Final Report: Cognitive Decline, Cardiovascular Changes, and Biological Aging in Response to Air Pollution

EPA Grant Number: R834798C002
Subproject: this is subproject number 002 , established and managed by the Center Director under grant R834798
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).

Center: Air Pollution Mixtures: Health Effects across Life Stages
Center Director: Koutrakis, Petros
Title: Cognitive Decline, Cardiovascular Changes, and Biological Aging in Response to Air Pollution
Investigators: Schwartz, Joel , Mittleman, Murray
Institution: Harvard University
EPA Project Officer: Ilacqua, Vito
Project Period: January 1, 2011 through December 31, 2015 (Extended to December 31, 2016)
RFA: Clean Air Research Centers (2009) RFA Text |  Recipients Lists
Research Category: Health Effects , Air

Objective:

In this Project we investigate the acute and chronic effects of air pollution on cognitive and neurological impairments, systemic inflammation, and vascular dysfunction in the Normative Aging Study (NAS) cohort. We examine how these effects differ depending on the composition of multi-pollutant mixtures and the source contributions to PM composition. Also we ascertain the level of increased effects in susceptible and vulnerable subpopulations by examining modifying factors of obesity, diabetes, diet, socioeconomic position, and psychosocial stress.

Summary/Accomplishments (Outputs/Outcomes):

In conjunction with the Biostatistics and Exposure Cores, Project 2 developed a spatio-temporal model to predict daily PM2.5 concentrations using land use regression terms and satellite remote sensing. The model was initially used and validated for the New England states (Kloog et al., 2011; Chudnovsky et al., 2012), then in the Mid-Atlantic States (Kloog et al., 2012) at a resolution of 10km x 10km. Methodological improvements to the second generation of the model to account for non-random missing-ness of satellite data, sub-regions, and covariates resulted in excellent model performance. Subsequently, we showed that higher-resolution satellite retrieval data could be used to develop models suitable to generate 1 x 1 km PM2.5 exposure data of sufficient quality for use in epidemiological studies. The spatial resolution of the model captured the pollution levels along the highways and many urban areas, extending our ability to investigate spatial patterns of urban air quality, such as examining exposures within areas of high traffic. These models were ultimately used to provide highly spatially resolved daily PM2.5 concentrations for many of the studies conducted under this Project, as well as other Center Projects.

Cognitive Effects of Air Pollution Exposure

Epidemiology studies have linked air pollution exposure with lower cognitive performance and cognitive decline in older individuals, but the biological process by which air pollution may impact cognition is yet not fully known. In our Normative Aging Study (NAS) cohort of elderly veterans living in the greater Boston metropolitan area, we conducted several studies to investigate the association of air pollution and traffic-derived particles on cognitive decline. Our key findings are highlighted below.

In Power at al. (2011), we found that exposure to traffic particles was associated with lower cognitive function, similar to a few years of aging. Adverse effects of BC were concentrated in overweight and obese individuals (p-value for interaction = 0.10) and in ever-smokers (p-value for interaction = 0.07), but we found no evidence in this study for effect modification by hypertension or diabetes (p-values for interactions > 0.1). Further, in Power et al. (2013) we found that the association of BC with cognitive function in the NAS was modified by polymorphisms in the hemochromatosis gene, which regulates metal uptake into cells. This suggests the involvement of metals associated with traffic particles may be related to their impact on cognitive decline.

In Colcino et al. (2014) we found that mitochondrial haplotypes may modify individual susceptibility to cognitive effects associated with exposure to particles. Mitochondrial haplotyping was used to identify nine haplogroups which were phylogenetically categorized in four clusters. We found that the association of BC with impaired cognition was worsened in carriers of phylogenetically-related mtDNA haplogroups in Cluster 4. No BC effects were detected in Cluster 2 and 3 carriers. Continuing this investigation, in Colicino et al. (2016) we investigated whether SNPs in miRNA-processing genes, which control gene expression and neuronal programming, are associated with cognition and modify the relationship between BC as marker of traffic-related pollution, and cognitive functions. In 533 NAS participants, each tested 1-4 times using seven different cognitive tests between 1995 and 2007, we investigated the interactions of 16 miRNA-related SNPs with 1-year average BC exposure estimated using our spatiotemporal model. We used covariate-adjusted logistic regression for low (≤25) Mini-Mental State Examination (MMSE) and mixed-effect regression for a global cognitive score combining six other tests. We found that global cognition was negatively associated with the homozygous minor variant of rs595961 AGO1 relative to the major variant. BC-MMSE association was stronger in heterozygous carriers of rs11077 XPO5 and minor variant carriers of GEMIN4 rs2740348, compared to their major variant. The BC-global-cognition association was stronger in heterozygous carriers of GEMIN4 rs4968104, and GEMIN4 rs910924 relative to the major variant. Blood miRNA expression analyses showed associations only of XPO5 rs11077 with miR-9 and miR-96. Our findings indicate that carriers of particular miRNA-processing SNPs had higher susceptibility to BC in BC–cognition associations, possibly due to influences on miRNA expression. In Colicino et al. (2017) we showed that the association was also modified by telomere length. Finally, in Wilker et al., 2015 we showed that that long term exposure to fine particles and traffic were associated with loss of white matter in the brain.

We also found that short term temperature changes were associated with cognitive deficits in the NAS participants, a finding that may provide some insight into why more people die on warm, but not extremely hot, days (Dai et al., 2016)

Inflammation and Epigenetic Gene Regulation

One of the major efforts of this project was to investigate the acute and chronic effects of air pollution on systemic inflammation. Results of several of our studies using the NAS cohort are highlighted here.

