DNA hypomethylation, ambient particulate matter, and increased blood pressure: findings from controlled human exposure experiments

Abstract

Background: Short-term exposures to fine (<2.5 μm aerodynamic diameter) ambient particulate-matter (PM) have been related with increased blood pressure (BP) in controlled-human exposure and community-based studies. However, whether coarse (2.5 to 10 μm) PM exposure increases BP is uncertain. Recent observational studies have linked PM exposures with blood DNA hypomethylation, an epigenetic alteration that activates inflammatory and vascular responses. No experimental evidence is available to confirm those observational data and demonstrate the relations between PM, hypomethylation, and BP.

Methods and results: We conducted a cross-over trial of controlled-human exposure to concentrated ambient particles (CAPs). Fifteen healthy adult participants were exposed for 130 minutes to fine CAPs, coarse CAPs, or HEPA-filtered medical air (control) in randomized order with ≥2-week washout. Repetitive-element (Alu, long interspersed nuclear element-1 [LINE-1]) and candidate-gene (TLR4, IL-12, IL-6, iNOS) blood methylation, systolic and diastolic BP were measured pre- and postexposure. After adjustment for multiple comparisons, fine CAPs exposure lowered Alu methylation (β-standardized=-0.74, adjusted-P=0.03); coarse CAPs exposure lowered TLR4 methylation (β-standardized=-0.27, adjusted-P=0.04). Both fine and coarse CAPs determined significantly increased systolic BP (β=2.53 mm Hg, P=0.001; β=1.56 mm Hg, P=0.03, respectively) and nonsignificantly increased diastolic BP (β=0.98 mm Hg, P=0.12; β=0.82 mm Hg, P=0.11, respectively). Decreased Alu and TLR4 methylation was associated with higher postexposure DBP (β-standardized=0.41, P=0.04; and β-standardized=0.84, P=0.02; respectively). Decreased TLR4 methylation was associated with higher postexposure SBP (β-standardized=1.45, P=0.01).

Conclusions: Our findings provide novel evidence of effects of coarse PM on BP and confirm effects of fine PM. Our results provide the first experimental evidence of PM-induced DNA hypomethylation and its correlation to BP.

Keywords: DNA methylation; air pollution; blood pressure; epigenetics; mediation.

Figure 1.

Effect of controlled exposures to fine CAPs (A) and coarse CAPs (B) on blood DNA methylation. Differences in CAPs vs medical air (control) exposures of DNA methylation in postexposure samples reported as standardized βs and 95% confidence intervals. βs indicate the differences between CAPs exposure and control exposure (HEPA‐filtered medical air) in the postexposure blood samples. βs are standardized to express the effect of CAPs exposure on DNA methylation as a fraction of the standard deviation of DNA methylation. Nominal P values (P), as well as P values adjusted for multiple testing (adjusted P) are shown for the significant effects. CAP indicates concentrated ambient particle; HEPA, high‐efficiency particulate air; LINE‐1, long interspersed nuclear element‐1; TLR4, toll‐like receptor‐4; IL‐6, interleukin 6; IL‐12, interleukin 12; iNOS, inducible nitric oxide synthase gene.

Figure 2.

Effect of controlled exposures to fine concentrated ambient particles (CAPs) and coarse CAPs on systolic and diastolic blood pressure (BP). Differences in CAPs vs medical air (control) exposures of systolic and diastolic BP in postexposure measurements. βs and 95% confidence intervals expressing the difference in BP (mm Hg) between CAPs exposures and control exposure (HEPA‐filtered medical air) in postexposures measurements. HEPA indicates high‐efficiency particulate air.

Figure 3.

Associations of Alu and TLR4 methylation with systolic and diastolic blood pressure (BP). Standardized βs and 95% confidence intervals are shown in the figure. Standardize βs express the changes in BP as fractions of the BP standard deviation associated with a decrease in DNA methylation equal to its standard deviation. TLR4 indicates toll‐like receptor‐4.