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Clinical Trial
. 2017 Mar 28;114(13):3503-3508.
doi: 10.1073/pnas.1618545114. Epub 2017 Mar 13.

B vitamins attenuate the epigenetic effects of ambient fine particles in a pilot human intervention trial

Jia Zhong  1 , Oskar Karlsson  2   3 , Guan Wang  4 , Jun Li  5   6 , Yichen Guo  7 , Xinyi Lin  8 , Michele Zemplenyi  7 , Marco Sanchez-Guerra  9 , Letizia Trevisi  10 , Bruce Urch  11   12   13   14 , Mary Speck  11 , Liming Liang  7 , Brent A Coull  7 , Petros Koutrakis  10 , Frances Silverman  11   12   13   14 , Diane R Gold  10   15 , Tangchun Wu  5   6 , Andrea A Baccarelli  16
Affiliations
Clinical Trial

B vitamins attenuate the epigenetic effects of ambient fine particles in a pilot human intervention trial

Jia Zhong et al. Proc Natl Acad Sci U S A. .

Erratum in

Abstract

Acute exposure to fine particle (PM2.5) induces DNA methylation changes implicated in inflammation and oxidative stress. We conducted a crossover trial to determine whether B-vitamin supplementation averts such changes. Ten healthy adults blindly received a 2-h, controlled-exposure experiment to sham under placebo, PM2.5 (250 μg/m3) under placebo, and PM2.5 (250 μg/m3) under B-vitamin supplementation (2.5 mg/d folic acid, 50 mg/d vitamin B6, and 1 mg/d vitamin B12), respectively. We profiled epigenome-wide methylation before and after each experiment using the Infinium HumanMethylation450 BeadChip in peripheral CD4+ T-helper cells. PM2.5 induced methylation changes in genes involved in mitochondrial oxidative energy metabolism. B-vitamin supplementation prevented these changes. Likewise, PM2.5 depleted 11.1% [95% confidence interval (CI), 0.4%, 21.7%; P = 0.04] of mitochondrial DNA content compared with sham, and B-vitamin supplementation attenuated the PM2.5 effect by 102% (Pinteraction = 0.01). Our study indicates that individual-level prevention may be used to complement regulations and control potential mechanistic pathways underlying the adverse PM2.5 effects, with possible significant public health benefit in areas with frequent PM2.5 peaks.

Keywords: B vitamins; DNA methylation; air pollution; mitochondria.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Proposed conceptual model linking fine particulate matter (PM2.5), systemic oxidative stress and inflammation, and altered DNA methylation landscape in Th cells. We hypothesized that PM2.5 inhalation triggers local and systemic inflammation and oxidative stress, which alters the DNA methylation landscape in circulating CD4+ Th cells and further stimulates CD4+ Th cells. In return, stimulated CD4+ Th cells undergo more epigenetic remodeling—possibly due to modulated methyl group availability—therefore creating a vicious circle which amplifies the inflammatory and oxidative effects of PM2.5.
Fig. S1.
Fig. S1.
Study design: a single-blind, cross-over intervention trial with controlled exposure experiments in 10 healthy volunteers.
Fig. 2.
Fig. 2.
The effect of 2-h exposure to PM2.5 on DNA methylation landscape and the reduction of PM2.5 effect by B-vitamin supplementation. A is the Volcano plot depicting the distribution of estimated effect of PM2.5 exposure on the epigenome. Each dot represents the estimated PM2.5 effect for one CpG. The vertical lines indicate suggestive threshold based on effect size, whereas the horizontal line reflects the suggestive threshold based on statistical significance. B is the quantile–quantile plot for associations of PM2.5 with DNA methylation in circulating CD4+ Th cells. C represents the top 10 loci associated with PM2.5 and the reduction of PM2.5 effect by B vitamins. Bar height indicates PM2.5 effect, whereas the gray part indicates the magnitude of effect attenuation by B vitamins. D is the Manhattan plot representing the chromosome location of each loci. The dashed horizontal line reflects the suggestive threshold for statistical significance. Analyses were adjusted for season, chamber humidity, and temperature.
Fig. 3.
Fig. 3.
Distribution of DNA methylation levels of cg06194186 and cg17157498 before and after each exposure experiment. Red solid lines and green dashed lines indicate the distribution of methylation levels measured before and after exposure, respectively.
Fig. S2.
Fig. S2.
Genome location of cg06194186 and related region. A displays the location of cg06194186 on chromosome two. B shows the region covering chromosome 2: 207303694–208303693. Reference genes are noted in different colors, classified by protein-coding function. The red line indicates that cg06194186 is related to the CPO gene, a protein-coding gene. C is the zoomed in view for cg06194186. There are no short variants (SNPs and indels) for this region genotyped in admixed American (AMR), East Asian (EAS), and European (EUR) individuals by the 1000 Genomes project (phase 3) with frequency of at least 1%.
Fig. S3.
Fig. S3.
Genome location of cg17157498 and related region. A displays the location of cg17157498 on chromosome 19. B shows the region covering chromosome 19: 883494–1883493. Reference genes are noted in different colors, classified by protein-coding function. The red line indicates that cg17157498 is related to the NDUFS7 gene, a protein-coding gene. C is the zoomed in view for cg17157498. There are no short variants (SNPs and indels) for this region genotyped in admixed American (AMR), East Asian (EAS), and European (EUR) individuals by the 1000 Genomes project (phase 3) with frequency of at least 1%.
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