender and black race are sensitive population.
Conclusions:
Based on our causal distributed lag modeling, we found that short-term exposure to an increased ambient PM2.5 level had the potential to induce higher risk of CVD hospitalization in a causal way. More attention should be paid to population of COPD, diabetes, female gender and black race.
... Whilst ambient PM 2.5 concentrations were not associated with changes in sICAM-1 or sVCAM-1, associations between BC and sVCAM were magnified in subjects with a glutathione S-transferase M1 (GSTM1) deletion. A genetic score approach, investigating interactions between relevant pathways and the environment, also suggests that OS plays a role in the association of ambient particles derived from oil combustion and endothelial dysfunction [25,26]. Research examining the association between PM oxidative potential (OP; the capacity of particles to cause damaging oxidative reactions) and adverse health outcomes is in its infancy, but a cohort panel study in 93 elderly non-smoking adults suggests that shortterm exposures to traffic-related air pollutants with a high OP contribute to microvascular endothelial dysfunction, represented by reactive hyperemia index (RHI) [27] (Fig. 1). ...
... Several epidemiological studies have demonstrated that exposure to PM 2.5 and diluted diesel exhaust were associated with rapid endothelial dysfunction and systemic inflammation in healthy adults ( Mills et al., 2005;Pope et al., 2016;Wu et al., 2013), the elderly ( Bind et al., 2012;Dai et al., 2016) and children (Calderon- Garciduenas et al., 2008). Our findings that exposure to PM 2.5 were associated with markers of endothelial dysfunction and inflammation are in agreement with those from previous studies. ...
... 5 Still, the variants we used were developed in an independent study and have been used in other studies since they were first described. 43,44 Moreover, the variants are representative of their respective biological pathways. Second, we used a validated spatiotemporal model to estimate 1-year BC levels at the participant home. ...
Importance
Elevated intraocular pressure is a major risk factor for glaucoma, a leading cause of irreversible blindness worldwide. Environmental air pollution has been suggested as a potential contributor to elevated intraocular pressure; however, no studies have demonstrated such an association to date.
Objective
To investigate the association of long-term ambient black carbon exposure with intraocular pressure in community-dwelling older adults.
Design, Setting, and Participants
This population-based analysis, conducted from October 18, 2017, through March 22, 2018, used data from the all-male, New England–based Normative Aging Study of the US Department of Veterans Affairs. The analysis included 419 older men with a total of 911 follow-up study visits between January 1, 2000, and December 30, 2011. Intraocular pressure was measured by Goldmann applanation tonometry during the study visits. Validated spatiotemporal models were used to generate 1-year black carbon exposure levels at the addresses of the participants.
Main Outcomes and Measures
An independently developed genetic score approach was used to calculate allelic risk scores for 3 pathways associated with black carbon toxicity: endothelial function, oxidative stress, and metal processing. The associations among black carbon exposure, allelic risk scores, and intraocular pressure were explored using linear mixed-effects models.
Results
All 419 participants were men with a mean (SD) age of 75.3 (6.9) years. The mean (SD) 1-year black carbon exposure was 0.51 (0.18) μg/m³, and the mean (SD) intraocular pressure for the left eye was 14.1 (2.8) mm Hg and for the right eye was 14.1 (3.0) mm Hg. Of the 911 visits, 520 (57.1%) had a high endothelial function allelic risk score, 644 (70.7%) had a high metal-processing allelic risk score, and 623 (68.4%) had a high oxidative stress allelic risk score. In fully adjusted linear mixed-effects models, the association of black carbon with intraocular pressure was greater in individuals with a high oxidative stress allelic score (β = 0.36; 95% CI, 0.003-0.73) compared with individuals with a low score (β = −0.35; 95% CI, −0.86 to 0.15).
Conclusions and Relevance
Ambient black carbon exposure may be a risk factor for increased intraocular pressure in individuals susceptible to other biological oxidative stressors. If additional studies confirm these results, monitoring ambient black carbon exposure and physiological oxidative stress may prevent the development and progression of intraocular pressure–related disease.
... 9 Vanadium exerts its effect by producing reactive oxygen species (ROS) as a result of the reduction of vanadate to vanadyl. 10 Vanadium traces from oil combustion are found throughout the environment, and for some biological systems, it is considered an essential trace element. 11,12 The levels of vanadium in the air have increased due to the increment of fuel combustion with high vanadium content. [13][14][15] A high concentration of vanadium in the particulate matter (PM 2.5 ) has been found in the liver, kidney, brain, heart, muscle and bone and is associated with oxidative stress and lipid peroxidation. ...
Carnosine (β‐alanyl‐L‐histidine) is synthesized in the olfactory system, has antioxidant activity as a scavenger of free radicals and has been reported to have neuroprotective action in diseases which have been attributed to oxidative damage. In neurodegenerative disorders, such as Parkinson's and Alzheimer's diseases, impairment of olfactory function has been described. Vanadium derivatives are environmental pollutants, and its toxicity has been associated with oxidative stress. Vanadium toxicity on the olfactory bulb was reported previously. This study investigates the neuroprotective effect of carnosine on the olfactory bulb in a mice model of vanadium inhalation. Male mice were divided into four groups: vanadium pentoxide (V2O5) [0.02 mol/L] inhalation for one hour twice a week; V2O5 inhalation plus 1 mg/kg of carnosine administered daily; carnosine only, and the control group that inhaled saline. The olfactory function was evaluated using the odorant test. Animals were sacrificed four weeks after exposure. The olfactory bulbs were dissected and processed using the rapid Golgi method; cytological and ultrastructural analysis was performed and malondialdehyde (MDA) concentrations were measured. The results showed evidence of olfactory dysfunction caused by vanadium exposure and also an increase in MDA levels, loss of dendritic spines and necrotic neuronal death in the granule cells. But, in contrast, vanadium‐exposed mice treated with carnosine showed an increase in dendritic spines and a decrease in neuronal death and in MDA levels when compared with the group exposed to vanadium without carnosine. These results suggest that dendritic spine loss and ultrastructural alterations in the granule cells induced by vanadium are mediated by oxidative stress and that carnosine may modulate the neurotoxic vanadium action, improving the olfactory function.
... One early study reported that exposure to the Ni ions released from mechanical polishing NiTi alloy of intravascular stents could lead to increased oxidative stress in human umbilical vein endothelial cells (Plant et al., 2005). In a large cohort study of elderly men from US, exposure to vanadium in PM 2.5 was found to be associated with markers of inflammation and endothelial dysfunction (Dai et al., 2016a). In an animal experiment, the nickel particles in PM 2.5 were associated with elevations in heart rate and significant reductions in heart rate variability, which were generally used as indicators of cardiac stress (Lippmann et al., 2006). ...
Substantial evidence has linked short-term exposure to ambient fine particulate matter (PM2.5) with increased cardiovascular mortality, however, the specific chemical constituent and emission source responsible for this effect remained largely unclear. A time series Poisson model was employed to quantify the association of cardiovascular mortality with two sets of shipping pollution emission: nickel (Ni), vanadium (V) (the indices of shipping emission) and estimated shipping emission using a source apportionment approach in Guangzhou, China in 2014. We observed that Ni, V, and estimated shipping emission in PM2.5 were associated with increased cardiovascular mortality, an inter-quartile range (IQR) increase in lag2 Ni was associated with 4.60% (95% CI: 0.14%, 9.26%) increase in overall cardiovascular mortality, and 13.35% (95% CI: 5.54%, 21.75%) increase in cerebrovascular mortality; each IQR increase of lag1 V was correlated with 6.01% (95% CI: 1.83%, 10.37%) increase in overall cardiovascular mortality, and 11.02% (95% CI: 3.15%, 19.49%) increase in cerebrovascular mortality; and each IQR increase in lag1 shipping emission was associated with 5.55% (95% CI: 0.78%, 10.54%) increase in overall cardiovascular mortality, and 10.39% (95% CI: 1.43%, 20.14%) increase in cerebrovascular mortality. The results remained robust to adjustment for PM2.5 mass and gaseous air pollutants. This study suggests that shipping emission is an important detrimental factor of cardiovascular mortality, and should be emphasized in air pollution control and management in order to protect the public health in Guangzhou, China.
... The use of penalized regression to select the relevant pollutants is highly relevant within the exposome concept to identify important exposures (Billionnet et al., 2012;Sun et al., 2013;Agier et al., 2016) and is a major strength of the study. Yet, the studies using penalized regression to consider the relevant pollutants are limited (Dai et al., 2016a;Dai et al., 2016b;Lenters et al., 2016;Forns et al., 2016). This approach allows collinearity of multiple exposures entered in one model, in contrast to least squares regression which is sensitive to collinearity. ...
Background:
Placental mitochondrial DNA (mtDNA) content can be indicative of oxidative damage to the placenta during fetal development and is responsive to external stressors. In utero exposure to environmental pollutants that may influence placental mtDNA needs further exploration.
Objectives:
We evaluated if placental mtDNA content is altered by environmental pollution in newborns and identified pollutants independently associated to alterations in placental mtDNA content.
Methods:
mtDNA content was measured in placental tissue of 233 newborns. Four perfluoroalkyl compounds and nine organochlorine compounds were quantified in cord blood plasma samples and six toxic metals in whole cord blood. We first applied a LASSO (least absolute shrinkage and selection operator) penalized regression model to identify independent associations between environmental pollutants and placental mtDNA content, without penalization of several covariates. Then adjusted estimates were obtained using an ordinary least squares (OLS) regression model evaluating the pollutants' association with placental mtDNA content, adjusted for several covariates.
Results:
Based on LASSO penalized regression, oxychlordane, p,p'-dichlorodiphenyldichloroethylene, β-hexachlorocyclohexane, perfluorononanoic acid, arsenic, cadmium and thallium were identified to be independently associated with placental mtDNA content. The OLS model showed a higher placental mtDNA content of 2.71% (95% CI: 0.3 to 5.2%; p=0.03) and 1.41% (0.1 to 2.8%, p=0.04) for a 25% concentration increase of respectively cord blood β-hexachlorocyclohexane and arsenic. For a 25% concentration increase of cord blood thallium, a 4.88% lower placental mtDNA content (95% CI: -9.1 to -0.5%, p=0.03) was observed.
Conclusion:
In a multi-pollutant approach, low fetal exposure levels of environmental organic and inorganic pollutants might compromise placental mitochondrial function as exemplified in this study by alterations in mtDNA content.
... The interactions between cells can be stabilized by cellular adhesion molecules (CAM) and the process of leukocyte adhesion and transendothelial migration is also mediated by it, where ICAM-1 and VCAM-1 are two main members that belong to the immunoglobulin family of CAM [23]. Due to this important role of ICAM-1 and VCAM-1 in the endothelial function and inflammation, epidemiological studies have been conducted on associations of ICAM-1 and VCAM-1 with particulate air pollution [24,25]. ...
