Abstract
Gestational lead (Pb) exposure may adversely impact offspring health through epigenetic alterations via DNA methylation (5mC), addition of a methyl group to the 5th carbon of cytosine, and hydroxymethylation (5hmC), an intermediate in oxidative demethylation associated with increased gene expression. Most current methods collectively measure 5mC and 5hmC without distinguishing between the two. This study aims to identify the association of prenatal Pb exposure at each trimester (T1, T2, T3) with 5mC and 5hmC levels at multiple cytosine-phosphate-guanine (CpG) sites within candidate regions of genes previously associated with prenatal Pb exposure (HCN2, NINJ2, RAB5A, and TPPP) in blood leukocytes of children ages 11-18 years. Participants from the Early Life Exposure in Mexico to Environmental Toxicants (ELEMENT) birth cohorts were selected (n=144) for pyrosequencing analysis following oxidative or standard sodium bisulfite treatment. Participants are 51% male with concurrent blood lead levels (BLL) averaging 3.29±4.44µg/dL and historical maternal BLL averaging 6.43±5.16µg/dL (T1), 5.66±5.21µg/dL (T2), and 5.86±4.34µg/dL (T3). 5mC levels were quantified in HCN2 (mean±SD, 81.3±9.63%), NINJ2 (36.7±22.5%), RAB5A (1.40±1.20%), and TPPP (92.5±8.03%). 5hmC levels were estimated in HCN2 (2.04±4.30%), NINJ2 (2.15±5.43%), RAB5A (0.64±0.80%), and TPPP (0.45±8.01%), providing evidence for 5hmC presence in blood leukocytes. Controlling for sex, current BLL, child’s age, and pyrosequencing batch, T1 maternal BLL was associated with 5mC in HCN2 (β=-1.256, p=0.019) and NINJ2 (β=0.426, p=0.004); T2 BLL with 5mC in HCN2 (β=0.368, p=0.028) and 5hmC in NINJ2 (β=0.232, p=0.011); and T3 BLL with 5mC in HCN2 (β=0.502, p=0.016) and 5hmC in NINJ2 (β=0.372, p=0.001). No associations were identified between Pb and RAB5A and TPPP. Together, these data suggest that perinatal Pb exposure results may alter 5mC and 5hmC in blood in a gene-specific manner that persists into adolescence.
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