Association of global DNA methylation and global DNA hydroxymethylation with metals and other exposures in human blood DNA samples.
BACKGROUND
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 for which selected metals had been measured in urine at baseline and DNA was available from 1989-1991 (visit 1) and 1998-1999 (visit 3).


METHODS
We measured the percentage of 5-methylcytosine (5-mC) and 5-hydroxymethylcytosine (5-hmC) in samples using 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 = 0.03) at visit 1 and 0.54 (p < 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, for the comparison of participants above and below the median percentage 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, for the comparison of participants above and below the median cadmium level. 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, especially 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.
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
Maria
M
Tellez-Plaza
Wan-Yee
WY
Tang
Yan
Y
Shang
Jason G
JG
Umans
Kevin A
KA
Francesconi
Walter
W
Goessler
Marta
M
Ledesma
Montserrat
M
Leon
Martin
M
Laclaustra
Jonathan
J
Pollak
Eliseo
E
Guallar
Shelley A
SA
Cole
M Dani
MD
Fallin
Ana
A
Navas-Acien
D044503:5-Methylcytosine / Q000097:blood / Q000031:analogs & derivatives; D000368:Aged; D001151:Arsenic / Q000378:metabolism; D002104:Cadmium / Q000378:metabolism; D003430:Cross-Sectional Studies; D003596:Cytosine / Q000031:analogs & derivatives / Q000097:blood; D004247:DNA; D019175:DNA Methylation / Q000187:drug effects*; D004781:Environmental Exposure / Q000706:statistics & numerical data; D044127:Epigenesis, Genetic; D005260:Female; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008670:Metals / Q000097:blood* / Q000378:metabolism / Q000633:toxicity / Q000652:urine; D008875:Middle Aged
D008670:Metals; D002104:Cadmium; C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine; D003596:Cytosine; D004247:DNA; D001151:Arsenic