Allergic rhinitis (AR) represents a clinical health issue affecting approximately 500 million people worldwide. This study aimed to explore the effects of airborne fine particulate matter (PM2.5) on the nasal mucosa of rats with AR. Seventy-five healthy male SD rats were included and randomly divided into the normal, model, low-concentration, middle-concentration, and high-concentration groups (15 rats each group). AR rat models were established using sensitized mixture and were stimulated using different concentrations of PM2.5. Sneeze and nose-scratching events were observed. Automatic hematology analyzer was utilized to count white blood cells (WBCs). The serum IgE, ICAM-1, and VCAM-1 expressions, eosinophil (EOS) infiltration, and IFN-γ, IL-4, IL-5, IL-33, and TSLP expressions were detected by ELISA, HE staining, and qRT-PCR. Greater numbers of WBCs, increased IgE level, elevated levels of ICAM-1, VCAM-1, EOS, IFN-γ, IL-4, IL-5, IL-33, and TSLP in the model, low-concentration, middle-concentration, and high-concentration groups than the normal group. The same trend also exhibited in rats of the middle-concentration and high-concentration groups than that of the model and low-concentration groups. Comparisons between normal rats and AR rats indicated that AR rats exhibit remarkably higher cytokine expression levels of IFN-γ, IL-4, IL-5, TSLP, and IL-33. The study revealed that as stimulation is triggered by PM2.5, AR rats result in increased levels of adhesion molecules and inflammatory cytokine expressions in a concentration-dependent manner. Analyses of PM2.5 as well as, its effects on AR are crucial in the continued drive for both prevention and management of the disease.
... As far as we know, oxidative stress is the main mechanism for PM 2.5 -caused toxicity (Dai et al. 2016;Weichenthal et al. 2016). In addition, inflammation, changes in blood viscosity, dysfunction of myocardial cell ion channel, and cardiac autonomic nerve also have a toxic effect on the cardiovascular Fig. 4 Significantly changed upregulated and downregulated pathways induced by PM 2.5 in AC16 are chosen by the KEGG database. ...
Air pollution has been a major environment-related health threat. Most of the studies on PM2.5 toxicity have verified on the cardiovascular system and endothelial cells. However, researches on PM2.5-induced myocardial-related toxicity are limited. This study aims to fully understand the toxic effects of PM2.5 on human myocardial cell (AC16) and explore its molecular mechanism based on microarray analysis and bioinformatics analysis. Microarray data analysis manifested that PM2.5-induced toxicity affected expression of 472 genes compared with the control group, including 166 upregulated genes and 306 downregulated genes in human myocardial (AC16) cells. GO analysis showed that cellular processes such as immune response, cell maturation, embryonic heart tube morphogenesis, cellular response to electrical stimulus, skeletal muscle tissue regeneration, and negative regulation of signal transduction were upregulated, while regulation of transcription (DNA-dependent), rhythmic process, protein destabilization apoptotic process, and innate immune response were downregulated. The pathway analysis indicates that cell signaling pathways such as cytokine-cytokine receptor interaction, NF-κB signaling pathway, chemokine signaling pathway, endocrine and other factor-regulated calcium reabsorption, HTLV-I infection, and cell adhesion molecules (CAMs) were upregulated, while the TGF-β signaling pathway was downregulated. In addition, Signal-net showed that the TUBA4A, ADRBK2, BRIX1, SMC4, EIF5B, PRMT1, ATG4B, and NDC80 genes were significantly decreased, while the expression of the KRT6B gene was markedly increased compared with the control group. All the genes were verified by qRT-PCR. This study had provided new bioinformatics evidences in PM2.5-induced myocardial tissue toxicity which is necessary for further cardiovascular system toxicity studies.
... 55 Earlier, we found that particles from oil combustion were associated with markers of inflammation and endothelial dysfunction, and with increased blood pressure in the NAS population. 56,57 The current study may indicate potential mechanisms of PM-related health effects on an epigenetic level: specifically, a proinflammatory stimulus such as air pollution may modify methylation in genes relevant to immune responses, inducing inflammation and endothelial dysfunction, thereby influencing cardiovascular health. Our study has several strengths. ...
Although there is growing evidence that exposure to ambient particulate matter is associated with global DNA methylation and gene-specific methylation, little is known regarding epigenome-wide changes in DNA methylation in relation to particles and, especially, particle components. Using the Illumina Infinium HumanMethylation450 BeadChip, we examined the relationship between one-year moving averages of PM2.5 species (Al, Ca, Cu, Fe, K, Na, Ni, S, Si, V, and Zn) and DNA methylation at 484,613 CpG probes in a longitudinal cohort that included 646 subjects. Bonferroni correction was applied to adjust for multiple comparisons. Bioinformatics analysis of the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment was also performed. We observed 20 Bonferroni significant (P-value < 9.4 × 10(-9)) CpGs for Fe, 8 for Ni, and 1 for V. Particularly, methylation at Schlafen Family Member 11 (SLFN11) cg10911913 was positively associated with measured levels of all three species. The SLFN11 gene codes for an interferon-induced protein that inhibits retroviruses and sensitizes cancer cells to DNA-damaging agents. Bioinformatics analysis suggests that gene targets may be relevant to pathways including cancers, signal transduction, and cell growth and death. Ours is the first study to examine the epigenome-wide association between ambient particles species and DNA methylation. We found that long-term exposures to specific components of ambient particle pollution, especially particles emitted during oil combustion, were associated with methylation changes in genes relevant to immune responses. Our findings provide insight into potential biological mechanisms on an epigenetic level.
... Besides the obesogen effect of tobacco smoking [23][24][25], an increasing number of associative studies have suggested that inhaled environmental pollutants, combined with unhealthy diet and lifestyle, are associated with a propensity to obesity, metabolic syndrome, and insulin resistance, and are able to contribute to chronic non transmissible diseases [26], including cardiovascular disease and type 2 diabetes mellitus, all conditions that are characterized by systemic inflammation, in both adults [27][28][29] and children [23]. In particular, the association between obesity and PM2.5 has been extensively evaluated by a meta-analysis including three large prospective cohort studies and 14 panel studies with short-term follow-up [30]. Results of this meta-analysis indicate that obese people may be more susceptible to the cardiovascular health effects of ambient PM2.5, also after adjusting for a number of potential confounding factors. ...
The aim of this review is to provide a general overview of the possible associations among the vitamin D status, air pollution and obesity. Sunlight exposure accounts in humans for more than 90 % of the production of vitamin D. Among emerging factors influencing sunlight-induced synthesis of vitamin D, prospective and observational studies proved that air pollution constitutes an independent risk factor in the pathogenesis of vitamin D hypovitaminosis. In addition, environmental pollutants can affect risk of obesity when inhaled, in combination with unhealthy diet and lifestyle. In turn, obesity is closely associated with a low vitamin D status and many possible mechanisms have been proposed to explain this association. The associations of air pollution with low vitamin D status on the hand and with obesity on the other hand, could provide a rationale for considering obesity as a further link between air pollution and low vitamin D status. In this respect, a vicious cycle could operate among low vitamin D status, air pollution, and obesity, with additive detrimental effects on cardio-metabolic risk in obese individuals. Besides vitamin D supplementation, nutrient combination, used to maximize the protective effects against air pollution, might also contribute to improve the vitamin D status by attenuating the “obesogen” effects of air pollution.
... Results of this meta-analysis suggested that obesity may modify the impact of PM 2.5 on cardiovascular health, as obese people may be more susceptible to the cardiovascular health effects of ambient PM 2.5 , with a higher risk of cardiovascular mortality among obese subjects also after adjusting for a number of potential confounding factors. Endothelial dysfunction and reactive oxygen species generation via activation of alveolar macrophage and systemic vascular oxidases including the NAD(P)H, mitochondrial and xanthine oxidases, appear to mediate this risk [89]. In addition, PM 2.5 exposure enhances the expression of proinflammatory cytokines, such as IL-6 and TNF-α [90]. ...
Growing evidence suggests the causal link between the endocrine-disrupting chemicals (EDCs) and the global obesity epidemics, in the context in the so-called "obesogenic environment". Dietary intake of contaminated foods and water, especially in association with unhealthy eating pattern, and inhalation of airborne pollutants represent the major sources of human exposure to EDCs. This is of particular concern in view of the potential impact of obesity on chronic non-transmissible diseases, such as type 2 diabetes, cardiovascular disease, and hormone-sensitive cancers. The key concept is the identification of adipose tissue not only as a preferential site of storage of EDCs, but also as an endocrine organ and, as such, susceptible to endocrine disruption. The timing of exposure to EDCs is critical to the outcome of that exposure, with early lifetime exposures (e.g., fetal or early postnatal) particularly detrimental because of their permanent effects on obesity later in life. Despite that the mechanisms operating in EDCs effects might vary enormously, this minireview is aimed to provide a general overview on the possible association between the pandemics of obesity and EDCs, briefly describing the endocrine mechanisms linking EDCs exposure and latent onset of obesity.
... Whilst ambient PM 2.5 concentrations were not associated with changes in sICAM-1 or sVCAM-1, associations between BC and sVCAM were magnified in subjects with a glutathione S-transferase M1 (GSTM1) deletion. A genetic score approach, investigating interactions between relevant pathways and the environment, also suggests that OS plays a role in the association of ambient particles derived from oil combustion and endothelial dysfunction [25,26]. Research examining the association between PM oxidative potential (OP; the capacity of particles to cause damaging oxidative reactions) and adverse health outcomes is in its infancy, but a cohort panel study in 93 elderly non-smoking adults suggests that shortterm exposures to traffic-related air pollutants with a high OP contribute to microvascular endothelial dysfunction, represented by reactive hyperemia index (RHI) [27] (Fig. 1). ...
Exposure to combustion-related particulate matter (PM), at concentrations experienced by populations throughout the world, contributes to pulmonary and cardiac disease through multiple mechanistic pathways that are complex and interdependent. Current evidence supports an interactive chain of events linking pollution-induced pulmonary and systemic oxidative stress, inflammatory events, and translocation of particle constituents with an associated risk of vascular dysfunction, atherosclerosis, altered cardiac autonomic function, and ischemic cardiovascular and obstructive pulmonary diseases. Because oxidative stress is believed to play such an instrumental role in these pathways, the capacity of particulate pollution to cause damaging oxidative reactions (the oxidative potential) has been used as an effective exposure metric, identifying toxic components and sources within diverse ambient PM mixes that vast populations are subjected to-from traffic emissions on busy roads in urban areas to biomass smoke that fills homes in rural areas of the developing world.
© 2015 New York Academy of Sciences.
Exposure to fine particulate matter (PM2.5) has been associated with adverse cardiovascular outcomes. However, the effects of toxic metals in PM2.5 on cardiovascular health remain unknown. To investigate the early cardiovascular effects of specific PM2.5 metal constituents at the personal level, we conducted a panel study on 45 healthy college students in Caofeidian, China. Personal exposure concentrations and cardiovascular effect markers were monitored simultaneously within one year in four study periods. Four linear mixed-effects models were used to analyze the relationship between personal exposure to PM2.5 and 15 metal fractions (Al, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, As, Se, Mo, Cd, Sb, and Pb) with soluble CD36 (sCD36), C-reactive protein (CRP), and oxidized low-density lipoprotein (OX-LDL) levels, heart rate, and blood pressure. The concentrations of most individual metals (Mn, Cu, Zn, As, Se, Mo, Cd, Sb and Pb) were the highest in winter. Meanwhile, there were significant differences in inflammatory (sCD36 and CRP) and oxidative stress (OX-LDL) markers in the serum of participants over the four seasons. In particular, the estimated effects of personal metal exposure (such as V, As, Se, Cd, and Pb) on sCD36 and pulse pressure (PP) levels were consistently significant across the four LME models. A significant mediating role of sCD36 was also found in the relationship between personal exposure to Zn and Cr and changes in PP levels. Our findings provide clues and potential mechanisms regarding the cardiovascular effects of specific toxic constituents of PM2.5 in healthy young adults.
