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Air pollution and homocysteine: more evidence that oxidative stress-related genes modify effects of particulate air pollution.

ABSTRACT: Ambient particles are associated with cardiovascular events and recently with total plasma homocysteine. High total plasma homocysteine is a risk for human health. However, the biologic mechanisms are not fully understood. One of the putative pathways is through oxidative stress. We aimed to examine whether associations of PM2.5 and black carbon with homocysteine were modified by genotypes including HFE H63D, C282Y, CAT (rs480575, rs1001179, rs2284367, and rs2300181), NQO1 (rs1800566), GSTP1 I105V, GSTM1, GSTT1 (deletion vs. nondeletion), and HMOX-1 (any short vs. both long). We attempted to replicate identified genes in an analysis of heart rate variability and in other outcomes reported in the literature.Study subjects were 1000 white non-Hispanic men in the Boston area, participating in a cohort study of aging. PM2.5, black carbon, total plasma homocysteine, and other covariates were measured at several points in time between 1995 and 2006. We fit mixed models to examine effect modification of genes on associations of pollution with total plasma homocysteine.Interquartile range increases in PM2.5 and black carbon (7-day moving averages) were associated with 1.5% (95% confidence interval = 0.2% to 2.8%) and 2.2% (0.6% to 3.9%) increases in total plasma homocysteine, respectively. GSTT1 and HFE C282Y modified effects of black carbon on total plasma homocysteine, and HFE C282Y and CAT (rs2300181) modified effects of PM2.5 on homocysteine. Several genotypes marginally modified effects of PM2.5 and black carbon on various endpoints. All genes with significant interactions with particulate air pollution had modest main effects on total plasma homocysteine.: Effects of PM2.5 and black carbon on various endpoints appeared to be mediated by genes related to oxidative stress pathways.

SUBMITTER: Ren C

PROVIDER: S-EPMC3939788 | biostudies-literature | 2010 Mar

REPOSITORIES: biostudies-literature

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Air pollution and homocysteine: more evidence that oxidative stress-related genes modify effects of particulate air pollution.

Ren Cizao C Park Sung Kyun SK Vokonas Pantel S PS Sparrow David D Wilker Elissa E Baccarelli Andrea A Suh Helen H HH Tucker Katherine L KL Wright Robert O RO Schwartz Joel J

Epidemiology (Cambridge, Mass.) 20100301 2

<h4>Background</h4>Ambient particles are associated with cardiovascular events and recently with total plasma homocysteine. High total plasma homocysteine is a risk for human health. However, the biologic mechanisms are not fully understood. One of the putative pathways is through oxidative stress. We aimed to examine whether associations of PM2.5 and black carbon with homocysteine were modified by genotypes including HFE H63D, C282Y, CAT (rs480575, rs1001179, rs2284367, and rs2300181), NQO1 (rs ...[more]

PMID: 20110814

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Project description:BackgroundEpidemiological evidence suggests that exposure to ambient air fine particulate matter (PM2.5) increases the risk of developing type 2 diabetes and cardiovascular disease. However, the mechanisms underlying these effects of PM2.5 remain unclear.ObjectivesWe tested the hypothesis that PM2.5 exposure decreases vascular insulin sensitivity by inducing pulmonary oxidative stress.MethodsMice fed control (10-13% kcal fat) and high-fat (60% kcal fat, HFD) diets, treated with 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPOL) or mice overexpressing lung-specific extracellular superoxide dismutase (ecSOD) were exposed to HEPA-filtered air or to concentrated PM2.5 (CAP) for 9 or 30 days, and changes in systemic and organ-specific insulin sensitivity and inflammation were measured.ResultsIn control diet-fed mice, exposure to CAP for 30 days decreased insulin-stimulated Akt phosphorylation in lung, heart, and aorta but not in skeletal muscle, adipose tissue, and liver and did not affect adiposity or systemic glucose tolerance. In HFD-fed mice, 30-day CAP exposure suppressed insulin-stimulated endothelial nitric oxide synthase (eNOS) phosphorylation in skeletal muscle and increased adipose tissue inflammation and systemic glucose intolerance. In control diet-fed mice, a 9-day CAP exposure was sufficient to suppress insulin-stimulated Akt and eNOS phosphorylation and to decrease IκBα (inhibitor of the transcription factor NF-κB levels in the aorta. Treatment with the antioxidant TEMPOL or lung-specific overexpression of ecSOD prevented CAP-induced vascular insulin resistance and inflammation.ConclusionsShort-term exposure to PM2.5 induces vascular insulin resistance and inflammation triggered by a mechanism involving pulmonary oxidative stress. Suppression of vascular insulin signaling by PM2.5 may accelerate the progression to systemic insulin resistance, particularly in the context of diet-induced obesity. Citation: Haberzettl P, O'Toole TE, Bhatnagar A, Conklin DJ. 2016. Exposure to fine particulate air pollution causes vascular insulin resistance by inducing pulmonary oxidative stress. Environ Health Perspect 124:1830-1839; http://dx.doi.org/10.1289/EHP212.

Project description:BackgroundDNA methylation (DNAm) may contribute to processes that underlie associations between air pollution and poor health. Therefore, our objective was to evaluate associations between DNAm and ambient concentrations of particulate matter (PM) ≤2.5, ≤10, and 2.5-10 μm in diameter (PM2.5; PM10; PM2.5-10).MethodsWe conducted a methylome-wide association study among twelve cohort- and race/ethnicity-stratified subpopulations from the Women's Health Initiative and the Atherosclerosis Risk in Communities study (n = 8397; mean age: 61.5 years; 83% female; 45% African American; 9% Hispanic/Latino American). We averaged geocoded address-specific estimates of daily and monthly mean PM concentrations over 2, 7, 28, and 365 days and 1 and 12 months before exams at which we measured leukocyte DNAm in whole blood. We estimated subpopulation-specific, DNAm-PM associations at approximately 485,000 Cytosine-phosphate-Guanine (CpG) sites in multi-level, linear, mixed-effects models. We combined subpopulation- and site-specific estimates in fixed-effects, inverse variance-weighted meta-analyses, then for associations that exceeded methylome-wide significance and were not heterogeneous across subpopulations (P < 1.0 × 10-7; PCochran's Q > 0.10), we characterized associations using publicly accessible genomic databases and attempted replication in the Cooperative Health Research in the Region of Augsburg (KORA) study.ResultsAnalyses identified significant DNAm-PM associations at three CpG sites. Twenty-eight-day mean PM10 was positively associated with DNAm at cg19004594 (chromosome 20; MATN4; P = 3.33 × 10-8). One-month mean PM10 and PM2.5-10 were positively associated with DNAm at cg24102420 (chromosome 10; ARPP21; P = 5.84 × 10-8) and inversely associated with DNAm at cg12124767 (chromosome 7; CFTR; P = 9.86 × 10-8). The PM-sensitive CpG sites mapped to neurological, pulmonary, endocrine, and cardiovascular disease-related genes, but DNAm at those sites was not associated with gene expression in blood cells and did not replicate in KORA.ConclusionsAmbient PM concentrations were associated with DNAm at genomic regions potentially related to poor health among racially, ethnically and environmentally diverse populations of U.S. women and men. Further investigation is warranted to uncover mechanisms through which PM-induced epigenomic changes may cause disease.

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Air pollution and homocysteine: more evidence that oxidative stress-related genes modify effects of particulate air pollution.

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Air pollution and homocysteine: more evidence that oxidative stress-related genes modify effects of particulate air pollution.

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