Academic journal article Environmental Health Perspectives

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

Academic journal article Environmental Health Perspectives

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

Article excerpt


DNA 5-methylcytosine (5-mC) modifications are increasingly recognized as a key process in the pathogenesis of complex disorders, including cancer, diabetes, and cardiovascular disease (Feinberg 2010; Ordovas and Smith 2010). Several recent studies have investigated epigenetic functions of 5-hydroxymethylcytosine (5-hmC), a hydroxylated and methylated form of cytosine. The conversion of 5-mC to 5-hmC is a step prior to demethylation (Shen et al. 2013; Song et al. 2013) and seems to play a direct role in the regulation of gene expression (Branco et al. 2012). Although 5-hmC is able to bind to DNA methylation binding domain (MBD) 3 (Baubec et al. 2013), it reduces the binding of other MBD proteins to methylated DNA and prevents DNA methyltransferase (DNMT) mediated methylation of the target cytosine (Tahiliani et al. 2009). Several studies have evaluated blood cell global DNA methylation and its determinants in population-based studies (reviewed by Terry et al. 2011). However, few human studies have evaluated global DNA hydroxymethylation. Specifically, the association between human blood cell global DNA methylation and global DNA hydroxymethylation has not been previously evaluated in epidemiologic studies.

Environmental exposures, such as to arsenic or cadmium, can disrupt gene expression (Andrew et al. 2008; Bourdonnay et al. 2009; Castillo et al. 2012; Cheng et al. 2012; Hossain et al. 2012; Su et al. 2006). Findings suggest that the health effects of environmental exposures, including exposure to metals, could be mediated in part by epigenetic mechanisms (Arita and Costa 2009; Reichard and Puga 2010; Ren et al. 2011; Smeester et al. 2011). Results of studies conducted in vitro and in primary human tissue samples also support that metals can have epigenetic effects (Huang et al. 2008; Kile et al. 2012; Lambrou et al. 2012; Smeester et al. 2011). No studies have evaluated environmental determinants of global DNA hydroxymethylation, including exposure to metals.

In this study, we examined the association between global DNA methylation and global DNA hydroxymethylation in a subsample of Strong Heart Study (SHS) participants who had metals measured in urine and also had buffy coat and blood available for DNA isolation (Lee et al. 1990; Scheer et al. 2012). In addition, we explored the association of participant characteristics (age, sex, education, adiposity, smoking, alcohol intake, metal exposure, and arsenic metabolism) with both global DNA methylation and global DNA hydroxymethylation. We had no a priori hypothesis on the direction of the associations under study.


Study population. The SHS is a population-based cohort study funded by the U.S. National Heart, Lung, and Blood Institute that recruited 4,549 participants from Arizona, Oklahoma, and North and South Dakota in 1989-1991 (overall response rate 62%) (Lee et al. 1990). Starting in 1998, an ancillary study to the SHS, the Strong Heart Family Study (SHFS) recruited extended family members of the original SHS participants who were > 18 years of age to evaluate genetic determinants of cardiometabolic disease in American Indian populations (North et al. 2003). For the present study, the population was restricted to SHS participants with measurements of metals in urine at baseline (visit 1) (Scheer et al. 2012) who also participated in the SHFS (North et al. 2003) and had biological samples collected at two follow-up clinic visits conducted in 1993-1995 (visit 2) and 1997-1999 (visit 3). A total of 517 participants met those criteria. To maximize the efficiency of this relatively small epigenetic study (Stuart and Hanna 2013; Zubizarreta et al. 2013), we used a stratified random sample to select 8 participants with moderate arsenic exposure and 8 participants with low arsenic exposure from each region (16 from Arizona, 16 from Oklahoma, and 16 from North or South Dakota), resulting in a total of 48 participants. …

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