This paper investigates the feasibility of developing national empirical models to predict ambient concentrations of sparsely monitored air pollutants at high spatial resolution. We used a data set of cooking organic aerosol (COA) and hydrocarbon-like organic aerosol (HOA; traffic primary organic PM) measured using aerosol mass spectrometry across the continental United States. The monitoring locations were selected to span the national distribution of land-use and source-activity variables commonly used for land-use regression modeling (e.g., road length, restaurant count, etc.). The models explain about 60% of the spatial variability of the measured data (R2 0.63 for the COA model and 0.62 for the HOA model). Extensive cross-validation suggests that the models are robust with reasonable transferability. The models predict large urban-rural and intra-urban variability with hotspots in urban areas and along the road corridors. The predicted national concentration surfaces show reasonable spatial correlation with source-specific national chemical transport model (CTM) simulations (R2: 0.45 for COA, 0.4 for HOA). Our measured data, empirical models, and CTM predictions all show that COA concentrations are about two times higher than HOA. Since COA and HOA are important contributors to the intra-urban spatial variability of the total PM2.5, our results highlight the potential importance of controlling commercial cooking emissions for air quality management in the United States.
Fine particulate matter (PM2.5 )-induced detrimental cardiovascular effects have been widely concerned, especially for endothelial cells, which is the first barrier of the cardiovascular system. Among potential mechanisms involved, reactive oxidative species take up a crucial part. However, source of oxidative stress and its relationship with inflammatory response have been rarely studied in PM2.5 -induced endothelial injury. Here, as a key oxidase that catalyzes redox reactions, NADPH oxidase (NOX) was investigated. Human umbilical vein endothelial cells (EA.hy926) were exposed to Standard Reference Material 1648a of urban PM2.5 for 24 h, which resulted in NOX-sourced oxidative stress, endothelial dysfunction, and inflammation induction. These are manifested by the up-regulation of NOX, increase of superoxide anion and hydrogen peroxide, elevated endothelin-1 (ET-1) and asymmetric dimethylarginine (ADMA) level, reduced nitric oxide (NO) production, and down-regulation of phosphorylation of endothelial NO synthase (eNOS) with increased levels of inducible NO synthase, as well as the imbalance between tissue-type plasminogen activator (tPA) and plasminogen activator inhibitor 1 (PAI-1), and changes in the levels of pro-inflammatory and anti-inflammatory factors. However, administration of NOX1/4 inhibitor GKT137831 alleviated PM2.5 -induced elevated endothelial dysfunction biomarkers (NO, ET-1, ADMA, iNOS, and tPA/PAI-1), inflammatory factors (IL-1β, IL-10, and IL-18), and adhesion molecules (ICAM-1, VCAM-1, and P-selectin) and also passivated NOX-dependent AKT and eNOS phosphorylation that involved in endothelial activation. In summary, PM2.5 -induced NOX up-regulation is the source of ROS in EA.hy926, which activated AKT/eNOS/NO signal response leading to endothelial dysfunction and inflammatory damage in EA.hy926 cells.
Air pollution is consistently linked with elevations in cardiovascular disease (CVD) and CVD-related mortality. Particulate matter (PM) is a critical factor in air pollution-associated CVD. PM forms in the air during the combustion of fuels as solid particles and liquid droplets and the sources of airborne PM range from dust and dirt to soot and smoke. The health impacts of PM inhalation are well documented. In the US, where CVD is already the leading cause of death, it is estimated that PM2.5 (PM < 2.5 μm in size) is responsible for nearly 200,000 premature deaths annually. Despite the public health data, definitive mechanisms underlying PM-associated CVD are elusive. However, evidence to-date implicates mechanisms involving oxidative stress, inflammation, metabolic dysfunction and dyslipidemia, contributing to vascular dysfunction and atherosclerosis, along with autonomic dysfunction and hypertension. For the benefit of susceptible individuals and individuals who live in areas where PM levels exceed the National Ambient Air Quality Standard, interventional strategies for mitigating PM-associated CVD are necessary. This review will highlight current state of knowledge with respect to mechanisms for PM-dependent CVD. Based upon these mechanisms, strategies for intervention will be outlined. Citing data from animal models and human subjects, these highlighted strategies include: 1) antioxidants, such as vitamins E and C, carnosine, sulforaphane and resveratrol, to reduce oxidative stress and systemic inflammation; 2) omega-3 fatty acids, to inhibit inflammation and autonomic dysfunction; 3) statins, to decrease cholesterol accumulation and inflammation; 4) melatonin, to regulate the immune-pineal axis and 5) metformin, to address PM-associated metabolic dysfunction. Each of these will be discussed with respect to its potential role in limiting PM-associated CVD.
Objective
Find the correlation between particulate matter (PM) and biomarkers related to blood coagulation, offer medical evidence to sensitive indicators and carry out early diagnosis of cardiovascular diseases.
Method
A combination of computer and manual retrieval was used to search for the keywords in PubMed (584 records), Cochrane Library (28 records), Web of Science (162 records) and Embase (163 records). Finally, a total of 25 articles were included in this meta-analysis. Stata 13.0 was applied to examine the heterogeneity among the studies and to calculate the combined effect estimates, percent variation (%) and 95% CI by selecting corresponding models. Additionally, sensitivity analysis and publication bias test were also conducted.
Results
Meta-analysis indicated that there was an association between PM2.5 exposure (per 10 µg/m³ increase) and fibrinogen. With the increase of PM2.5 exposure (per 10 µg/m³ increase), the content of fibrinogen revealed a high level (2.26%; 95% CI: 1.08–3.44%); and the increase of UFPs exposure (per 5000/cm³ increase) was correlated with some biomarkers such as cell surface antigen and protein ligand including ICAM-1, sCD40L, P-selectin, E-selectin and PAI-1 that indirectly related to blood coagulation, yielding a percent variation of 10.83% (95% CI: 3.49%−18.17%).
Conclusion
This meta-analysis expounded that PM-related biomarkers were associated with blood coagulation, and the relationship with fibrinogen was much stronger.
Background:
The mechanisms by which exposure to particulate matter might increase risk of cardiovascular morbidity and mortality are not fully known. However, few existing studies have investigated the potential role of particle radioactivity. Naturally occurring radionuclides attach to particulate matter and continue to release ionizing radiation after inhalation and deposition in the lungs. We hypothesize that exposure to particle radioactivity increases biomarkers of inflammation.
Methods:
Our repeated-measures study included 752 men in the greater Boston area. We estimated regional particle radioactivity as a daily spatial average of gross beta concentrations from five monitors in the study area. We used linear mixed-effects regression models to estimate short- and medium-term associations between particle radioactivity and biomarkers of inflammation and endothelial dysfunction, with and without adjustment for additional particulate air pollutants.
Results:
We observed associations between particle radioactivity on C-reactive protein (CRP), intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion moleducle-1 (VCAM-1), but no associations with fibrinogen. An interquartile range width increase in mean 7-day particle radioactivity (1.2 10 Bq/m) was associated with a 4.9% increase in CRP (95% CI: 0.077, 9.9), a 2.8% increase in ICAM-1 (95% CI: 1.4, 4.2), and a 4.3% increase in VCAM-1 (95% CI: 2.5, 6.1). The main effects of particle radioactivity remained similar after adjustment in most cases. We also obtained similar effect estimates in a sensitivity analysis applying a robust causal model.
Conclusions:
Regional particle radioactivity is positively associated with inflammatory biomarkers, indicating a potential pathway for radiation-induced cardiovascular effects.
Current studies indicate that long-term exposure to ambient fine particulate matter (PM2.5) is related with global mortality, yet no studies have explored relationships of PM2.5 and its species with DNAm PhenoAge acceleration (DNAmPhenoAccel), a new epigenetic biomarker of phenotypic age. We identified which PM2.5 species had association with DNAmPhenoAccel in a one-year exposure window in a longitudinal cohort. We collected whole blood samples from 683 elderly men in the Normative Aging Study between 1999 and 2013 (n = 1254 visits). DNAm PhenoAge was calculated using 513 CpGs retrieved from the Illumina Infinium HumanMethylation450 BeadChip. Daily concentrations of PM2.5 species were measured at a fixed air-quality monitoring site and one-year moving averages were computed. Linear mixed-effect (LME) regression and Bayesian kernel machine (BKM) regression were used to estimate the associations. The covariates included chronological age, body mass index (BMI), cigarette pack years, smoking status, estimated cell types, batch effects etc. Benjamini-Hochberg false discovery rate at a 5% false positive threshold was used to adjust for multiple comparison. During the study period, the mean DNAm PhenoAge and chronological age in our subjects were 68 and 73 years old, respectively. Using LME model, only lead and calcium were significantly associated with DNAmPhenoAccel. For example, an interquartile range (IQR, 0.0011 μg/m3) increase in lead was associated with a 1.29-year [95% confidence interval (CI): 0.47, 2.11] increase in DNAmPhenoAccel. Using BKM model, we selected PM2.5, lead, and silicon to be predictors for DNAmPhenoAccel. A subsequent LME model showed that only lead had significant effect on DNAmPhenoAccel: 1.45-year (95% CI: 0.46, 2.46) increase in DNAmPhenoAccel following an IQR increase in one-year lead. This is the first study that investigates long-term effects of PM2.5 components on DNAmPhenoAccel. The results demonstrate that lead and calcium contained in PM2.5 was robustly associated with DNAmPhenoAccel.
Epidemiological evidences have indicated that fine particulate matter (PM 2.5 ) is associated with the increased risk of cardiovascular morbidity and mortality. Although several mechanisms linking PM 2.5 and inflammatory responses have been widely implicated, the detailed mechanisms involving the occurrence of inflammation in PM 2.5 -induced adverse effects are lacking. This study aims to investigate whether PM 2.5 exposure-induced cardiovascular injury is associated with NLRP3 inflammasome activation in apolipoprotein E -/- (Apo E -/- ) mice. Thirty-two Apo E -/- mice were randomly divided into four groups. The mice were fed with normal chow (NC) or high-fat chow (HFC) for 10 weeks, respectively. From week 11, the mice were exposed to concentrated PM 2.5 (PM) or filter air (FA) using Shanghai Meteorological and Environmental Animal Exposure System for 16 weeks. The cardiac function and myocardial injury were evaluated by echocardiography and histopathological examination. Meanwhile, the expression of NLRP3-related signaling pathway in myocardium was detected. Compared with the FA mice, the PM mice showed the underlying cardiac dysfunction and injury in both NC and HFC groups. Mononuclear macrophages (CD11c ⁺ ) were significant higher in bone marrow of the PM mice than that in the FA mice, whilst CD206 ⁺ macrophages were lower. Accordingly, PM 2.5 exposure induced the increase of circulating inflammatory cytokine TNF-α and decrease of anti-inflammatory cytokine IL-10. PM 2.5 exposure was also associated with the activation of NLRP3 inflammasome, which characterized by elevated protein expression of NLRP3, ASC, caspase-1, IL-1β and IL-18 in myocardium. All these results demonstrated PM 2.5 -related cardiac injury is mediated by macrophages polarization and NLRP3 inflammasome activation.
Background:
Assessment of the cumulative effect of correlated exposures is an open methodological issue in environmental epidemiology. Most previous studies have applied regression models with interaction terms or dimension reduction methods. The combined effect of pollutants has been also evaluated through the use of exposure scores that incorporate weights based on the strength of the component-specific associations with health outcomes.
