Biomarkers of Lead Exposure and DNA Methylation within Retrotransposons

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 (+/- SD) was 26.3 +/- 1.0 as measured by Alu and 76.8 +/- 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. Editor's SummaryEpigenetics is the study of the temporal and spatial regulation of gene expression. It has been hypothesized that epigenetic processes, such as changes in DNA methylation, may be affected by cumulative exposure to environmental agents. To test this hypothesis, Wright et al. (p. 790) analyzed global DNA methylation markers in a cohort of 517 elderly men from the Normative Aging Study who had been well characterized for cumulative exposure to lead. The authors report that LINE-1 (long interspersed nuclear elements-1) DNA methylation was inversely associated with lead exposure, as estimated from patella lead levels. They conclude that this finding may have implications for the mechanisms of action of lead on health outcomes and suggest that DNA methylation changes may represent a biomarker of past lead exposure.