In Lepeule et al. (2012), we studied the cross-sectional association between DNA methylation in nine inflammatory genes and lung function. We found that DNA methylation may be part of the biological processes underlying the lung function decline and that interferon gamma (IFNγ) and interleukin-6 (IL-6) may have ambivalent roles through activation of negative feedback. Furthermore, in we investigated the short and intermediate term air pollution effects on repeated measurements of: fibrinogen, C-reactive protein (CRP), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1), and epigene-environment interactions by DNA methylation of Alu, long interspersed nuclear elements (LINE-1), tissue factor (F3), Toll-like receptor 2 (TLR-2), and ICAM-1. 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.

In Lepule et al. (2014) we evaluated the lag structure of air pollutant associations with lung function and potential effect modification by DNA methylation at 26 CpG sites in 9 candidate genes in the NAS population. In this study, we found that interquartile range increases in subchronic (but not acute) exposure to BC, total and non-traffic PM2.5, and traffic related gases were associated with a decrease in forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1). Non-traffic-related pollutants had weaker associations. Furthermore, associations were more pronounced in participants with low methylation in TLR2 and high methylation in GCR genes. The findings indicate that DNA methylation may modify the effects of traffic-related pollutants via epigenetic mechanisms related to inflammation and immunity.

In Bind et al. (2014a), we found that ambient temperature and relative humidity are related to methylation of LINE-1, Alu, and 9 candidate genes controlling coagulation, inflammation, cortisol, DNA repair, and metabolic pathway. DNA methylation in blood cells may reflect biological effects of temperature and relative humidity. Temperature and relative humidity may interact to produce stronger effects. In addition, results of this study also indicate there may be a potential health effect of relative humidity independent of temperature.

Using mediation analysis, a novel analytical methodology, in Bind et al. (2014b) we investigated whether air pollution exposures were related to methylation on genes related to two different pathways, coagulation and inflammation. We examined whether the association between exposure and gene-specific methylation varied by participant characteristics; we also investigated whether the association between exposure and cardiovascular biomarkers was mediated via change in gene-specific methylation.

In Bind et al. (2014c) we developed a new pathway analysis approach to investigate whether gene variants within relevant pathways (e.g., oxidative stress, endothelial function, and metal processing) modified the association between particulate air pollution exposures and fibrinogen, CRP, ICAM-1, and VCAM-1. To investigate the role of biological mechanisms, while reducing the number of comparisons in the analysis, we created pathway-specific scores using gene variants related to each pathway. Appropriate gene variants were selected using the least absolute shrinkage and selections operator (LASSO) to relate independent outcomes representative of each pathway to gene variants. The resulting two-stage penalization method is easy to implement and can be used for large-scale genetic applications.

In Bind et al. (2015), we examined whether the association between particulate air pollution and DNA methylation differs across quantiles of the methylation distribution. We focused on methylation of candidate genes related to coagulation and inflammation: coagulation factor III (F3), ICAM-1, IFN-γ, IL-6, and TRL-2. We measured gene-specific blood DNA methylation repeatedly in the NAS participants during the period 1999–2010. We fit quantile regressions for longitudinal data to investigate whether the associations of particle number, PM2.5, and BC concentrations (4-week moving average) with DNA methylation varied across deciles of the methylation distribution. We found that interquartile range increases in particle number, PM2.5 and BC concentrations were associated with significantly lower methylation in the lower tails of the IFN-γ and ICAM-1 methylation distributions. In our study population of older men, air pollution exposures were thus associated with a left shift in the lower tails of the IFN-γ and ICAM-1 methylation distributions, an association that would not have been captured using mean regression analyses. Since lower methylation is associated with greater expression, this indicates that people already at risk of systemic inflammation and endothelial activation are differentially impacted by particles, particularly from traffic.

In non-diabetic individuals, elevated fasting blood glucose (FBG) is an independent predictor of diabetes risk, cardiovascular disease and dementia. Ambient PM2.5 is an emerging determinant of glucose dysregulation, although the effects of PM2.5 exposure and the mechanism of action in non-diabetic individuals are not well understood. In Peng et al. (2016), we investigated whether PM2.5 is associated with increase in FBG and explored the potential mediating roles of epigenetic gene regulation. FBG and DNA methylation of four inflammatory genes (IFN-γ, IL-6, ICAM-1, and TLR-2) were measured up to four times between 2000 and 2011 (median=2) in 551 non-diabetic participants in the NAS. We estimated short- and medium-term (1-, 7-, and 28-day preceding each clinical visit) ambient PM2.5 concentrations at each participant’s address using our validated spatio-temporal model. Fitting covariate-adjusted regression models that accounted for repeated measures, we found that 18% of the participants had impaired fasting glucose (IFG) at first visit. Interquartile increases in 1-, 7-, and 28-day PM2.5 exposures were associated with higher odds of IFG, at 13% (95% CI: -3%; 33%; p=0.12), 27% (95% CI: 6%; 52%, p=0.01) and 32% (95% CI: 10%; 58%, p=0.003), respectively. A negative correlation of PM2.5 was observed with ICAM-1 methylation (p=0.01), but not with other genes. Mediation analysis estimated that ICAM-1methylation mediated 9% of the association of 28-day PM2.5 with FBG.

Vascular dysfunction/disease

Studies have consistently found associations between PM2.5 exposure and cardiovascular events, though the effects of different components or sources of PM2.5 and the mechanisms by which they act are not well understood. We have investigated this in our NAS cohort, and some of our key findings are highlighted below.

In Dai et al., 2016, we examined associations of particle components with blood pressure, and used the adaptive lasso to identify Ni as an important predictor of blood pressure.