Methods:
We compared three approaches addressing multi-pollutant exposures in epidemiological models: main effects models, the adaptive least absolute shrinkage and selection operator (LASSO) and a weighted exposure score. We assessed the performance of the methods by simulations under various scenarios for the pollutants' correlations. We further applied these methods to time series data from Athens, Greece in 2007-12 to investigate the combined effect of short-term exposure to six regulated pollutants on all-cause and respiratory mortality.
Results:
The exposure score provided the least biased estimate under all correlation scenarios for both mortality outcomes. The adaptive LASSO performed well in the case of low and medium correlation between exposures while the main effect model resulted in severe bias. In the real data application, the cumulative effect estimate was similar between approaches for all-cause mortality ranging from 0.7% increase per interquartile range (IQR) (score) to 1.1% (main effects), while for respiratory mortality conclusions were contradictive and ranged from - 0.6% (adaptive LASSO) to 2.8% (score).
Conclusions:
Τhe use of a weighted exposure score to address cumulative effects of correlated metrics may perform well under different exposure correlation and variability in the health outcomes.
Purpose of review:
The purpose of this review is to describe the most recent statistical approaches to estimate the effect of multi-pollutant mixtures or multiple correlated exposures on human health.
Recent findings:
The health effects of environmental chemicals or air pollutants have been widely described. Often, there exists a complex mixture of different substances, potentially highly correlated with each other and with other (environmental) stressors. Single-exposure approaches do not allow disentangling effects of individual factors and fail to detect potential interactions between exposures. In the last years, sophisticated methods have been developed to investigate the joint or independent health effects of multi-pollutant mixtures or multiple environmental exposures. A classification of the most recent methods is proposed. A non-technical description of each method is provided, together with epidemiological applications and operational details for implementation with standard software.
Exposure to ambient air pollution is associated with adverse cardiovascular outcomes. These are manifested through several, likely overlapping, pathways including at the functional level, endothelial dysfunction, atherosclerosis, pro-coagulation and alterations in autonomic nervous system balance and blood pressure. At numerous points within each of these pathways, there is potential for cellular oxidative imbalances to occur. The current review examines epidemiological, occupational and controlled exposure studies and research employing healthy and diseased animal models, isolated organs and cell cultures in assessing the importance of the pro-oxidant potential of air pollution in the development of cardiovascular disease outcomes. The collective body of data provides evidence that oxidative stress (OS) is not only central to eliciting specific cardiac endpoints, but is also implicated in modulating the risk of succumbing to cardiovascular disease, sensitivity to ischemia/reperfusion injury and the onset and progression of metabolic disease following ambient pollution exposure. To add to this large research effort conducted to date, further work is required to provide greater insight into areas such as (a) whether an oxidative imbalance triggers and/or or worsens the effect and/or is representative of the consequence of disease progression, (b) OS pathways and cardiac outcomes caused by individual pollutants within air pollution mixtures, or as a consequence of inter-pollutant interactions and (c) potential protection provided by nutritional supplements and/or pharmacological agents with antioxidant properties, in susceptible populations residing in polluted urban cities.
Recent studies have reported robust associations of long-term PM2.5 exposure with DNA methylation-based measures of aging; yet, the molecular implications of these relationships remain poorly understood. We evaluated if genetic variation in three biological pathways implicated in PM2.5-related disease - oxidative stress, endothelial function, and metal processing - could modify the effect of PM2.5 on DNAm-age, one prominent DNA methylation-based measure of biological age. This analysis was based on 552 individuals from the Normative Aging Study with at least one visit between 2000 and 2011 (n = 940 visits). A genetic-score approach was used to calculate aging-risk variant scores for endothelial function, oxidative stress, and metal processing pathways. One-year PM2.5 and PM2.5 component (sulfate and ammonium) levels at participants' addresses were estimated using the GEOS-chem transport model. Blood DNAm-age was calculated using CpG sites on the Illumina HumanMethylation450 BeadChip. In fully-adjusted linear mixed-effects models, the effects of sulfate on DNAm-age (in years) were greater in individuals with high aging-risk endothelial function variant scores when compared to individuals with low aging-risk endothelial function variant scores (Pinteraction=0.0007; βHigh=1.09, 95%CIHigh: 0.70, 1.48; βLow=0.40, 95%CILow: 0.14, 0.67). Similar trends were observed in fully-adjusted models of ammonium and total PM2.5 alone. No effect modification was observed by oxidative stress and metal processing variant scores. Secondary analyses revealed significant associations of serum endothelial markers, ICAM1 (β = 0.01, 95%CI: 0.002, 0.012) and VCAM1 (β = 0.002, 95%CI: 0.0005, 0.0026), with DNAm-age. Our results add novel evidence that endothelial physiology may be important to DNAm-age relationships, but further research is required to establish their generalizability.
Background:
Long-term PM2.5 exposure and aging have been implicated in multiple shared diseases; studying their relationship is a promising strategy to further understand the adverse impact of PM2.5 on human health.
Objective:
We assessed the relationship of major PM2.5 component species (ammonium, elemental carbon, organic carbon, nitrate, and sulfate) with Horvath and Hannum DNA methylation (DNAm) age, two DNA methylation-based predictors of chronological age.
Methods:
This analysis included 552 participants from the Normative Aging Study with multiple visits between 2000 and 2011 (n=940 visits). We estimated 1-year PM2.5 species levels at participants' addresses using the GEOS-chem transport model. Blood DNAm-age was calculated using CpG sites on the Illumina HumanMethylation450 BeadChip. We fit linear mixed-effects models, controlling for PM2.5 mass and lifestyle/environmental factors as fixed effects, with the adaptive LASSO penalty to identify PM2.5 species associated with DNAm-age.
Results:
Sulfate and ammonium were selected by the LASSO in the Horvath DNAm-age models. In a fully-adjusted multiple-species model, interquartile range increases in both 1-year sulfate (95%CI: 0.28, 0.74, P<0.0001) and ammonium (95%CI: 0.02, 0.70, P=0.04) levels were associated with at least a 0.36-year increase in Horvath DNAm-age. No PM2.5 species were selected by the LASSO in the Hannum DNAm-age models. Our findings persisted in sensitivity analyses including only visits with 1-year PM2.5 levels within US EPA national ambient air quality standards.
Conclusion:
Our results demonstrate that sulfate and ammonium were most associated with Horvath DNAm-age and suggest that DNAm-age measures differ in their sensitivity to ambient particle exposures and potentially disease.
PM2.5 has been associated with adverse cardiovascular outcomes, but it is unclear whether specific PM2.5 components, particularly metals, may be responsible for cardiovascular effects.
To determine which PM2.5 components are associated with blood pressure in a longitudinal cohort.
We fit linear mixed-effects models with the adaptive LASSO penalty to longitudinal data from 718 elderly men in the Veterans Affairs Normative Aging Study, 1999-2010. We controlled for PM2.5 mass, age, body mass index, use of antihypertensive medication (ACE inhibitors, non-ophthalmic beta blockers, calcium channel blockers, diuretics, and angiotensin receptor antagonists), smoking status, alcohol intake, years of education, temperature, and season as fixed effects in the models, and additionally applied the adaptive LASSO method to select PM2.5 components associated with blood pressure. Final models were identified by the Bayesian Information Criterion (BIC).
For systolic blood pressure (SBP), Ni and Na were selected by the adaptive LASSO, whereas only Ni was selected for diastolic blood pressure (DBP). An IQR increase (2.5 ng/m(3)) in 7-day moving average Ni was associated with 2.48 (95% CI: 1.45, 3.50) mm Hg increase in SBP and 2.22 (95% CI: 1.69, 2.75) mm Hg increase in DBP, respectively. Associations were comparable when the analysis was restricted to study visits with PM2.5 below the 75th percentile of the distribution (12 µg/m(3)).
Our study suggested exposure to ambient Ni was associated with increased blood pressure independent of PM2.5 mass in our study population of elderly men. Further research is needed to confirm our findings, assess generalizability to other populations, and identify potential mechanisms for Ni effects.
Air pollution has been associated with increased systemic inflammation markers. We developed a new pathway analysis approach to investigate whether gene variants within relevant pathways (oxidative stress, endothelial function, and metal processing) modified the association between particulate air pollution and fibrinogen, C-reactive protein (CRP), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1). Our study population consisted of 822 elderly participants of the Normative Aging Study (1999-2011). To investigate the role of biological mechanisms and to reduce the number of comparisons in the analysis, we created pathway-specific scores using gene variants related to each pathway. To select the most appropriate gene variants, we used the least absolute shrinkage and selection operator (Lasso) to relate independent outcomes representative of each pathway (8-hydroxydeoxyguanosine for oxidative stress, augmentation index for endothelial function, and patella lead for metal processing) to gene variants. A high genetic score corresponds to a higher allelic risk profile. We fit mixed-effects models to examine modification by the genetic score of the weekly air pollution association with the outcome. Among participants with higher genetic scores within the oxidative stress pathway, we observed significant associations between particle number and fibrinogen, while we did not find any association among participants with lower scores (pinteraction = 0.04). Compared to individuals with low genetic scores of metal processing gene variants, participants with higher scores had greater effects of particle number on fibrinogen (pinteraction = 0.12), CRP (pinteraction = 0.02), and ICAM-1 (pinteraction = 0.08). This two-stage penalization method is easy to implement and can be used for large-scale genetic applications.
Experimental evidence suggests that inhaled particles from vehicle exhaust have systemic effects on inflammation, endothelial activation and oxidative stress. In the present study we assess the relationships of short-term exposures with inflammatory endothelial activation and oxidative stress biomarker levels in a population of trucking industry workers.
Blood and urine samples were collected pre and post-shift, at the beginning and end of a workweek from 67 male non-smoking US trucking industry workers. Concurrent measurements of microenvironment concentrations of elemental and organic carbon (EC & OC), and fine particulate matter (PM2.5) combined with time activity patterns allowed for calculation of individual exposures. Associations between daily and first and last-day average levels of exposures and repeated measures of intercellular and vascular cell adhesion molecule-1 (ICAM-1 & VCAM-1), interleukin 6 (IL-6) and C-reactive protein (CRP) blood levels and urinary 8-Hydroxy-2[prime]-Deoxyguanosine (8-OHdG) were assessed using linear mixed effects models for repeated measures.
There was a statistically significant association between first and last-day average PM2.5 and 8-OHdG (21% increase, 95% CI: 2, 42%) and first and last-day average OC and IL-6 levels (18% increase 95% CI: 1, 37%) per IQR in exposure. There were no significant findings associated with EC or associations suggesting acute cross-shift effects.
Our findings suggest associations between weekly average exposures of PM2.5 on markers of oxidative stress and OC on IL-6 levels.
There is increasing interest in evaluating the association between specific fine-particle (particles with aerodynamic diameters
less than 2.5 µm; PM2.5) constituents and adverse health outcomes rather than focusing solely on the impact of total PM2.5. Because PM2.5 may be related to both constituent concentration and health outcomes, constituents that are more strongly correlated with
PM2.5 may appear more closely related to adverse health outcomes than other constituents even if they are not inherently more toxic.
