Blood DNA Methylation Biomarkers of Cumulative Lead Exposure in Adults

BACKGROUND: Lead is a ubiquitous toxicant following three compartment kinetics with the longest half-life found in bones. Patella and tibia lead levels—validated measures of cumulative exposure—require specialized X-ray-fluorescence-spectroscopy available only in a few centers worldwide. We developed minimally-invasive biomarkers reflecting individual cumulative lead exposure using blood DNA methylation profiles—obtainable via Illumina450K or IlluminaEPIC bead-chip assays. METHODS: We developed and tested two methylation-based biomarkers from 348 Normative Aging Study (NAS) elderly men. We selected methylation sites with strong associations with bone lead levels via robust regressions analysis and constructed the biomarkers using elastic nets. Results were validated in a NAS subset, reporting specificity and sensitivity. FINDINGS: Participants were 73 years old on average (standard deviation, SD=6), with moderate lead levels of (mean±SD patella:27±18 μg/g; tibia:21±13 μg/g). Methylation-based biomarkers for lead in patella and tibia included 59 and 138 DNA methylation sites, respectively. Estimated lead levels were significantly correlated with actual measured values, (r=0.62 patella, r=0.59 tibia) and had low mean square error (MSE) (MSE=0.68 patella, MSE=0.53 tibia). Means and distributions of the estimated and actual lead levels were not significantly different across patella and tibia bones (p>0.05). Methylation-based biomarkers discriminated participants highly exposed (>median) to lead with a specificity of 74% and 73% for patella and tibia lead levels, respectively, with 70% sensitivity. INTERPRETATION: DNA-methylation-based lead biomarkers are novel tools that can be used to reconstruct decades’ worth of individual cumulative lead exposure using only blood DNA methylation profiles and may help identify the consequences of cumulative exposure.