Biomarkers of Lead Exposure and DNA Methylation within Retrotransposons
Wright, Robert O., Schwartz, Joel, Wright, Rosalind J., Bollati, Valentina, Tarantini, Letizia, Park, Sung Kyun, Hu, Howard, Sparrow, David, Vokonas, Pantel, Baccarelli, Andrea, Environmental Health Perspectives
Background: DNA methylation is an epigenetic mark that regulates gene expression. Changes in DNA methylation within white blood cells may result from cumulative exposure to environmental metals such as lead. Bone lead, a marker of cumulative exposure, may therefore better predict DNA methylation than does blood lead.
OBJECTIVE: In this study we compared associations between lead biomarkers and DNA methylation.
METHODS: We measured global methylation in participants of the Normative Aging Study (all men) who had archived DNA samples. We measured patella and tibia lead levels by K-X Ray fluorescence and blood lead by atomic absorption spectrophotometry. DNA samples from blood were used to determine global methylation averages within CpG islands of long interspersed nuclear elements-1 (LINE-1.) and Alu retrotransposons. A mixed-effects model using repeated measures of Alu or LINE-1 as the dependent variable and blood/bone lead (tibia or patella in separate models) as the primary exposure marker was fit to the data.
RESULTS: Overall mean global methylation ([+ or -] SD) was 26.3 [+ or -] 1.0 as measured by Alu and 76.8 [+ or -] 1.9 as measured by LINE-1. In the mixed-effects model, patella lead levels were inversely associated with LINE-1 [beta] = -0.25;p < 0.01) but not Alu ([beta] = -0.03; p = 0.4). Tibia lead and blood lead did not predict global methylation for either Alu or LINE-1.
CONCLUSION: Patella lead levels predicted reduced global DNA methylation within LINE-1 elements. The association between lead exposure and LINE-1 DNA methylation may have implications for the mechanisms of action of lead on health outcomes, and also suggests that changes in DNA methylation may represent a biomarker of past lead exposure.
KEYWORDS: aging, DNA methylation, epigenetics, lead, metals. Environ Health Perspect 118:790-795 (2010). doi:10.1289/ehp.090l429 [Online 11 January 2010]
Epigenetics can be defined broadly as the study of the temporal and spatial regulation of gene expression. Changes in epigenetic marks can be as profound as DNA sequence mutations, but unlike DNA mutations, epigenetic marks are reversible and responsive to the environment (Baccarelli and Bollati 2009). DNA methylation is the best studied of the epigenetic processes that regulate gene expression. DNA methylation typically occurs in cytosines within CpG repeat sequences found in gene promoter regions. Areas enriched in CpG repeats are frequently referred to as "CpG islands." Methylation of DNA within promoter regions regulates local gene transcription. In general, increased DNA methylation is inversely associated with gene expression. Much epigenetic research has been focused on the heritability of phenotypic traits not attributable to alterations in DNA sequence, but such epigenetic modifications would have to occur in germ cells to be truly heritable. Changes in epigenetic marks in somatic cells are also of great interest, as these changes can also be induced by environmental exposures and may play a role in the toxicity of environmental agents, even if they are not heritable.
Previous research in both animals and humans has noted that DNA methylation can be altered by exposure to environmental metals (Reichard et al. 2007; Sciandrello et al. 2004; Takiguchi et al. 2003). Oxidative stress may be a unifying process to explain these findings across different metals. Metals are known to increase production of reactive oxygen species in a catalytic fashion via redox cycling (Fowler et al. 2004; Valko et al. 2005). Oxidative DNA damage can interfere with the ability of methyltransferases to interact with DNA (Turk et al. 1995; Valinluck et al. 2004), thus resulting in a generalized hypo-methylation of cytosine residues at CpG sites (Turk et al. 1995). Long-term exposure to oxidative stress has been shown to result in oxidative damage of methylated cytosine residues and depletion in the level of 5-methyl-cytosine in repeated elements (Pogribny et al. …