Rodosthenis S Rodosthenous1, Itai Kloog2, Elena Colicino3, Jia Zhong4, Luis A Herrera5, Pantel Vokonas6, Joel Schwartz7, Andrea A Baccarelli8, Diddier Prada9. 1. Department of Environmental Health, Harvard T.H. Chan School of Public Health, Harvard University, 665 Huntington Ave, Boston, MA 02115, United States; Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA 02114, United States. Electronic address: rrodosth@hsph.harvard.com. 2. Department of Geography and Environmental Development, Ben-Gurion University of the Negev, 663 Beer Sheva, Israel. Electronic address: ikloog@gmail.com. 3. Department of Environmental Health, Harvard T.H. Chan School of Public Health, Harvard University, 665 Huntington Ave, Boston, MA 02115, United States; Icahn School of Medicine, Mount Sinai Hospital, 1 Gustave L. Levy Place, New York, NY 10029-5674, United States. Electronic address: elena.colicino@mssm.edu. 4. Department of Environmental Health, Harvard T.H. Chan School of Public Health, Harvard University, 665 Huntington Ave, Boston, MA 02115, United States. Electronic address: Jia.zhong@analysisgroup.com. 5. Unidad de Investigación Biomédica en Cáncer, Instituto Nacional de Cancerología - Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City 14080, Mexico. Electronic address: herreram@biomedicas.unam.mx. 6. Veterans Affairs Boston Healthcare System, 150 South Huntington Ave, Boston, MA 02130, United States; Department of Epidemiology, Boston University School of Public Health, 715 Albany Street, Boston, MA 02118, United States; Department of Medicine, Boston University School of Medicine, 72 East Concord Street, Boston, MA 02118, United States. Electronic address: Pantel.Vokonas@va.gov. 7. Department of Environmental Health, Harvard T.H. Chan School of Public Health, Harvard University, 665 Huntington Ave, Boston, MA 02115, United States. Electronic address: joel@hsph.harvard.edu. 8. Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY 10032, United States. Electronic address: ab4303@cumc.columbia.edu. 9. Department of Environmental Health, Harvard T.H. Chan School of Public Health, Harvard University, 665 Huntington Ave, Boston, MA 02115, United States; Unidad de Investigación Biomédica en Cáncer, Instituto Nacional de Cancerología - Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City 14080, Mexico. Electronic address: dpradao@incan.edu.mx.
Abstract
BACKGROUND: Several studies have shown that exposure to particulate matter (PM) may lead to increased systemic blood pressure, but the underlying biological mechanisms remain unknown. Emerging evidence shows that extracellular vesicle-enriched miRNAs (evmiRNAs) are associated with PM exposure and cardiovascular risk. In this study, we investigated the role of evmiRNAs in the association between PM and blood pressure, as well as their epigenetic regulation by DNA methylation. METHODS:Participants (n = 22, men) were randomly selected from the Veterans Affairs Normative Aging Study (NAS). Long-term (1-year and 6-month average) PM2.5 exposure was estimated at 1 × 1-km resolution using spatio-temporal prediction models and BC was estimated using validated time varying land use regression models. We analyzed 31 evmiRNAs detected in ≥ 90% of all individuals and for statistical analysis, we used mixed effects models with random intercept adjusted for age, body mass index, smoking, C-reactive protein, platelets, and white blood cells. RESULTS: We found that per each 2-standard deviations increase in 6-month PM2.5 ambient levels, there was an increase in 0.19 mm Hg (95% Confidence Interval [95%CI]: 0.11, 0.28 mmHg; p < 0.001) in systolic blood pressure (SBP). Per each 2-standard deviations increase in 1-year PM2.5 levels, there was an increase in 0.11 mm Hg (95% Confidence Interval [95% CI]: 0.03, 0.19 mmHg; p = 0.012) in SBP in older male individuals. We also found that both miR-199a/b (β = 6.13 mmHg; 95% CI: 0.87, 11.39; pinteraction = 0.07) and miR-223-3p (β = 30.17 mmHg; 95% CI: 11.96, 48.39 mmHg; pinteraction = 0.01) modified the association between 1-year PM2.5 and SBP. When exploring DNA methylation as a potential mechanism that could epigenetically regulate expression of evmiRNAs, we found that PM2.5 ambient levels were negatively associated with DNA methylation levels at CpG (cg23972892) near the enhancer region of miR-199a/b (β = -13.11; 95% CI: -17.70, -8.52; pBonferroni< 0.01), but not miR-223-3p. CONCLUSIONS: Our findings suggest that expression of evmiRNAs may be regulated by DNA methylation in response to long-term PM2.5 ambient levels and modify the magnitude of association between PM2.5 and systolic blood pressure in older individuals.
RCT Entities:
BACKGROUND: Several studies have shown that exposure to particulate matter (PM) may lead to increased systemic blood pressure, but the underlying biological mechanisms remain unknown. Emerging evidence shows that extracellular vesicle-enriched miRNAs (evmiRNAs) are associated with PM exposure and cardiovascular risk. In this study, we investigated the role of evmiRNAs in the association between PM and blood pressure, as well as their epigenetic regulation by DNA methylation. METHODS:Participants (n = 22, men) were randomly selected from the Veterans Affairs Normative Aging Study (NAS). Long-term (1-year and 6-month average) PM2.5 exposure was estimated at 1 × 1-km resolution using spatio-temporal prediction models and BC was estimated using validated time varying land use regression models. We analyzed 31 evmiRNAs detected in ≥ 90% of all individuals and for statistical analysis, we used mixed effects models with random intercept adjusted for age, body mass index, smoking, C-reactive protein, platelets, and white blood cells. RESULTS: We found that per each 2-standard deviations increase in 6-month PM2.5 ambient levels, there was an increase in 0.19 mm Hg (95% Confidence Interval [95%CI]: 0.11, 0.28 mmHg; p < 0.001) in systolic blood pressure (SBP). Per each 2-standard deviations increase in 1-year PM2.5 levels, there was an increase in 0.11 mm Hg (95% Confidence Interval [95% CI]: 0.03, 0.19 mmHg; p = 0.012) in SBP in older male individuals. We also found that both miR-199a/b (β = 6.13 mmHg; 95% CI: 0.87, 11.39; pinteraction = 0.07) and miR-223-3p (β = 30.17 mmHg; 95% CI: 11.96, 48.39 mmHg; pinteraction = 0.01) modified the association between 1-year PM2.5 and SBP. When exploring DNA methylation as a potential mechanism that could epigenetically regulate expression of evmiRNAs, we found that PM2.5 ambient levels were negatively associated with DNA methylation levels at CpG (cg23972892) near the enhancer region of miR-199a/b (β = -13.11; 95% CI: -17.70, -8.52; pBonferroni< 0.01), but not miR-223-3p. CONCLUSIONS: Our findings suggest that expression of evmiRNAs may be regulated by DNA methylation in response to long-term PM2.5 ambient levels and modify the magnitude of association between PM2.5 and systolic blood pressure in older individuals.
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