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Blood DNA Methylation Biomarkers of Cumulative Lead Exposure in Adults
26 Pages Posted: 2 Mar 2019More...
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 lead 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 beadchip assays.
Methods: We developed and tested two methylation-based biomarkers using Illumina450K data 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 final biomarkers using elastic nets. All results were validated in a NAS subset.
Findings: Participants were 73 years old on average (standard deviation, SD=6), with moderate lead levels of (mean±SD patella:27±18µg/g; tibia:21±13µg/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 the two 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 lead exposure sequences of cumulative lead exposure.
Funding Statement: EC and ROW were supported by the National Institute of Environmental Health Sciences (NIEHS) (grant: P30ES023515); ACJ was supported by NIEHS (grant: R00ES023450); MAK was supported by NIEHS (grants: R01ES028805 and P30 ES009089); MW was supported by NIEHS (grant: P30ES000002); JS was supported by NIEHS (grants: R01ES015172, P30ES000002, and R01ES027747); HH was supported by NIH (grants: R01ES021446, and R01ES005257); AAB was supported by NIEHS (grants: P30ES009089, R01ES021733, R01ES025225, and R01ES027747). The VA Normative Aging Study is supported by the Cooperative Studies Program/Epidemiology Research and Information Center of the U.S. Department of Veterans Affairs and is a component of the Massachusetts Veterans Epidemiology Research and Information Center, Boston, Massachusetts.
Declaration of Interests: All authors declare no conflict of interest.
Ethics Approval Statement: Approval from the Institutional Review Boards at the Veterans Affairs Boston Healthcare System, Brigham and Women’s Hospital, and the Harvard T.H. Chan School of Public Health was obtained prior to study commencement. All subjects provided written informed consent before participating.
Keywords: lead, DNA methylation, exposure reconstruction, cumulative exposure, machine learning
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