In another paper by Dai et al. (2016), we examined associations of PM2.5 species and sources with markers of inflammation and endothelial dysfunction (including IL-6, CRP, ICAM-1, and VCAM-1) measured repeatedly for participants in the NAS. 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. We further 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 ICAM-1 and VCAM-1. An IQR increase (3.2 ng/m3) in 2-day moving average V was associated with significant changes in both ICAM-1 and VCAM-1. Source apportionment analysis found that an oil combustion source rich in V was linked to these adhesion molecules. Responses may be stronger in people with higher allelic risk profiles related to oxidative stress (P-value of interaction = 0.11). Our findings suggest that particles derived from oil combustion may be associated with inflammation and endothelial dysfunction, and further, it is likely that oxidative stress plays a role in the associations.

Impairment of renal function may be a mediating factor of the cardiovascular effects of long-term PM2.5 exposure, since the kidney is a vascularized organ and susceptible to large vessel atherosclerotic disease and microvascular dysfunction. Impaired renal function, as determined from the estimated glomerular filtration rate (eGFR), has also been associated with cardiovascular events and mortality. In Mehta et al. (2016), we evaluated whether long-term PM2.5 exposure is associated with lower renal function or higher age-related decline in renal function. This longitudinal analysis included 669 participants from the NAS with up to four visits between 2000 and 2011 (n=1,715). Serum creatinine was measured at each visit and eGFR was calculated. One-year exposure to PM2.5 prior to each participant visit was assessed using our previously validated hybrid land-use regression/satellite-based spatiotemporal model. eGFR was modeled in a time-varying linear mixed-effects regression model as a continuous function of 1-year PM2.5 adjusting for important covariates. We found that 1-year PM2.5 exposure was associated with lower eGFR level; an interquartile range increase in 1-year PM2.5 was associated with a 1.87 mL/min/1.73 m2 lower eGFR (95%CI: -2.99, -0.76). A 2.1 μg/m3 higher 1-year PM2.5 was also associated with an additional annual decrease in eGFR of 0.60 mL/min/1.73 m2 per year (95%CI: -0.79, -0.40). There was no statistically significant effect modification by participant characteristics on the association between 1-year PM2.5 and eGFR level. Our findings support the hypothesis that long-term PM2.5 exposure negatively affects renal function and renal function decline, but should be verified in other study populations with longitudinal follow-up.

Gene regulation by microRNAs (miRNAs) that are transferred between cells by extracellular vesicles (EVs) may also play an important role in PM-induced cardiovascular risk. In Rodosthenous et al. 2016, we sought to determine whether ambient PM2.5 levels are, in fact, associated with expression of EV-encapsulated miRNAs (evmiRNAs), and further to investigate the participation of such evmiRNAs in pathways related to cardiovascular disease (CVD). To do this, we collected 42 serum samples from 22 randomly selected NAS participants, and screened for 800 miRNAs. In addition, we estimated the short- (1-day), intermediate- (1-week and 1-month) and long-term (3-month, 6-month, and 1-year) moving averages of ambient PM2.5 levels at participants’ addresses using our validated hybrid spatio-temporal land-use regression model. Using mixed effects regression models, and adjusting for potential confounders, we assessed the association between ambient PM2.5 levels and evmiRNAs. All p-values were adjusted for multiple comparisons. In-silico Ingenuity Pathway Analysis was performed to identify the biological pathways that are regulated by PM-associated evmiRNAs. We found that there was a significant association between long-term ambient PM2.5 exposures and levels of multiple evmiRNAs circulating in serum. In the 6-month window, ambient PM2.5 exposures were associated with increased levels of miR-126-3p (0.74 ± 0.21; p = 0.02), miR-19b-3p (0.52 ± 0.15; p = 0.02), miR-93-5p (0.78 ± 0.22; p = 0.02), miR-223-3p (0.74 ± 0.22; p = 0.02), and miR-142-3p (0.81 ± 0.21; p = 0.03). Similarly, in the 1-year window, ambient PM2.5 levels were associated with increased levels of miR-23a-3p (0.83 ± 0.23; p = 0.02), miR-150-5p (0.90 ± 0.24; p = 0.02), miR-15a-5p (0.70 ± 0.21; p = 0.02), miR-191-5p (1.20 ± 0.35; p = 0.02), and let-7a-5p (1.42 ± 0.39; p = 0.02). In silico pathway analysis on PM2.5-associated evmiRNAs identified several key CVD-related pathways including oxidative stress, inflammation, and atherosclerosis. These important findings should be confirmed and extended by further observational studies in larger and more diverse populations, as well as experimental studies to elucidate the exact roles of evmiRNAs in PM-induced CVD.

Electrical control of the heart

In Mordukhovich et al., 2016, we showed that particulate air pollution was associated with QT prolongation, which increases risk for arrhythmias.In Zhong et al., 2015, we showed cardiovascular effects of particles on heart rate variability were mediated both by dietary flavonoid intake and by methylation of the Toll like receptor 2 gene.

 

Conclusions:

Throughout the studies conducted in Project 2, we have shown that exposure to ambient particles is associated with a wide variety of adverse health outcomes.  Exposures have greater impact on sensitive populations, including the elderly, those with cardiovascular disease, diabetes, and other chronic health conditions. Our studies, in conjunction with prior studies and extensive toxicological support, indicate that the association between PM2.5 and deaths is almost certainly causal. Furthermore, this causal association holds at concentrations that are below current U.S. air quality standards, indicating that important public health benefits can follow from further control efforts.