Therefore, it is important to properly account for potential confounding by PM2.5 in these analyses. Usually, confounding is due to a factor that is distinct from the exposure and outcome. However, because
constituents are a component of PM2.5, standard covariate adjustment is not appropriate. Similar considerations apply to source-apportioned concentrations and
studies assessing either short-term or long-term impacts of constituents. Using data on 18 constituents and data from 1,060
patients admitted to a Boston medical center with ischemic stroke in 2003–2008, the authors illustrate several options for
modeling the association between constituents and health outcomes that account for the impact of PM2.5. Although the different methods yield results with different interpretations, the relative rankings of the association between
constituents and ischemic stroke were fairly consistent across models.
Exposure to traffic-related air pollution (TRAP) contributes to increased cardiovascular risk. Land-use regression models can improve exposure assessment for TRAP.
We examined the association between medium-term concentrations of black carbon (BC) estimated by land-use regression and levels of soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1), both markers of inflammatory and endothelial response.
We studied 642 elderly men participating in the Veterans Administration (VA) Normative Aging Study with repeated measurements of sICAM-1 and sVCAM-1 during 1999-2008. Daily estimates of BC exposure at each geocoded participant address were derived using a validated spatiotemporal model and averaged to form 4-, 8-, and 12-week exposures. We used linear mixed models to estimate associations, controlling for confounders. We examined effect modification by statin use, obesity, and diabetes.
We found statistically significant positive associations between BC and sICAM-1 for averages of 4, 8, and 12 weeks. An interquartile-range increase in 8-week BC exposure (0.30 μg/m3) was associated with a 1.58% increase in sICAM-1 (95% confidence interval, 0.18-3.00%). Overall associations between sVCAM-1 and BC exposures were suggestive but not statistically significant. We found a significant interaction with diabetes-where diabetics were more susceptible to the effect of BC-for both sICAM-1 and sVCAM-1. We also observed an interaction with statin use, which was statistically significant for sVCAM-1 and suggestive for sICAM-1. We found no evidence of an interaction with obesity.
Our results suggest that medium-term exposure to TRAP may induce an increased inflammatory/endothelial response, especially among diabetics and those not using statins.
Hourly concentrations of ambient fine particle sulfate and carbonaceous aerosols (elemental carbon [EC], organic carbon [OC], and black carbon [BC]) were measured at the Harvard-U.S. Environmental Protection Agency Supersite in Boston, MA, between January 2007 and October 2008. These hourly concentrations were compared with those made using integrated filter-based measurements over 6-day or 24-hr periods. For sulfate, the two measurement methods showed good agreement. Semicontinuous measurements of EC and OC also agreed (but not as well as for sulfate) with those obtained using 24-hr integrated filter-based and optical BC reference methods. During the study period, 24-hr PM2.5 (particulate matter [PM] < or = 2.5 microm in aerodynamic diameter) concentrations ranged from 1.4 to 37.6 microg/m3, with an average of 9.3 microg/m3. Sulfate as the equivalent of ammonium sulfate accounted for 39.1% of the PM2.5 mass, whereas EC and OC accounted for 4.2 and 35.2%, respectively. Hourly sulfate concentrations showed no distinct diurnal pattern, whereas hourly EC and BC concentrations peaked during the morning rush hour between 7:00 and 9:00 a.m. OC concentrations also exhibited nonpronounced, small peaks during the day, most likely related to traffic, secondary organic aerosol, and local sources, respectively.
GeneCards (www.genecards.org) is a comprehensive, authoritative compendium of annotative information about human genes, widely used for nearly 15 years. Its gene-centric content is automatically mined and integrated from over 80 digital sources, resulting in a web-based deep-linked card for each of >73 000 human gene entries, encompassing the following categories: protein coding, pseudogene, RNA gene, genetic locus, cluster and uncategorized. We now introduce GeneCards Version 3, featuring a speedy and sophisticated search engine and a revamped, technologically enabling infrastructure, catering to the expanding needs of biomedical researchers. A key focus is on gene-set analyses, which leverage GeneCards’ unique wealth of combinatorial annotations. These include the GeneALaCart batch query facility, which tabulates user-selected annotations for multiple genes and GeneDecks, which identifies similar genes with shared annotations, and finds set-shared annotations by descriptor enrichment analysis. Such set-centric features address a host of applications, including microarray data analysis, cross-database annotation mapping and gene-disorder associations for drug targeting. We highlight the new Version 3 database architecture, its multi-faceted search engine, and its semi-automated quality assurance system. Data enhancements include an expanded visualization of gene expression patterns in normal and cancer tissues, an integrated alternative splicing pattern display, and augmented multi-source SNPs and pathways sections. GeneCards now provides direct links to gene-related research reagents such as antibodies, recombinant proteins, DNA clones and inhibitory RNAs and features gene-related drugs and compounds lists. We also portray the GeneCards Inferred Functionality Score annotation landscape tool for scoring a gene’s functional information status. Finally, we delineate examples of applications and collaborations that have benefited from the GeneCards suite.
Database URL: www.genecards.org
Particulate matter has been associated with acute cardiovascular outcomes, but our understanding of the mechanism is incomplete. We examined the association between particulate matter and cell adhesion molecules. We also investigated the modifying effect of genotype and phenotype variation to gain insight into the relevant biological pathways for this association.
We used mixed regression models to examine the association of PM(2.5) (particulate matter < or = 2.5 microm in diameter) and black carbon with serum concentrations of soluble intercellular adhesion molecule (sICAM-1) and soluble vascular cell adhesion molecule (sVCAM-1), markers of endothelial function and inflammation, in a longitudinal study of 809 participants in the Normative Ageing Study (1819 total observations). We also examined whether this association was modified by genotype, obesity or diabetes status. Genes selected for analyses were either related to oxidative stress, endothelial function, lipid metabolism or metal processing.
Black carbon during the 2 days prior to blood draw was significantly associated with increased sVCAM-1 (4.5% increase per 1 microg/m(3), 95% CI 1.1 to 8.0). Neither pollutant was associated with sICAM-1. Larger effects of black carbon on sVCAM were seen in subjects with obesity (p=0.007) and who were GSTM1 null (p=0.02).
Black carbon is associated with markers of endothelial function and inflammation. Genes related to oxidative defence may modify this association.
Mechanisms involving oxidative stress and inflammation have been proposed to explain associations of ambient air pollution with cardiovascular morbidity and mortality. Experimental evidence suggests that organic components and ultrafine particles (UFP) are important.
We conducted a panel study of 60 elderly subjects with coronary artery disease living in retirement communities within the Los Angeles, California, air basin. Weekly biomarkers of inflammation included plasma interleukin-6, tumor necrosis factor-alpha soluble receptor II (sTNF-RII), soluble platelet selectin (sP-selectin), and C-reactive protein (CRP). Biomarkers of erythrocyte antioxidant activity included glutathione peroxidase-1 and superoxide dismutase. Exposures included outdoor home daily particle mass [particulate matter < 0.25, 0.25-2.5, and 2.5-10 microm in aerodynamic diameter (PM(0.25), PM(0.25-2.5), PM(2.5-10))], and hourly elemental and black carbon (EC-BC), estimated primary and secondary organic carbon (OC(pri), SOC), particle number (PN), carbon monoxide (CO), and nitrogen oxides-nitrogen dioxide (NO(x)-NO(2)). We analyzed the relation of biomarkers to exposures with mixed effects models adjusted for potential confounders.
Primary combustion markers (EC-BC, OC(pri), CO, NO(x)-NO(2)), but not SOC, were positively associated with inflammatory biomarkers and inversely associated with erythrocyte anti-oxidant enzymes (n = 578). PN and PM(0.25) were more strongly associated with biomarkers than PM(0.25-2.5). Associations for all exposures were stronger during cooler periods when only OC(pri), PN, and NO(x) were higher. We found weaker associations with statin (sTNF-RII, CRP) and clopidogrel use (sP-selectin).
Traffic-related air pollutants are associated with increased systemic inflammation, increased platelet activation, and decreased erythrocyte antioxidant enzyme activity, which may be partly behind air pollutant-related increases in systemic inflammation. Differences in association by particle size, OC fraction, and seasonal period suggest components carried by UFP are important.
Altered patterns of gene expression mediate the effects of particulate matter (PM) on human health, but mechanisms through which PM modifies gene expression are largely undetermined.
We aimed at identifying short- and long-term effects of PM exposure on DNA methylation, a major genomic mechanism of gene expression control, in workers in an electric furnace steel plant with well-characterized exposure to PM with aerodynamic diameters < 10 microm (PM(10)).
We measured global genomic DNA methylation content estimated in Alu and long interspersed nuclear element-1 (LINE-1) repeated elements, and promoter DNA methylation of iNOS (inducible nitric oxide synthase), a gene suppressed by DNA methylation and induced by PM exposure in blood leukocytes. Quantitative DNA methylation analysis was performed through bisulfite PCR pyrosequencing on blood DNA obtained from 63 workers on the first day of a work week (baseline, after 2 days off work) and after 3 days of work (postexposure). Individual PM(10) exposure was between 73.4 and 1,220 microg/m(3).
Global methylation content estimated in Alu and LINE-1 repeated elements did not show changes in postexposure measures compared with baseline. PM(10) exposure levels were negatively associated with methylation in both Alu [beta = -0.19 %5-methylcytosine (%5mC); p = 0.04] and LINE-1 [beta = -0.34 %5mC; p = 0.04], likely reflecting long-term PM(10) effects. iNOS promoter DNA methylation was significantly lower in postexposure blood samples compared with baseline (difference = -0.61 %5mC; p = 0.02).
We observed changes in global and gene specific methylation that should be further characterized in future investigations on the effects of PM.
Elevated levels of ambient particulate matter (PM(10)) have been associated with increased cardiopulmonary morbidity and mortality. We previously showed that the deposition of particles in the lung induces a systemic inflammatory response that includes stimulation of the bone marrow. This marrow response is related to mediators released by alveolar macrophages (AM) and in this study we measured cytokines produced by human AM exposed to ambient particles of different composition and size. Identified cytokines were also measured in the circulation of healthy young subjects exposed to air pollutants during the 1997 Southeast Asian forest fires. Human AM were incubated with particle suspensions of residual oil fly ash (ROFA), ambient urban particles (EHC 93), inert carbon particles, and latex particles of different sizes (0.1, 1, and 10 microm) and concentrations for 24 h. Tumor necrosis factor-alpha (TNF-alpha) increases in a dose-dependent manner when AM were exposed to EHC 93 particles (p < 0.02). The TNF response of AM exposed to different sizes of latex particles was similar. The latex (158 +/- 31%), inert carbon (179 +/- 32%), and ROFA (216 +/- 34%) particles all show a similar maximum TNF response (percent change from baseline) whereas EHC 93 (1,020 +/- 212%, p < 0.05) showed a greater maximum response that was similar to lipopolysaccharide (LPS) 1 microg/ml (812 +/- 320%). Macrophages incubated with an optimal dose of EHC 93 particles (0.1 mg/ml) also produce a broad spectrum of other proinflammatory cytokines, particularly interleukin (IL)-6 (p < 0.01), IL-1 beta (p < 0.05), macrophage inflammatory protein-1 alpha (MIP-1 alpha) (p < 0.05), and granulocyte macrophage colony-stimulating factor (GM-CSF) (p < 0.01) with no difference in concentrations of the anti-inflammatory cytokine IL-10 (p = NS). Circulating levels of IL-1 beta, IL-6, and GM-CSF were elevated in subjects exposed to high levels of PM(10) during an episode of acute air pollution. These results show that a range of different particles stimulate AM to produce proinflammatory cytokines and these cytokines are also present in the blood of subjects during an episode of acute atmospheric air pollution. We postulate that these cytokines induced a systemic response that has an important role in the pathogenesis of the cardiopulmonary adverse health effects associated with atmospheric pollution.
