Early Life Lead Exposure and DNA Methylation: Birth through Adolescence

Abstract

Epigenetic modification is a plausible mechanism linking early life exposures to adult disease susceptibility. Evidence suggests lead (Pb) exposure during sensitive periods in child development may modify the epigenome. We assessed whether early life Pb exposures altered DNA methylation levels (globally at repetitive elements and at candidate genes) in blood samples at birth and peripuberty and evaluated epigenetic drift between these two life stages. Mothers were recruited during pregnancy and children followed for 7-15 years. Exposures were estimated at three time points: 1) prenatal (average of trimester-specific maternal blood Pb levels), 2) birth (cord blood Pb), and 3) early childhood (average of multiple child blood Pb, sampled 3-48 months). DNA was isolated and bisulfite converted from peripubertal blood leukocytes and cord blood samples (n=79). Percent methylation was quantified via bisulfite sequencing at long interspersed nuclear elements (LINE-1) and growth-related genes (HSD11B2, IGF2, H19). Multivariable linear regression was used to evaluate the influence of Pb exposures on DNA methylation and epigenetic drift (peripubertal minus cord blood DNA methylation) adjusting for sex and age (when applicable). Prenatal and/or cord blood Pb were associated with higher LINE-1 and HSD11B2 methylation at birth (p<0.05). Each µg/dL of mean blood Pb 3-48 months was associated with a 0.2% decrease in peripubertal DNA methylation of HSD11B2 (p=0.01). Hypomethylation of H19 and hypermethylation of IGF2 occurred between birth and peri-puberty over time regardless of Pb exposure (p<0.05). Epigenetic drift was significantly altered by Pb exposure at LINE-1 and HSD11B2. Results suggest early life Pb exposure modifies DNA methylation at birth and impacts epigenetic drift from birth to peri-puberty. Future work will examine DNA methylation change as a mediator of Pb-induced impacts on childhood growth.