Journal Articles on this Report : 85 Displayed | Download in RIS Format

Other subproject views: All 87 publications 87 publications in selected types All 87 journal articles
Other center views: All 408 publications 345 publications in selected types All 345 journal articles
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Journal Article Bind M-A, Zanobetti A, Gasparrini A, Peters A, Coull B, Baccarelli A, Tarantini L, Koutrakis P, Vokonas P, Schwartz J. Effects of temperature and relative humidity on DNA methylation. Epidemiology 2014;25(4):561-569. R834798 (2014)
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  • Journal Article Bind M-A, Baccarelli A, Zanobetti A, Tarantini L, Suh H, Vokonas P, Schwartz J. Air pollution and markers of coagulation, inflammation, and endothelial function:associations and epigene-environment interactions in an elderly cohort. Epidemiology 2012;23(2):332-340. R834798 (2012)
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  • Journal Article Bind M-A, Coull B, Suh H, Wright R, Baccarelli A, Vokonas P, Schwartz J. A novel genetic score approach using instruments to investigate interactions between pathways and environment: application to air pollution. PLoS One 2014;9(4):e96000 (8 pp.). R834798 (2014)
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  • Journal Article Bind M-A, Lepeule J, Zanobetti A, Gasparrini A, Baccarelli A, Coull BA, Tarantini L, Vokonas PS, Koutrakis P, Schwartz J. Air pollution and gene-specific methylation in the Normative Aging Study: association, effect modification, and mediation analysis. Epigenetics 2014;9(3):448-458. R834798 (2014)
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  • Journal Article Bind M-AC, Coull BA, Peters A, Baccarelli AA, Tarantini L, Cantone L, Vokonas PS, Koutrakis P, Schwartz JD. Beyond the mean: quantile regression to explore the association of air pollution with gene-specific methylation in the Normative Aging Study. Environmental Health Perspectives 2015;123(8):759-765. R834798 (2015)
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  • Journal Article Chiu Y-HM, Coull BA, Sternthal MJ, Kloog I, Schwartz J, Cohen S, Wright RJ. Effects of prenatal community violence and ambient air pollution on childhood wheeze in an urban population.Journal of Allergy and Clinical Immunology 2014;133(3):713-722.e4. R834798 (Final)
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  • Journal Article Chudnovsky AA, Koutrakis P, Kloog I, Melly S, Nordio F, Lyapustin A, Wang Y, Schwartz J. Fine particulate matter predictions using high resolution Aerosol Optical Depth (AOD) retrievals. Atmospheric Environment 2014;89:189-198. R834798 (2014)
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  • Journal Article Colicino E, Power MC, Cox DG, Weisskopf MG, Hou L, Alexeeff SE, Sanchez-Guerra M, Vokonas P, Spiro III A, Schwartz J, Baccarelli AA. Mitochondrial haplogroups modify the effect of black carbon on age‐related cognitive impairment. Environmental Health 2014;13(1):42. R834798 (Final)
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  • Journal Article Colicino E, Giuliano G, Power MC, Lepeule J, Wilker EH, Vokonas P, Brennan KJ, Fossati S, Hoxha M, Spiro III A, Weisskopf MG Schwartz J, Baccarelli AA. Long-term exposure to black carbon, cognition and single nucleotide polymorphisms in microRNA processing genes in older men. Environment International 2016;88:86-93. R834798 (Final)
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  • Journal Article Dai L, Zanobetti A, Koutrakis P, Schwartz JD. Associations of fine particulate matter species with mortality in the United States: a multicity time-series analysis. Environmental Health Perspectives 2014;122(8):837-842. R834798 (2014)
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  • Journal Article Dai L, Koutrakis P, Coull BA, Sparrow D, Vokonas PS, Schwartz JD. Use of the adaptive LASSO method to identify PM2.5 components associated with blood pressure in elderly men: the Veterans Affairs Normative Aging Study. Environmental Health Perspectives 2016;124(1):120-125. R834798 (2015)
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  • Journal Article Dai L, Bind MA, Koutrakis P, Coull BA, Sparrow D, Vokonas PS, Schwartz JD. Fine particles, genetic pathways, and markers of inflammation and endothelial dysfunction: analysis on particulate species and sources. Journal of Exposure Science and Environmental Epidemiology 2016;26(4):415-421. R834798 (Final)
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  • Journal Article Dai L, Kloog I, Coull BA, Sparrow D, Spiro III A, Vokonas PS, Schwartz JD. Cognitive function and short-term exposure to residential air temperature:A repeated measures study based on spatiotemporal estimates of temperature. Environmental Research 2016;150:446-451. R834798 (Final)
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  • Journal Article Di Q, Wang Y, Zanobetti A, Wang Y, Koutrakis P, Choirat C, Dominici F, Schwartz JD. Air pollution and mortality in the Medicare population. New England Journal of Medicine 2017;376(26):2513-2522. R834798 (Final)
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  • Journal Article Fang SC, Mehta AJ, Alexeeff SE, Gryparis A, Coull B, Vokonas P, Christiani DC, Schwartz J. Residential black carbon exposure and circulating markers of systemic inflammation in elderly males:the normative aging study. Environmental Health Perspectives 2012;120(5):674-680. R834798 (2013)
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  • Journal Article Fang SC, Schwartz J, Yang M, Yaggi HK, Bliwise DL, Araujo AB. Traffic‐related air pollution and sleep in the Boston Area Community Health Survey. Journal of Exposure Science & Environmental Epidemiology 2015;25(5):451-456. R834798 (Final)
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  • Journal Article Fossati S, Baccarelli A, Zanobetti A, Hoxha M, Vokonas PS, Wright RO, Schwartz J. Ambient particulate air pollution and MicroRNAs in elderly men. Epidemiology 2014;25(1):68-78. R834798 (2014)
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  • Journal Article Hoffmann B, Luttmann-Gibson H, Cohen A, Zanobetti A, de Souza C, Foley C, Suh HH, Coull BA, Schwartz J, Mittleman M, Stone P, Horton E, Gold DR. Opposing effects of particle pollution, ozone, and ambient temperature on arterial blood pressure. Environmental Health Perspectives 2012;120(2):241-246. R834798 (2012)
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  • Journal Article Hou L, Zhang X, Zheng Y, Wang S, Dou C, Guo L, Byun H-M, Motta V, McCracken J, Díaz A, Kang C-M, Koutrakis P, Bertazzi PA, Li J, Schwartz J, Baccarelli AA. Altered methylation in tandem repeat element and elemental component levels in inhalable air particles. Environmental and Molecular Mutagenesis 2014;55(3):256-265. R834798 (2014)
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  • Journal Article Kloog I, Koutrakis P, Coull BA, Lee HJ, Schwartz J. Assessing temporally and spatially resolved PM2.5 exposures for epidemiological studies using satellite aerosol optical depth measurements. Atmospheric Environment 2011;45(35):6267-6275. R834798 (2012)