Recent epidemiological studies have shown an association between daily morbidity and mortality and ambient particulate matter (PM) air pollution. It has been proposed that bioavailable metal constituents of PM are responsible for many of the reported adverse health effects. Studies of instilled residual oil fly ash (ROFA) demonstrated immediate and delayed responses, consisting of bradycardia, hypothermia, and arrhythmogenesis in conscious, unrestrained rats. Further investigation of instilled ROFA-associated transition metals showed that vanadium (V) induced the immediate responses, while nickel (Ni) was responsible for the delayed effects. Furthermore, Ni potentiated the immediate effects caused by V when administered concomitantly. The present study examined the responses to these metals in a whole-body inhalation exposure. To ensure valid dosimetric comparisons with instillation studies, 4 target exposure concentrations ranging from 0.3-2.4 mg/m(3) were used to incorporate estimates of total inhalation dose derived using different ventilatory parameters. Rats were implanted with radiotelemetry transmitters to continuously acquire heart rate (HR), core temperature (T(CO)), and electrocardiographic data throughout the exposure. Animals were exposed to aerosolized Ni, V, or Ni + V for 6 h per day x 4 days, after which serum and bronchoalveolar lavage samples were taken. Even at the highest concentration, V failed to induce any significant change in HR or T(CO). Ni caused delayed bradycardia, hypothermia, and arrhythmogenesis at concentrations > 1.2 mg/m(3). When combined, Ni and V produced observable delayed effects at 0.5 mg/m(3) and potentiated responses at 1.3 mg/m(3), greater than were produced by the highest concentration of Ni (2.1 mg/m(3)) alone. These results indicate a possible synergistic relationship between inhaled Ni and V, and provide insight into potential interactions regarding the toxicity of PM-associated metals.
Epidemiologic studies have demonstrated increased human morbidity and mortality with elevations in the concentration of ambient air particulate matter (PM). Fugitive fly ash from the combustion of oil and residual fuel oil significantly contributes to the ambient air particle burden. Residual oil fly ash (ROFA) is remarkable in the capacity to provoke injury in experimental systems. The unique composition of this emission source particle makes it particularly useful as a surrogate for ambient air PM in studies of biologic effects testing the hypothesis that metals mediate the biologic effects of air pollution particles. A majority of the in vitro and animal model investigations support the postulate that transition metals present in ROFA (especially vanadium) participate in Fenton-like chemical reactions to produce reactive oxygen species. This is associated with tyrosine phosphorylation, nuclear factor kappa B and other transcription factor activation, induction of inflammatory mediator expression, and inflammatory lung injury. It is also evident that vanadium accounts for a significant portion of the biologic activity of ROFA. The extrapolation of this body of investigation on ROFA to the field of ambient air PM is difficult, as particles in numerous environments have such small amounts of vanadium.
Particulate matter (PM) pollution adversely affects the airways, with asthmatic subjects thought to be especially sensitive. The authors hypothesised that exposure to diesel exhaust (DE), a major source of PM, would induce airway neutrophilia in healthy subjects, and that either these responses would be exaggerated in subjects with mild allergic asthma, or DE would exacerbate pre-existent allergic airways.
Healthy and mild asthmatic subjects were exposed for 2 h to ambient levels of DE (particles with a 50% cut-off aerodynamic diameter of 10 µm (PM10) 108 µg·m–3) and lung function and airway inflammation were assessed.
Both groups showed an increase in airway resistance of similar magnitude after DE exposure. Healthy subjects developed airway inflammation 6 h after DE exposure, with airways neutrophilia and lymphocytosis together with an increase in interleukin-8 (IL-8) protein in lavage fluid, increased IL-8 messenger ribonucleic acid expression in the bronchial mucosa and upregulation of the endothelial adhesion molecules. In asthmatic subjects, DE exposure did not induce a neutrophilic response or exacerbate their pre-existing eosinophilic airway inflammation. Epithelial staining for the cytokine IL-10 was increased after DE in the asthmatic group.
Differential effects on the airways of healthy subjects and asthmatics of particles with a 50% cut-off aerodynamic diameter of 10 µm at concentrations below current World Health Organisation air quality standards have been observed in this study. Further work is required to elucidate the significance of these differential responses.
Epidemiologic studies report associations between particulate air pollution and cardiopulmonary morbidity and mortality. Although the underlying pathophysiologic mechanisms remain unclear, it has been hypothesized that altered autonomic function and pulmonary/systemic inflammation may play a role. In this study we explored the effects of air pollution on autonomic function measured by changes in heart rate variability (HRV) and blood markers of inflammation in a panel of 88 elderly subjects from three communities along the Wasatch Front in Utah. Subjects participated in multiple sessions of 24-hr ambulatory electrocardiographic monitoring and blood tests. Regression analysis was used to evaluate associations between fine particulate matter [aerodynamic diameter less than or equal to 2.5 microm (PM2.5)] and HRV, C-reactive protein (CRP), blood cell counts, and whole blood viscosity. A 100- microg/m3 increase in PM2.5 was associated with approximately a 35 (SE = 8)-msec decline in standard deviation of all normal R-R intervals (SDNN, a measure of overall HRV); a 42 (SE = 11)-msec decline in square root of the mean of the squared differences between adjacent normal R-R intervals (r-MSSD, an estimate of short-term components of HRV); and a 0.81 (SE = 0.17)-mg/dL increase in CRP. The PM2.5-HRV associations were reasonably consistent and statistically robust, but the CRP association dropped to 0.19 (SE = 0.10) after excluding the most influential subject. PM2.5 was not significantly associated with white or red blood cell counts, platelets, or whole-blood viscosity. Most short-term variability in temporal deviations of HRV and CRP was not explained by PM2.5; however, the small statistically significant associations that were observed suggest that exposure to PM2.5 may be one of multiple factors that influence HRV and CRP.
Increased concentrations of particles in air have been related to changes in inflammatory markers that in turn are hypothesized in mediating the particle effects on cardiovascular disease. The present work examined this association in an elderly cohort in the Greater Boston area and addresses the relative role of particles from different sources.
The study included 710 subjects, active members of the VA Normative Aging Study cohort with measurements of blood markers. Concentrations of particle number (PN), black carbon (BC), fine particulate matter (PM(2.5)), and sulphates were measured at a central site near the examination site.
Positive associations were found between traffic-related particles (PN and BC) and inflammatory markers, but only suggestive associations were found with exposures to PM(2.5) and sulphates. The particle effect on the inflammatory markers was greater among subjects older than 78 years and among obese. A suggestion for a greater effect of particles on inflammatory markers among GSTM1-null subjects and non-users of statin drugs was also seen.
The findings of the study support the hypothesis that particles can induce cardiovascular disease through inflammatory pathways, suggestive of a greater toxicity of traffic-related particles.
Fine particulate matter (FPM) in ambient air causes premature mortality due to cardiac disease in susceptible populations.
Our objective in this study was to determine the most influential FPM components.
A mouse model of atherosclerosis (ApoE-/-) was exposed to either filtered air or concentrated FPM (CAPs) in Tuxedo, New York (85 microg/m3 average, 6 hr/day, 5 days/week, for 6 months), and the FPM elemental composition was determined for each day. We also examined associations between PM components and mortality for two population studies: National Mortality and Morbidity Air Pollution Study (NMMAPS) and Hong Kong.
For the CAPs-exposed mice, the average of nickel was 43 ng/m3, but on 14 days, there were Ni peaks at approximately 175 ng/m3 and unusually low FPM and vanadium. For those days, back-trajectory analyses identified a remote Ni point source. Electrocardiographic measurements on CAPs-exposed and sham-exposed mice showed Ni to be significantly associated with acute changes in heart rate and its variability. In NMMAPS, daily mortality rates in the 60 cities with recent speciation data were significantly associated with average Ni and V, but not with other measured species. Also, the Hong Kong sulfur intervention produced sharp drops in sulfur dioxide, Ni, and V, but not other components, corresponding to the intervention-related reduction in cardiovascular and pulmonary mortality.
Known biological mechanisms cannot account for the significant associations between Ni with the acute cardiac function changes in the mice or with cardiovascular mortality in people at low ambient air concentrations; therefore, further research is needed.
Particulate air pollution has been associated with several adverse cardiovascular health outcomes, and people with diabetes may be especially vulnerable. One potential pathway is inflammation and endothelial dysfunction-processes in which cell adhesion molecules and inflammatory markers play important roles.
To examine whether plasma levels of soluble intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1) and von Willebrand factor (vWF) were associated with particle exposure in 92 Boston area residents with type 2 diabetes.
Daily average ambient levels of air pollution (fine particles (PM2.5), black carbon (BC) and sulphates) were measured approximately 500 m from the patient examination site and evaluated for associations with ICAM-1, VCAM-1 and vWF. Linear regressions were fit to plasma levels of ICAM-1, VCAM-1 and vWF, with the particulate pollutant index, apparent temperature, season, age, race, sex, glycosylated haemoglobin, cholesterol, smoking history and body mass index as predictors.
Air pollutant exposure measures showed consistently positive point estimates of association with the inflammatory markers. Among participants not taking statins and those with a history of smoking, associations between PM(2.5), BC and VCAM-1 were particularly strong.
These results corroborate evidence suggesting that inflammatory mechanisms may explain the increased risk of air pollution-associated cardiovascular events among those with diabetes.
Numerous studies have found that ambient air pollution has been associated with cardiovascular disease exacerbation.
Given previous findings, we hypothesized that particulate air pollution might induce systemic inflammation in myocardial infarction (MI) survivors, contributing to an increased vulnerability to elevated concentrations of ambient particles.
A prospective longitudinal study of 1,003 MI survivors was performed in six European cities between May 2003 and July 2004. We compared repeated measurements of interleukin 6 (IL-6), fibrinogen, and C-reactive protein (CRP) with concurrent levels of air pollution. We collected hourly data on particle number concentrations (PNC), mass concentrations of particulate matter (PM) < 10 microm (PM(10)) and < 2.5 microm (PM(2.5)), gaseous pollutants, and meteorologic data at central monitoring sites in each city. City-specific confounder models were built for each blood marker separately, adjusting for meteorology and time-varying and time-invariant covariates. Data were analyzed with mixed-effects models.
Pooled results show an increase in IL-6 when concentrations of PNC were elevated 12-17 hr before blood withdrawal [percent change of geometric mean, 2.7; 95% confidence interval (CI), 1.0-4.6]. Five day cumulative exposure to PM(10) was associated with increased fibrinogen concentrations (percent change of arithmetic mean, 0.6; 95% CI, 0.1-1.1). Results remained stable for smokers, diabetics, and patients with heart failure. No consistent associations were found for CRP.
Results indicate an immediate response to PNC on the IL-6 level, possibly leading to the production of acute-phase proteins, as seen in increased fibrinogen levels. This might provide a link between air pollution and adverse cardiac events.
Exposure to particulate matter (PM) has been associated with increased cardiovascular morbidity; however, causative components are unknown. Zinc is a major element detected at high levels in urban air.
We investigated the role of PM-associated zinc in cardiac injury.
