Maternal blood lead concentrations, DNA methylation of MEG3 DMR regulating the DLK1/MEG3 imprinted domain and early growth in a multiethnic cohort

Prenatal exposure to lead (Pb) is known to decrease fetal growth; but its effects on postnatal growth and mechanistic insights linking Pb to growth are not clearly defined. Genomically imprinted genes are powerful regulators of growth and energy utilization, and may be particularly vulnerable to environmental Pb exposure. Because imprinting is established early and maintained via DNA methylation, we hypothesized that prenatal Pb exposure alters DNA methylation of imprinted genes resulting in lower birth weight and rapid growth. Pb was measured by inductively coupled plasma mass spectrometry (ICP-MS) in peripheral blood of 321 women of the Newborn Epigenetic STudy (NEST) obtained at gestation ~12 weeks. Linear and logistic regression models were used to evaluate associations between maternal Pb levels, methylation of differentially methylated regions (DMRs) regulating H19, MEG3, PEG3, and PLAGL1, measured by pyrosequencing, birth weight, and weight-for-height z score gains between birth and age 1yr, ages 1-2yrs, and 2-3yrs. Children born to women with Pb levels in the upper tertile had higher methylation of the regulatory region of the MEG3 DMR imprinted domain (β= 1.57, se= 0.82, p= 0.06). Pb levels were also associated with lower birth weight (β= -0.41, se= 0.15, p= 0.01) and rapid gains in adiposity (OR= 12.32, 95%CI=1.25-121.30, p= 0.03) by age 2-3 years. These data provide early human evidence for Pb associations with hypermethylation at the MEG3 DMR regulatory region and rapid adiposity gain-a risk factor for childhood obesity and cardiometabolic diseases in adulthood.