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CARDIOVASCULAR RESPONSES IN THE NORMATIVE AGING STUDY: EXPLORING THE PATHWAYS OF PARTICLE TOXICITY

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Impact/Purpose:

Since 1997, epidemiological and animal studies have identified many potential mechanisms by which particles may impact health. However, the relative importance of these potential pathways and the steps along these pathways are not well understood, particularly as to how they relate to specific particle components and sources, for which pathways are likely to differ. We propose to examine the importance and relevance of the inflammatory, endothelial and autonomic pathways to particle toxicity using the cohort of individuals participating in the Normative Aging Study (NAS), a large prospective cohort living in Eastern Massachusetts.

Description:

The NAS cohort has informed us about toxicity of PM2.5, BC, O3 and SO42- on autonomic dysfunction, inflammation, and endothelial dysfunction. We also have gained new insights on individuals at higher risk, such as those with obesity or diabetes. Moreover, we have studied genetic susceptibility factors that inform us about both at-risk groups and possible mechanisms of action of PM. We began exploring multiple pollutants and interactions, and new outcomes including cognition and biomarkers of oxidative stress. We highlight results from our NAS studies below.
 
Multiple pollutants and interactions: We have extended beyond our single-pollutant models to investigate multiple-pollutant models and pollutant interactions. We have demonstrated that higher cumulative lead exposures (predominantly from past gasoline lead) modified associations between air pollution and HRV among our NAS subjects (Park, et al., 2008a). We found graded, significant reductions in both high- and low-frequency (HF and LF) powers of HRV in relation to O3 and SO42- across quartiles of tibia lead (Park, et al., 2006). We also found that polymorphisms of the hemochromatosis (HFE) gene protected against the effects of PM2.5 on HRV (Park, et al., 2006). Two polymorphisms in the HFE gene (C282Y and H63D) are associated with increased uptake of Fe and other transition metals into cells as compared to the wild type genotype, hence our results suggest a role of transition metals in this PM2.5 effect. Concerning air pollution sources and mixtures, we have examined the differences in impact of PM2.5 on HRV by air mass origin using “back-trajectories” (Park, et al., 2007). We found that the effects of BC on all HRV measures were strongest on days with southwest trajectories, while the strongest associations of HRV with O3 occurred on days when air parcels came from the west. PM2.5, BC, and SO42- were associated with increased LF/HF ratio on days related to local, slow moving air masses.
 
Black Carbon Spatio-temporal model: We developed a GIS-based spatial smoothing model to predict 24-hr BC levels. We used this model to predict address-specific exposures for NAS subjects and for subjects in other Boston-area cohorts. We identified an inverse association between address-specific annual BC and telomere length in NAS subjects, using predicted BC from this model (McCracken, et al., 2009).
 
Inflammation, Endothelial Function, and Oxidative Stress: We observed positive associations between traffic-related PM (particle number and black carbon) and inflammatory markers (CRP, WBC count, sediment rate, and fibrinogen) among subjects in the NAS cohort (Zeka, et al., 2006). A follow-up study looking at repeated measures of CRP and fibrinogen now is under review (Bind, et al., in review). We also found that exposures to traffic-related PM (black and organic carbon) were associated with elevated plasma total homocysteine (Park, et al., 2008b). A follow-up analysis showed effect modification by genes related to oxidative stress (Ren, et al., 2010a). PM2.5 and black carbon were associated with increased vascular cell adhesion in subjects and this association was modified by obesity, and by genes (Wilker, et al., 2009). Finally, we report associations between 8-OHdG and both PM2.5 and SO42-, but not BC in a cross-sectional study (Ren, et al., 2010b).
 
Autonomic Dysfunction: We reported an association between short-term PM2.5 exposure and decreased HRV (Park, et al., 2005). We found that subjects with wild type endothelial related genes (APOE, LPL and VEGF) showed stronger effects of PM2.5 on HRV compared to those with hetero- or homozygous genotypes (Ren, et al., 2010c). We found a negative association between PM2.5 and HRV in subjects with lower dietary intakes of methyl nutrients (folate, vitamins B(6) and B(12), methionine), but not in subjects with higher intakes. This association also was modified by methyl-related gene polymorphisms in MTHFR and cSHMT genes and genes related to oxidative stress (Chahine, et al., 2007).
 
Telomere Length: We recently have reported that exposure to traffic was associated with shortened telomere length in blood leukocytes in a study comparing traffic officers to controls (Hoxha, et al., 2009). Preliminary results among nonsmokers in the NAS show an association between shorter telomere length and address-specific annual BC (under review).
 
Susceptibility: In addition to looking at genetic and dietary susceptibility factors, we have investigated obesity and diabetes as susceptibility factors for increased risk to air pollution responsiveness. We found obesity to be a significant susceptibility factor for O3 acute effects on lung function, with twice the estimated decrease in FEV1 due to O3 in obese subjects compared to non-obese subjects (Alexeev, et al., 2007). In addition, we found a greater effect of traffic-related PM on inflammatory markers in obese individuals (Zeka, et al., 2006).

Record Details:

Record Type:PROJECT( ABSTRACT )
Start Date:10/01/2005
Completion Date:09/30/2010
Record ID: 144552