We repeatedly exposed 12- to 14-week-old male Wistar Kyoto rats intratracheally (1x/week for 8 or 16 weeks) to a) saline (control); b) PM having no soluble zinc (Mount St. Helens ash, MSH); or c) whole-combustion PM suspension containing 14.5 microg/mg of water-soluble zinc at high dose (PM-HD) and d ) low dose (PM-LD), e) the aqueous fraction of this suspension (14.5 microg/mg of soluble zinc) (PM-L), or f ) zinc sulfate (rats exposed for 8 weeks received double the concentration of all PM components of rats exposed for 16 weeks).
Pulmonary inflammation was apparent in all exposure groups when compared with saline (8 weeks > 16 weeks). PM with or without zinc, or with zinc alone caused small increases in focal subepicardial inflammation, degeneration, and fibrosis. Lesions were not detected in controls at 8 weeks but were noted at 16 weeks. We analyzed mitochondrial DNA damage using quantitative polymerase chain reaction and found that all groups except MSH caused varying degrees of damage relative to control. Total cardiac aconitase activity was inhibited in rats receiving soluble zinc. Expression array analysis of heart tissue revealed modest changes in mRNA for genes involved in signaling, ion channels function, oxidative stress, mitochondrial fatty acid metabolism, and cell cycle regulation in zinc but not in MSH-exposed rats.
These results suggest that water-soluble PM-associated zinc may be one of the causal components involved in PM cardiac effects.
We propose a new method for estimation in linear models. The ‘lasso’ minimizes the residual sum of squares subject to the sum of the absolute value of the coefficients being less than a constant. Because of the nature of this constraint it tends to produce some coefficients that are exactly 0 and hence gives interpretable models. Our simulation studies suggest that the lasso enjoys some of the favourable properties of both subset selection and ridge regression. It produces interpretable models like subset selection and exhibits the stability of ridge regression. There is also an interesting relationship with recent work in adaptive function estimation by Donoho and Johnstone. The lasso idea is quite general and can be applied in a variety of statistical models: extensions to generalized regression models and tree‐based models are briefly described.
Recent epidemiological studies have shown an association between daily morbidity and mortality and ambient particulate matter (PM) air pollution. It has been proposed that bioavailable metal constituents of PM are responsible for many of the reported adverse health effects. Studies of instilled residual oil fly ash (ROFA) demonstrated immediate and delayed responses, consisting of bradycardia, hypothermia, and arrhythmogenesis in conscious, unrestrained rats. Further investigation of instilled ROFA-associated transition metals showed that vanadium (V) induced the immediate responses, while nickel (Ni) was responsible for the delayed effects. Furthermore, Ni potentiated the immediate effects caused by V when administered concomitantly. The present study examined the responses to these metals in a whole-body inhalation exposure. To ensure valid dosimetric comparisons with instillation studies, 4 target exposure concentrations ranging from 0.3-2.4 mg/m 3 were used to incorporate estimates of total inhalation dose derived using different ventilatory parameters. Rats were implanted with radiotelemetry transmitters to continuously acquire heart rate (HR), core temperature (T CO ), and electrocardiographic data throughout the exposure. Animals were exposed to aerosolized Ni, V, or Ni + V for 6 h per day x 4 days, after which serum and bronchoalveolar lavage samples were taken. Even at the highest concentration, V failed to induce any significant change in HR or T CO . Ni caused delayed bradycardia, hypothermia, and arrhythmogenesis at concentrations > 1.2 mg/m 3 . When combined, Ni and V produced observable delayed effects at 0.5 mg/m 3 and potentiated responses at 1.3 mg/m 3 , greater than were produced by the highest concentration of Ni (2.1 mg/m 3 ) alone. These results indicate a possible synergistic relationship between inhaled Ni and V, and provide insight into potential interactions regarding the toxicity of PM-associated metals.
The Normative Aging Study is a comprehensive interdisciplinary longitudinal study located in the VA Outpatient Clinic in Boston, Mass. The study was inaugurated in 1963 by the VA because of its statutory responsibility for the medical care of 25 million war veterans of whom 2 million are now 65 years of age and over, a figure which will rise to over 7 million in the next 20 years. Approximately 2,000 male veterans are enrolled for their lifetime as research subjects and undergo recurrent examinations administered on an outpatient basis. The focus of the study is on non-pathological aging, so that the subjects were carefully screened in advance to satisfy rigid health criteria regardless of age. The study is distinctive because of its large N and the socioeconomic diversity of its population. Parameters include clinical medicine, biochemistry, special senses, oral medicine, anthropometry and behavior. The study is designed to investigate the relationship between normal aging and the natural history of chronic diseases. The investigation of environmental correlates of age change throughout the logitudinal design will also suggest the intrinsic or extrinsic nature of the aging process. The hybrid cross-sectional-longitudinal design will also enable the partialing of secular from true aging effects. Functional ages pertaining to various aspects of aging are being developed as a tool for assessing relative aging rates and the relationship among such differences in aging.
A statistical approach, Specific Rotation Factor Analysis (SRFA), has been developed to identify and apportion sources of ambient air pollutants. To increase the statistical weight of the source tracer elements, this technique is based on the analysis of the covariance matrix. The obtained eigenvectors are obliquely rotated in order to maximize the loadings of the tracer quantities of the corresponding source (specific rotations). Source contributions and profiles are estimated by regressing elemental and mass concentrations on the factor loadings.The ability of the SRFA technique to resolve major aerosol sources and determine their profiles and contributions at the receptor site is demonstrated by applying it to a subset of fine particle elemental and mass concentration data from Steubenville, OH.
Previous studies suggest that air pollution is related to thrombosis, inflammation, and endothelial dysfunction. Mechanisms and sources of susceptibility are still unclear. One possibility is that these associations can be modified by DNA methylation states.
We conducted a cohort study with repeated measurements of fibrinogen, C-reactive protein, intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) in 704 elderly men participating in the Veterans Administration Normative Aging Study (2000-2009). We investigated short- and intermediate-term air pollution effects on these blood markers, and epigene-environment interactions by DNA methylation of Alu, LINE-1, tissue factor (F3), Toll-like receptor 2 (TLR-2), and ICAM-1.
We found effects of particle number, black carbon, nitrogen dioxide (NO(2)), and carbon monoxide (CO) on fibrinogen. Ozone was a predictor of C-reactive protein and ICAM-1. Particle number, black carbon, NO(2), CO, PM(2.5), and sulfates were associated with ICAM-1 and VCAM-1. An interquartile range increase in 24-hour exposure for NO(2) was associated with a 1.7% (95% confidence interval = 0.2%-3.3%) increase in fibrinogen for ozone; a 10.8% (2.2%-20.0%) increase in C-reactive protein for particle number; a 5.9% (3.6%-8.3%) increase in ICAM-1; and for PM(2.5), a 3.7% (1.7%-5.8%) increase in VCAM-1. The air pollution effect was stronger among subjects having higher Alu, lower LINE-1, tissue factor, or TLR-2 methylation status.
We observed associations of traffic-related pollutants on fibrinogen, and both traffic and secondary particles on C-reactive protein, ICAM-1, and VCAM-1. There was effect modification by DNA methylation status, indicating that epigenetic states can convey susceptibility to air pollution.
Vanadium is a transition metal released into the atmosphere, as air-suspended particles, as a result of the combustion of fossil fuels and some metallurgic industry activities. Air-suspended particle pollution causes inflammation-related processes such as thrombosis and other cardiovascular events. Our aim was to evaluate the effect of vanadium pentoxide (V2O5) on endothelial cells since they are key participants in the pathogenesis of several cardiovascular and inflammatory diseases. Cell adhesion, the expression of adhesion molecules and oxidative stress, as well as proliferation, morphology and cell death of human umbilical vein endothelial cells (HUVECs) exposed to V2O5, were evaluated. Vanadium pentoxide at a 3.12 µg cm(-2) concentration induced an enhanced adhesion of the U937 macrophage cell line to HUVECs, owing to an increased expression of late adhesion molecules. HUVECs exposed to V2O5 showed an increase in ROS and nitric oxide production, and a diminished proliferation. These changes in vanadium-treated HUVECs were accompanied by severe morphological changes and apoptotic cell death. Vanadium pentoxide induced serious endothelial cell damage, probably related to the increased cardiovascular morbidity and mortality observed in individuals living in highly air-polluted areas.
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.
The problem of selecting one of a number of models of different dimensions is treated by finding its Bayes solution, and evaluating the leading terms of its asymptotic expansion. These terms are a valid large-sample criterion beyond the Bayesian context, since they do not depend on the a priori distribution.
Air pollution epidemiology has established a strong association between exposure to ambient particulate matter (PM) and cardiovascular outcomes. Experimental studies in both humans and laboratory animals support varied biological mechanisms including endothelial dysfunction as potentially a central step to the elicitation of cardiovascular events. We therefore hypothesized that relevant early molecular alterations on endothelial cells should be assessable in vitro upon acute exposure to PM components previously shown to be involved in health outcomes. Using a model emission PM, residual oil fly ash and one of its predominant constituents (vanadium-V), we focused on the development of gene expression profiles to fingerprint that particle and its constituents to explore potential biomarkers for PM-induced endothelial dysfunction. Here we present differential gene expression and transcription factor activation profiles in human vascular endothelial cells exposed to a non-cytotoxic dose of fly ash or V following semi-global gene expression profiling of approximately 8000 genes. Both fly ash and it's prime constituent, V, induced alterations in genes involved in passive and active transport of solutes across the membrane; voltage-dependent ion pumps; induction of extracellular matrix proteins and adhesion molecules; and activation of numerous kinases involved in signal transduction pathways. These preliminary data suggest that cardiovascular effects associated with exposure to PM may be mediated by perturbations in endothelial cell permeability, membrane integrity; and ultimately endothelial dysfunction.
Several epidemiologic studies have demonstrated a consistent association between levels of particulate matter (PM) in the ambient air with increases in cardiovascular and respiratory mortality and morbidity. Diesel exhaust (DE), in addition to generating other pollutants, is a major contributor to PM pollution in most places in the world. Although the epidemiologic evidence is strong, there are as yet no established biological mechanisms to explain the toxicity of PM in humans. To determine the impact of DE on human airways, we exposed 15 healthy human volunteers to air and diluted DE under controlled conditions for 1 h with intermittent exercise. Lung functions were measured before and after each exposure. Blood sampling and bronchoscopy were performed 6 h after each exposure to obtain airway lavages and endobronchial biopsies. While standard lung function measures did not change following DE exposure, there was a significant increase in neutrophils and B lymphocytes in airway lavage, along with increases in histamine and fibronectin. The bronchial biopsies obtained 6 h after DE exposure showed a significant increase in neutrophils, mast cells, CD4+ and CD8+ T lymphocytes along with upregulation of the endothelial adhesion molecules ICAM-1 and VCAM-1, with increases in the numbers of LFA-1+ cells in the bronchial tissue. Significant increases in neutrophils and platelets were observed in peripheral blood following DE exposure. This study demonstrates that at high ambient concentrations, acute short-term DE exposure produces a well-defined and marked systemic and pulmonary inflammatory response in healthy human volunteers, which is underestimated by standard lung function measurements.