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  • Journal Article Kloog I, Coull BA, Zanobetti A, Koutrakis P, Schwartz JD. Acute and chronic effects of particles on hospital admissions in New-England. PLoS ONE 2012;7(4):e34664 (8 pp.). R834798 (2012)
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  • Journal Article Kloog I, Chudnovsky A, Koutrakis P, Schwartz J. Temporal and spatial assessments of minimum air temperature using satellite surface temperature measurements in Massachusetts, USA. Science of The Total Environment 2012;432:85-92. R834798 (2013)
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  • Journal Article Kloog I, Melly SJ, Ridgway WL, Coull BA, Schwartz J. Using new satellite based exposure methods to study the association between pregnancy PM2.5 exposure, premature birth and birth weight in Massachusetts. Environmental Health 2012;11:40 (8 pp.). R834798 (2012)
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  • Journal Article Kloog I, Nordio F, Coull BA, Schwartz J. Incorporating local land use regression and satellite aerosol optical depth in a hybrid model of spatiotemporal PM2.5 exposures in the Mid-Atlantic states. Environmental Science & Technology 2012;46(21):11913-11921. R834798 (2013)
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  • Journal Article Kloog I, Ridgway B, Koutrakis P, Coull BA, Schwartz JD. Long- and short-term exposure to PM2.5 and mortality: using novel exposure models. Epidemiology 2013;24(4):555-561. R834798 (2013)
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  • Journal Article Kloog I, Nordio F, Zanobetti A, Coull BA, Koutrakis P, Schwartz JD. Short term effects of particle exposure on hospital admissions in the Mid-Atlantic states:a population estimate. PLoS ONE 2014;9(2):e88578 (7 pp.). R834798 (2014)
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  • Journal Article Kloog I, Nordio F, Coull BA, Schwartz J. Predicting spatiotemporal mean air temperature using MODIS satellite surface temperature measurements across the Northeastern USA. Remote Sensing of Environment 2014;150:132-139. R834798 (2014)
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  • Journal Article Kloog I, Zanobetti A, Nordio F, Coull BA, Baccarelli AA, Schwartz J. Effects of airborne fine particles (PM2.5) on deep vein thrombosis admissions in the northeastern United States. Journal of Thrombosis and Haemostasis 2015;13(5):768-774. R834798 (2015)
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  • Journal Article Lee M, Kloog I, Chudnovsky A, Lyapustin A, Wang Y, Melly S, Coull B, Koutrakis P, Schwartz J. Spatiotemporal prediction of fine particulate matter using high-resolution satellite images in the Southeastern US 2003-2011. Journal of Exposure Science & Environmental Epidemiology 2016;26(4):377-384. R834798 (2015)
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  • Journal Article Lepeule J, Laden F, Dockery D, Schwartz J. Chronic exposure to fine particles and mortality: an extended follow-up of the Harvard Six Cities study from 1974 to 2009. Environmental Health Perspectives 2012;120(7):965-970. R834798 (2012)
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  • Journal Article Lepeule J, Baccarelli A, Tarantini L, Motta V, Cantone L, Litonjua AA, Sparrow D, Vokonas PS, Schwartz J. Gene promoter methylation is associated with lung function in the elderly:the Normative Aging Study. Epigenetics 2012;7(3):261-269. R834798 (2012)
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  • Journal Article Lepeule J, Bind M-AC, Baccarelli AA, Koutrakis P, Tarantini L, Litonjua A, Sparrow D, Vokonas P, Schwartz JD. Epigenetic influences on associations between air pollutants and lung function in elderly men: the Normative Aging Study. Environmental Health Perspectives 2014;122(6):566-572. R834798 (2014)
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  • Journal Article Lepeule J, Litonjua AA, Coull B, Koutrakis P, Sparrow D, Vokonas PS, Schwartz J. Long-term effects of traffic particles on lung function decline in the elderly.American Journal of Respiratory and Critical Care Medicine 2014;190(5):542-548. R834798 (Final)
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  • Journal Article Link MS, Luttmann-Gibson H, Schwartz J, Mittleman MA, Wessler B, Gold DR, Dockery DW, Laden F. Acute exposure to air pollution triggers atrial fibrillation. Journal of the American College of Cardiology 2013;62(9):816-825. R834798 (2013)
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  • Journal Article Madrigano J, Baccarelli A, Mittleman MA, Sparrow D, Spiro III A, Vokonas PS, Cantone L, Kubzansky L, Schwartz J. Air pollution and DNA methylation: interaction by psychological factors in the VA Normative Aging Study. American Journal of Epidemiology 2012;176(3):224-232. R834798 (2013)
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  • Journal Article Madrigano J, Kloog I, Goldberg R, Coull BA, Mittleman MA, Schwartz J. Long-term exposure to PM2.5 and incidence of acute myocardial infarction. Environmental Health Perspectives 2013;121(2):192-196. R834798 (2013)
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  • Journal Article Mehta AJ, Zanobetti A, Koutrakis P, Mittleman MA, Sparrow D, Vokonas P, Schwartz J. Associations between short-term changes in air pollution and correlates of arterial stiffness: the Veterans Affairs Normative Aging Study, 2007-2011. American Journal of Epidemiology 2014;179(2):192-199. R834798 (2014)
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  • Journal Article Mehta AJ, Zanobetti A, Bind MA, Kloog I, Koutrakis P, Sparrow D, Vokonas PS, Schwartz JD. Long-term exposure to ambient fine particulate matter and renal function in older men: the Veterans Administration Normative Aging Study. Environmental Health Perspectives 2016;124(9):1353-1360. R834798 (Final)
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  • Journal Article Nordio F, Kloog I, Coull BA, Chudnovsky A, Grillo P, Bertazzi PA, Baccarelli AA, Schwartz J. Estimating spatio-temporal resolved PM10 aerosol mass concentrations using MODIS satellite data and land use regression over Lombardy, Italy. Atmospheric Environment 2013;74:227-236. R834798 (2013)
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  • Journal Article Panni T, Mehta AJ, Schwartz JD, Baccarelli AA, Just AC, Wolf K, Wahl S, Cyrys J, Kunze S, Strauch K, Waldenberger M. Genome-wide analysis of DNA methylation and fine particulate matter air pollution in three study populations:KORA F3, KORA F4, and the Normative Aging Study. Environmental Health Perspectives 2016;124(7):983-990. R834798 (Final)
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  • Journal Article Peng C, Bind MA, Colicino E, Kloog I, Byun HM, Cantone L, Trevisi L, Zhong J, Brennan K, Dereix AE, Vokonas PS, Coull BA, Schwartz JD, Baccarelli AA. Particulate air pollution and fasting blood glucose in nondiabetic individuals:associations and epigenetic mediation in the normative aging study, 2000–2011. Environmental Health Perspectives 2016;124(11):1715-1721. R834798 (Final)
