Skip to content


Research Advance Publication

Environ Health Perspect; DOI:10.1289/ehp.1306674

Association of Global DNA Methylation and Global DNA Hydroxymethylation with Metals and other Exposures in Human Blood DNA Samples

Maria Tellez-Plaza,1,2,3 Wan-yee Tang,2 Yan Shang,2,4 Jason G. Umans,5,6 Kevin A. Francesconi,7 Walter Goessler,7 Marta Ledesma,8 Montserrat Leon,8 Martin Laclaustra,9 Jonathan Pollak,2 Eliseo Guallar,1,10 Shelley A. Cole,11 M. Dani Fallin,1 and Ana Navas-Acien1,2
Author Affiliations close
1Department of Epidemiology and Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA; 2Department of Environmental Health Sciences, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA; 3Fundacion de Investigacion del Hospital Clinico de Valencia-INCLIVA, Valencia, Spain; 4Department of Respiratory Disease, Changhai Hospital, Second Military Medical University, Shanghai, China; 5MedStar Health Research Institute, Hyattsville, Maryland, USA; 6Georgetown-Howard Universities Center for Clinical and Translational Science, Washington DC, USA; 7Institute of Chemistry – Analytical Chemistry, Karl-Franzens University Graz, Austria; 8Aragon Health Sciences Institute, Zaragoza, Spain; 9Department of Epidemiology, Atherothrombosis and Imaging, National Center of Cardiovascular Research-CNIC, Madrid, Spain; 10Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA; 11Department of Genetics, Texas Biomedical Research Institute, San Antonio, Texas, USA
About This Article open

This EHP Advance Publication article has been peer-reviewed, revised, and accepted for publication. EHP Advance Publication articles are completely citable using the DOI number assigned to the article. This document will be replaced with the copyedited and formatted version as soon as it is available. Through the DOI number used in the citation, you will be able to access this document at each stage of the publication process.

Citation: Tellez-Plaza M, Tang WY, Shang Y, Umans JG, Francesconi KA, Goessler W, Ledesma M, Leon M, Laclaustra M, Pollak J, Guallar E, Cole SA, Fallin MD, Navas-Acien A. Association of Global DNA Methylation and Global DNA Hydroxymethylation with Metals and other Exposures in Human Blood DNA Samples. Environ Health Perspect;

Received: 19 February 2013
Accepted: 22 April 2014
Advance Publication: 25 April 2014

For materials with complex tables, EHP offers “Alt 508″ versions optimized for use with screen-reading software.

Accessible PDF icon PDF Version (603 KB) | Accessible PDF icon Supplemental Material (1.3 MB)


Introduction: The association between human blood DNA global methylation and global hydroxymethylation has not been evaluated in population-based studies. No studies have evaluated environmental determinants of global DNA hydroxymethylation, including exposure to metals.

Objective: We evaluated the association between global DNA methylation and global DNA hydroxymethylation in 48 Strong Heart Study participants who had selected metals measured in urine at baseline and DNA available in 1989-1991 and 1998-1999.

Methods: % 5-methylcytosine (5-mC) and % 5-hydroxymethyl-cytosine (5-hmC) levels were measured by capture and detection antibodies followed by colorimetric quantification. We explored the association of participant characteristics (i.e. age, adiposity, smoking, and metal exposure) with both global DNA methylation and global DNA hydroxymethylation.

Results: The Spearman’s correlation coefficient for 5-mC and 5-hmC levels was 0.32 (p –value = 0.03) at visit 1 and 0.54 (p – value < 0.001) at visit 3. Trends for both epigenetic modifications were consistent across potential determinants. In cross-sectional analyses the odds ratios of methylated and hydroxymethylated DNA were 1.56 (95% CI: 0.95, 2.57) and 1.76 (95% CI: 1.07, 2.88), respectively, comparing participants above and below the median of % dimethylarsinate. The corresponding odds ratios were 1.64 (95% CI: 1.02, 2.65) and 1.16 (95% CI: 0.70, 1.94), respectively, comparing participants above and below median cadmium. Arsenic exposure and metabolism were consistently associated with both epigenetic markers in cross-sectional and prospective analyses. The positive correlation of 5-mC and 5-hmC levels was confirmed in an independent study population.

Conclusions: Our findings support that both epigenetic measures are related at the population level. The consistent trends in the associations between these two epigenetic modifications and the characteristics evaluated, specially arsenic exposure and metabolism, suggest the need for understanding which of the two measures is a better biomarker for environmental epigenetic effects in future large-scale epidemiologic studies.

WP-Backgrounds Lite by InoPlugs Web Design and Juwelier Schönmann 1010 Wien