Current levels of air pollution particles in American cities can increase human mortality. Both the mechanism of injury and the responsible components are not known. We have postulated that injury following air pollution particle exposure is produced through a generation of oxygen-based free radicals catalyzed by metals present in the particles. As a result of its abundance in the atmosphere, sulfate appears to potentially be the most successful ligand to complex metal cations. We tested the hypothesis that (1) some portion of iron in ambient air pollution particles is present as sulfate and (2) this relationship between iron and sulfate results from the capacity of the latter to function as a ligand to mobilize the metal from the oxide. Concentrations of sulfate and iron in acid extracts of 20 filters (total suspended particles) from Utah were measured using inductively coupled plasma emission spectroscopy. In vitro oxidant generation was also measured using thiobarbituric acid-reactive products of deoxyribose. There were significant correlations between sulfate content, iron concentrations, and oxidant generation. Agitation of calcium sulfate with iron(III) oxide produced concentrations of water-soluble, catalytically active iron. We conclude that some portion of iron in the atmosphere is present as a sulfate. This relationship between sulfate and iron concentrations is likely the product of SO42- functioning as a ligand for the meal after its mobilization from an oxide by photoreduction. There were also associations between sulfate content, iron concentrations, and oxidant generation. However, sulfates had no capacity to support electron transport unless they were present with iron.
Episodes of increased air pollution are associated with increases in hospital admissions for cardiovascular disease. Even modest acute phase responses are associated with increased risk of coronary heart disease. The study investigates whether induction of an acute phase response by exposure to air pollution may contribute to cardiovascular pathology.
A prospective cohort study based on a survey in 1984/85 with a 3-year follow-up was conducted in 631 randomly selected men aged 45 to 64 years free of cardiovascular disease at entry 1984/85. Serum C-reactive protein concentrations were determined by a high sensitivity immunoradiometric assay. C-reactive protein concentration was increased in association with the 1985 air pollution episode. In multivariate analyses, elevated concentrations were independently associated with concentrations of total suspended particles and the sulphur dioxide episode. At ambient concentrations of pollution, as noted during the 1985 air pollution episode, the odds of observing C-reactive protein concentrations above 5.7 mg. l(-1)(>90th percentile) tripled, and increases of 26 microg. m(-3)total suspended particles (mean of 5 days) raised the odds of C-reactive protein levels 50% above the 90th percentile.
Exposure to current levels of particulate matter in the atmosphere elicits an acute phase response in randomly selected healthy middle-aged men, which may contribute to the increased cardiovascular risk caused by air pollution.
Background:
Vascular cell adhesion molecule (VCAM)-1, intercellular adhesion molecule (ICAM)-1, and E-selectin mediate adhesion and transmigration of leukocytes to the vascular endothelial wall and may promote plaque growth and instability. In a prospective study, we evaluated the effect of soluble adhesion molecules on the risk of future cardiovascular events among patients with angiographically documented coronary artery disease (CAD). Methods and Results- -We obtained baseline samples from a prospective cohort of 1246 patients with CAD. Besides various markers of inflammation, soluble VCAM-1 (sVCAM-1), sICAM-1, and sE-selectin were determined. Follow-up information on cardiovascular events was obtained (mean, 2.7; maximum, 4.1 years). Independently higher levels of sVCAM-1 (1932 versus 1128 ng/mL; P<0.0001), sICAM-1 (353 versus 287 ng/mL; P=0.015), and sE-selectin (81 versus 63 ng/mL; P=0.003) were observed in patients with future death from cardiovascular causes. In a multivariate model, fatal risk was 2.1-fold (1.1 to 4.0) higher in patients within the top quartile of baseline sVCAM-1 concentrations compared with lower quartiles. This association was present independent of general inflammatory response as reflected by low or high C-reactive protein (hs-CRP) levels. In a model that simultaneously controlled for all inflammatory and soluble adhesion markers determined, only sVCAM-1 remained independently significant for future fatal cardiovascular events, with a 2.8-fold increase in risk (P=0.003).
Conclusions:
Soluble adhesion molecules sVCAM-1, sICAM-1, and sE-selectin were significantly related to future death from cardiovascular causes among patients with documented CAD. Especially sVCAM-1 added to the predictive value of classic risk factors and hs-CRP in determining the risk of future cardiovascular death.
Elevated levels of soluble cellular adhesion molecules have been linked to the development of occlusive coronary events in otherwise healthy individuals. It is not certain, however, whether similar relationships exist for the development of early systemic atherosclerosis.
In a prospective, nested case-control study conducted among 14 916 middle-aged men, we evaluated the relationship between baseline levels of soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), and the subsequent development of symptomatic peripheral arterial disease (PAD) during a 9-year follow-up period. Median levels of sICAM-1 but not sVCAM-1 were significantly higher at baseline among men who developed PAD than among those who did not (285.2 versus 267.8 ng/mL [P=0.005] for sICAM-1 and 701.0 versus 709.3 ng/mL [P=0.8] for sVCAM-1). In analyses adjusted for age and smoking, the odds ratio in the highest compared with the lowest quartile of sICAM-1 was 3.9 (95% CI 1.7 to 8.6; P(trend)=0.001). After additional adjustment for lipid and nonlipid risk factors, including C-reactive protein, elevated sICAM-1 remained significantly associated with subsequent PAD (OR 3.5, 95% CI 1.4 to 8.5, P(trend)=0.008). Whereas a monotonic dose-response relationship was evident over the full spectrum of ICAM-1 levels, elevated sVCAM-1 was not associated with future PAD in either age- and smoking-adjusted or fully adjusted models.
Elevated levels of sICAM-1 are independently associated with the development of accelerated atherosclerosis among otherwise healthy men even in the absence of acute coronary occlusion.
The Epidemiological Study of Myocardial Infarction Study which enrolled 9758 apparently healthy men aged 50-59 years, is a prospective cohort study designed to evaluate markers of coronary risk. Soluble forms of the intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) levels were measured in plasma obtained at baseline from 317 subjects who suffered a coronary event during the 5-year follow-up and in twice the number of control subjects who were matched for center, age and day of inclusion in a nested case-control design. The relative risk associated with the highest compared with the lowest thirds of ICAM-1 (>625 versus <502 ng/ml) was 2.45 (95% CI: 1.64-3.65, P<0.001) without adjustment; it decreased moderately (RR: 2.09; 95% CI: 1.34-3.24, P<0.001) after control for lipid and non-lipid factors and remained significantly elevated after adjustment for C-reactive protein (CRP) (RR: 1.90; 95% CI: 1.21-2.96, P=0.005). Plasma ICAM-1 was essentially associated with the risk of myocardial infarction or coronary death and also with angina pectoris. Subjects with CRP presented elevated coronary risk only if ICAM-1 was high. An elevated level of VCAM-1 was not associated with any risk of future acute coronary event, or with angina pectoris. This data indicates that plasma levels of ICAM-1 may serve as risk markers for future coronary events whatever their clinical presentation and that risk is better defined using simultaneous measurements of ICAM-1 and CRP than any of these levels separately.
Air pollution is a heterogeneous, complex mixture of gases, liquids, and particulate matter. Epidemiological studies have demonstrated a consistent increased risk for cardiovascular events in relation to both short- and long-term exposure to present-day concentrations of ambient particulate matter. Several plausible mechanistic pathways have been described, including enhanced coagulation/thrombosis, a propensity for arrhythmias, acute arterial vasoconstriction, systemic inflammatory responses, and the chronic promotion of atherosclerosis. The purpose of this statement is to provide healthcare professionals and regulatory agencies with a comprehensive review of the literature on air pollution and cardiovascular disease. In addition, the implications of these findings in relation to public health and regulatory policies are addressed. Practical recommendations for healthcare providers and their patients are outlined. In the final section, suggestions for future research are made to address a number of remaining scientific questions.
Ambient air pollution has been shown to be associated with cardiovascular morbidity and mortality.
A prospective panel study was conducted to study the early physiologic reactions characterized by blood biomarkers of inflammation, endothelial dysfunction, and coagulation in response to daily changes in air pollution in Erfurt, Germany.
Blood parameters were repeatedly measured in 57 male patients with coronary heart disease during the winter of 2000/2001. Fixed-effects linear and logistic regression models were applied, adjusting for trend, weekday, and meteorologic parameters.
Hourly data on ultrafine particles (UFPs; number concentration of particles from 0.01 to 0.1 microm), mass concentration of particles less than 10 (PM(10)) and 2.5 microm in diameter, elemental and organic carbon, gaseous pollutants, and meteorologic data were collected at central monitoring sites.
Increased levels of C-reactive protein above the 90th percentile were observed for an increase in air pollution concentrations of one interquartile range. The effect was strongest for accumulation mode particles, with a delay of 2 d (odds ratio [OR], 3.2; confidence interval [CI], 1.7, 6.0). Results were consistent for UFPs and PM(10), which also showed a 2-d delayed response (OR, 2.3; CI, 1.3, 3.8; and OR, 2.2; CI, 1.2, 3.8, respectively). However, not all of the blood markers of endothelial dysfunction and coagulation increased consistently in association with air pollutants.
These results suggest that inflammation as well as parts of the coagulation pathway may contribute to the association between particulate air pollution and coronary events.
Ambient levels of particulate matter have been linked to cardiovascular disease. The mechanisms mediating these associations are poorly understood. One candidate mechanism is inflammation. Using data from the Multi-Ethnic Study of Atherosclerosis (2000-2002), the authors investigated the relation between exposure to particulate matter of less than or equal to 2.5 microm in diameter (PM2.5) and C-reactive protein concentration in 5,634 persons aged 45-84 years who were free of cardiovascular disease. Data from US Environmental Protection Agency monitors were used to estimate PM2.5 exposures for the prior day, prior 2 days, prior week, prior 30 days, and prior 60 days. Only the 30-day and 60-day mean exposures showed a weak positive association with C-reactive protein, and confidence intervals were wide: relative increases in C-reactive protein per 10 microg/m3 of PM2.5 adjusted for person-level covariates were 3% (95% confidence interval (CI): -2, 10) for a 30-day mean and 4% (95% CI: -3, 11.0) for a 60-day mean. The means of 7-day, 30-day, and 60-day exposures were weakly, positively, and nonsignificantly associated with the odds of C-reactive protein of greater than or equal to 3 mg/liter: adjusted odds ratios were 1.05 (95% CI: 0.96, 1.15), 1.12 (95% CI: 0.98, 1.29), and 1.12 (95% CI: 0.96, 1.32), respectively. Slightly stronger associations were observed in persons without other risk factors for elevated C-reactive protein, but this heterogeneity was not statistically significant. The authors' results are not compatible with strong effects of particulate matter exposures on population levels of C-reactive protein.
The lasso is a popular technique for simultaneous estimation and variable selection. Lasso variable selection has been shown to be consistent under certain conditions. In this work we derive a necessary condition for the lasso variable selection to be consistent. Consequently, there exist certain scenarios where the lasso is inconsistent for variable selection. We then propose a new version of the lasso, called the adaptive lasso, where adaptive weights are used for penalizing different coefficients in the l1 penalty. We show that the adaptive lasso enjoys the oracle properties; namely, it performs as well as if the true underlying model were given in advance. Similar to the lasso, the adaptive lasso is shown to be near-minimax optimal. Furthermore, the adaptive lasso can be solved by the same efficient algorithm for solving the lasso. We also discuss the extension of the adaptive lasso in generalized linear models and show that the oracle properties still hold under mild regularity conditions. As a byproduct of our theory, the nonnegative garotte is shown to be consistent for variable selection.
Nickel-regulated heart rate variability: the roles of oxidative stress and inflammation
- H C Chuang
- T W Hsueh
- C C Chang
- J S Hwang
- K J Chuang
- Y H Yan
- HC Chuang