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  • Journal Article Peters JL, Kubzansky LD, Ikeda A, Spiro III A, Wright RO, Weisskopf MG, Kim D, Sparrow D, Nie LH, Hu H, Schwartz J. Childhood and adult socioeconomic position, cumulative lead levels, and pessimism in later life: the VA Normative Aging Study. American Journal of Epidemiology 2011;174(12):1345-1353. R834798 (2010)
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  • Journal Article Power, MC, Weisskopf MG, Alexeef SE, Coull BA, Spiro III A , Schwartz J. Traffic-related air pollution and cognitive function in a cohort of older men. Environmental Health Perspectives 2011;119(5):682-687. R834798 (2010)
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  • Journal Article Schwartz J, Alexeeff SE, Mordukhovich I, Gryparis A, Vokonas P, Suh H, Coull BA. Association between long-term exposure to traffic particles and blood pressure in the Veterans Administration Normative Aging Study. Occupational and Environmental Medicine 2012;69(6):422-427. R834798 (2012)
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  • Journal Article Shi L, Liu P, Wang Y, Zanobetti A, Kosheleva A, Koutrakis P, Schwartz J. Chronic effects of temperature on mortality in the Southeastern USA using satellite-based exposure metrics. Scientific Reports 2016;6:30161 (8 pp.). R834798 (Final)
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  • Journal Article Sivagangabalan G, Spears D, Masse S, Urch B, Brook RD, Silverman F, Gold DR, Lukic KZ, Speck M, Kusha M, Farid T, Poku K, Shi E, Floras J, Nanthakumar K. The effect of air pollution on spatial dispersion of myocardial repolarization in healthy human volunteers. Journal of the American College of Cardiology 2011;57(2):198-206. R834798 (2012)
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  • Journal Article Sofer T, Maity A, Coull B, Baccarelli A, Schwartz J, Lin X. Multivariate gene selection and testing in studying the exposure effects on a gene set. Statistics in Bioscience 2012;4(2):319-338. R834798 (2013)
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  • Journal Article Sofer T, Baccarelli A, Cantone L, Coull B, Maity A, Lin X, Schwartz J. Exposure to airborne particulate matter is associated with methylation pattern in the asthma pathway. Epigenomics 2013;5(2):147-154. R834798 (2013)
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  • Journal Article von Klot S, Zanobetti A, Schwartz J. Influenza epidemics, seasonality, and the effects of cold weather on cardiac mortality. Environmental Health 2012;11:74. R834798 (2013)
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  • Journal Article Wang Y, Eliot MN, Koutrakis P, Gryparis A, Schwartz JD, Coull BA, Mittleman MA, Milberg WP, Lipsitz LA, Wellenius GA. Ambient air pollution and depressive symptoms in older adults: results from the MOBILIZE Boston Study. Environmental Health Perspectives 2014;122(6):553-558. R834798 (Final)
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  • Journal Article Wang Y, Eliot MN, Kuchel GA, Schwartz J, Coull BA, Mittleman MA, Lipsitz LA, Wellenius GA. Long-term exposure to ambient air pollution and serum leptin in older adults: results from the MOBILIZE Boston Study. Journal of Occupational and Environmental Medicine 2014;56(9):e73-e77. R834798 (Final)
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  • Journal Article Wellenius GA, Boyle LD, Wilker EH, Sorond FA, Coull BA, Koutrakis P, Mittleman MA, Lipsitz LA. Ambient fine particulate matter alters cerebral hemodynamics in the elderly. Stroke 2013;44(6):1532-1536. R834798 (2013)
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  • Journal Article Wilker EH, Mittleman MA, Coull BA, Gryparis A, Bots ML, Schwartz J, Sparrow D. Long-term exposure to black carbon and carotid intima-media thickness: the Normative Aging Study. Environmental Health Perspectives 2013;121(9):1061-1067. R834798 (2013)
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  • Journal Article Zanobetti A, O'Neill MS, Gronlund CJ, Schwartz JD. Summer temperature variability and long-term survival among elderly people with chronic disease. Proceedings of the National Academy of Sciences of the United States of America 2012;109(17):6608-6613. R834798 (2012)
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  • Journal Article Zanobetti A, Coull BA, Gryparis A, Kloog I, Sparrow D, Vokonas PS, Wright RO, Gold DR, Schwartz J. Associations between arrhythmia episodes and temporally and spatially resolved black carbon and particulate matter in elderly patients. Occupational and Environmental Medicine 2014;71(3):201-207. R834798 (2014)
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  • Journal Article Zanobetti A, Coull B, Kloog I, Sparrow D, Vokonas P, Gold DR, Schwartz J. Fine-scale spatial and temporal variation in temperature and arrhythmia episodes in the VA Normative Aging Study. Journal of the Air & Waste Management Association 2017;67(1):96-104. R834798 (Final)
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  • Journal Article Schwartz, J., Austin, E., Bind, M.A., Zanobetti, A., and Koutrakis, P. (2015). Estimating Causal Associations of Low PM2.5 on Daily Deaths in Boston. American Journal of Epidemiology 182, 644-650. R834798C002 (Final)
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    Journal Article Zhong, J., Cayir, A., Trevis, L., Sanchez-Guerra, M., Peng, L.X., Bind, M.A., Prada, D., Laue, H., Brennan, K.J.D., A., Sparrow, D., Vokonas, P., Schwartz, J., and. R834798C002 (Final)
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    Journal Article Rodosthenous, S., Coull, B.A., Lu, Q., Vokonas, P.S., Schwartz, J.D., and Baccarelli, A.A. (2016). Ambient Particulate Matter and MicroRNAs in Extracellular Vesicles:a Pilot Study of Older Individuals. Particle and Fibre Toxicology 13, 1-13. R834798C002 (Final)
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    Journal Article Mordukhovich, I., Coull, B.A., Kloog, I., Koutrakis, P., Vokonas, P., and Schwartz, J. (2015). Exposure to Sub-Chronic and Long-t4erm Particulate Air Pollution and Heart Rate Variability in an Elderly Cohort:the Normative Aging Study. Environmental Health 14, 1-10. R834798C002 (Final)
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    Journal Article Wang, Y., Kloog, I., Coull, B., Kosheleva, A., Zanobetti, A., and Schwartz, J. (2016). Estimating Causal Effects of Long-Term PM2.5 Exposure on Mortality in New Jersey. Environmental Health Perspectives, 1-38. R834798C002 (Final)
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    Journal Article Shi, L., Kloog, I., Zanobetti, A., Liu, P., and Schwartz, J. (2015). Impacts of Temperature and its Variability on Mortality in New England. Nature Climate Change 5, 1-6. R834798C002 (Final)
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    Journal Article Lee, M., Kloog, I., Chudnovsky, A., Lyapustin, A., Wang, Y., Melly, S., Coull, B., Koutrakis, P., and Schwartz, J. (2015). Spatiotemporal Prediction of Fine Particulate Matter using High-resolution Satellite Images in the Southeastern US 2003-2011. J Expos Sci Environ Epidemiol, 1-8. R834798C002 (Final)
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    Journal Article Di, Q., Koutrakis, P., Lyapustin, A., Wang, Y., and Schwartz, J. (2016). Assessing PM2.5 Exposures with High Spatio-Temporal Resolution across the Continental United States. Environmental Science & Technology DOI:10.1021/acs.est.5b06121, 1-35. R834798C002 (Final)
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    Journal Article Dai, L., Koutrakis, P., Coull, B.A., Sparrow, D., Vokonas, P.S., and Schwartz, J. (2015). Use of the Adaptive LASSO method to Identify PM2.5 components Associated with Blood Pressure in Elderly Men:Veterans Affairs Normative Aging Study. Environmental Health Perspectives 121, 120-125. R834798C002 (Final)
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    Journal Article Mehta, A., Kubzansky, L., Coull, B., Kloog, I., Koutrakis, P., Sparrow, D., Spiro, A., Vokonas, P., and Schwartz, J. (2015). Associations Between Air Pollution and Perceived Stress:the Veterans Administration Normative Aging Study. Environmental Health 14, 10. R834798C002 (Final)
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    Journal Article Mordukhovich, I., Lepeule, J., Coull, B.A., Sparrow, D., Vokonas, P., and Schwartz, J. (2015). The Effect of Oxidative Stress Polymorphisms on the Association between Long-term Black Carbon Exposure and Lung Function among Elderly Men. Thorax 70, 133-137. R834798C002 (Final)
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    Journal Article Shi, L., Liu, P., Kloog, I., Lee, M., Kosheleva, A., and Schwartz, J. (2016). Estimating Daily Air Temperature Across the Southeastern United States Using High-Resolution Satellite Data:A Statistical Modeling Study. Environmental Research 146, 51-58. R834798C002 (Final)
    R834798C005 (Final)
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    Journal Article Madrigano, J., Mittleman, M., Baccarelli, A., Goldberg, R., Melly, S.J., Von Klot, S., and Schwartz, J. (2013). Temperature, Myocardial Infarction, and Mortality Effect Modification by Individual-and Area-level Characteristics. Epidemiology 24, 439-446. R834798C002 (Final)
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    Journal Article Mostofsky, E., Schwartz, J., Coull, B., Koutrakis, P., Wellenius, G.A., Suh, H.H., Gold, D.R., and Mittleman, M.A. (2012). Modeling the Association between Particle Constituents of Air Pollution and Health Outcomes. American Journal of Epidemiology 176, 317 – 326. R834798C002 (Final)
    R834798C003 (Final)
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    Journal Article Wang, Y., Shi, L., Zanobetti, A., and Schwartz, J.D. (2016). Estimating and Projecting the Effect of Cold Waves on Mortality in 209 US Cities. Environment International 94, 141-149. R834798C002 (Final)
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    Journal Article Kloog, I., Zanobetti, A., Nordio, F., Coull, B., Baccarelli, A., and Schwartz, J. (2015). Effects of Airborne Fine Particles (PM2.5) on Deep Vein Thrombosis Admissions in the Northeastern United States. Journal of Thrombosis and AHaemostasis 13, 768-774. R834798C002 (Final)
    R834798C005 (Final)
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    Journal Article Shi, L., Zanobetti, A., Kloog, I., Coull, B.A., Koutrakis, P., Melly, S.J., and Schwartz, J. (2015). Low-Concentration PM2.5 and Mortality:Estimating Acute and Chronic Effects in a Population-Based Study. Environmental Health Perspectives 124, 46-52. R834798C002 (Final)
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    Journal Article Schwartz, J., and Baccarelli, A.A. (2015). Cardiac Autonomic Dysfunction:Particulate Air Pollution Effects Are Modulated by Epigenetic Immunoregulation of Toll‐like Receptor 2 and Dietary Flavonoid Intake. Journal of the American Heart Association 4. R834798C002 (Final)
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    Journal Article Bind, M.-A., Peters, A., Koutrakis, P., Coull, B., Vokonas, P., and Schwartz, J. (2016). Quantile Regression Analysis of the Distributional Effects of Air Pollution on Blood Pressure, Heart Rate Variability, Blood Lipids, and Biomarkers of Inflammation in Elderly American Men:The Normative Aging Study. Environmental Health Perspectives http://doi.org/10.1289/ehp.1510044, 1-34. R834798C002 (Final)
    R834798C005 (Final)
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    Journal Article Kioumourtzoglou, M.-A., Schwartz, J., James, P., Dominici, F., and Zanobetti, A. (2016). PM2.5 and Mortality in 207 US Cities:Modification by Temperature and City Characteristics. Epidemiology 27, 221-227. R834798C002 (Final)
    R834798C005 (Final)
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    Journal Article Colicino E, Wilson A, Frisardi MC, Prada D, Power MC, Hoxha M, Dioni L, Spiro A III, Vokonas PS, Weisskopf MG, Schwartz JD, Baccarelli AA. 2017. Telomere length, long-term black carbon exposure, and cognitive function in a cohort of older men:the VA Normative Aging Study. Environ Health Perspect 125:76–81; http://dx.doi.org/10.1289/EHP241; Erratum:http://dx.doi.org/10.1289/EHP1813. R834798C002 (Final)
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    Journal Article Baccarelli, A.A. (2015). Traffic Related Air Pollution, Blood Pressure, and Adaptive Response of Mitochondrial Abundance. Circulation CIRCULATIONAHA.115.018802. R834798C002 (Final)
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    Journal Article Baccarelli, A.A. (2016). Long-term Exposure to Black Carbon, Cognition and Single Nucleotide Polymorphisms in MicroRNA Processing Genes in Older Men. Environment International 88, 86-93. R834798C002 (Final)
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    Journal Article Mordukhovich I, Coull BA, Kloog I, Koutrakis P, Vokonas P, Schwartz J. Association between Particulate Air Pollution and QT Interval Duration in an Elderly Cohort. Epidemiol, 2016 Mar;27(2):284-90. doi:10.1097/EDE.0000000000000424. R834798C002 (Final)
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    Journal Article Schwartz, J.B., M-A., and Koutrakis, P. (2016). Estimating Causal Effects of Local Air Pollution on Daily Deaths:Effect of Low Levels. Environmental Health Perspectives http://dx.doi.org/10.1289/EHP232, 1-30. R834798C002 (Final)
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    Journal Article Lee, M.H., Koutrakis, P., Coull, B.A., Kloog, I., and Schwartz, J. (2015). Acute Effects of Fine Particulate Matter on Mortality in Three Southeastern States from 2007-2011. Journal of Exposure Science and Environmental Epidemiology, 1-7. R834798C002 (Final)
    R834798C005 (Final)
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    Journal Article Wilker, E.H., Preis, S.R., Beiser, A.S., Wolf, P.A., Au, R., Kloog, I., Li, W., Schwartz, J., Koutrakis, P., DeCarli, C., Seshadri, S., and Mittleman, M.A. (2015). Long-Term Exposure to Fine Particulate Matter, Residential Proximity to Major Roads and Measures of Brain Structure. Stroke 46, 1161-1166. R834798C002 (Final)
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    Supplemental Keywords:

    Scientific Discipline, Air, air toxics, Health Risk Assessment, Air Pollution Effects, Biochemistry, Environmental Monitoring, Biology, ambient air quality, complex mixtures, health effects, particulates, sensitive populations, children's health, air pollutants, biological sensitivities, aerosol particles, exposure and effects, lung epithelial cells, susceptible populations, chemical composition, neurotoxicity, human exposure, toxicity, coronary artery disease, cardiopulmonary, cardiotoxicity, environmental effects, mortality, human health

    Relevant Websites:

    The Harvard CLARC website, with links to investigators, projects, reports and publications can be found at: 

    Air Pollution Mixtures: Health Effects Across Life Stages

    Progress and Final Reports:

    Original Abstract
  • 2010 Progress Report
  • 2011 Progress Report
  • 2012 Progress Report
  • 2013 Progress Report
  • 2014 Progress Report

  • Main Center Abstract and Reports:

    R834798    Air Pollution Mixtures: Health Effects across Life Stages

    Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
    R834798C001 Relative Toxicity of Air Pollution Mixtures
    R834798C002 Cognitive Decline, Cardiovascular Changes, and Biological Aging in Response to Air Pollution
    R834798C003 Identifying the Cognitive and Vascular Effects of Air Pollution Sources and Mixtures in the Framingharn Offspring and Third Generation Cohorts
    R834798C004 Longitudinal Effects of Multiple Pollutants on Child Growth, Blood Pressure and Cognition
    R834798C005 A National Study to Assess Susceptibility, Vulnerability, and Effect Modification of Air Pollution Health Risks