Influence of Prenatal Lead Exposure on Genomic Methylation of Cord Blood DNA

J. Richard Pilsner, Howard Hu, Adrienne Ettinger, Brisa N. Sanchez, Robert O. Wright, David Cantonwine, Alicia Lazarus, Hector Lamadrid-Figueroa, Adriana Mercado-Garcia, Martha Maria Tellez-Rojo, and Mauricio Hernandez-Avila

Background: Fetal lead exposure is associated with adverse pregnancy outcomes and developmen- tal and cognitive deficits; however, the mechanism(s) by which lead-induced toxicity occurs remains unknown. Epigenetic fetal programming via DNA methylation may provide a pathway by which environmental lead exposure can influence disease susceptibility.

Objective: This study was designed to determine whether prenatal lead exposure is associated with alterations in genomic methylation of leukocyte DNA levels from umbilical cord samples.

Methods: We measured genomic DNA methylation, as assessed by Alu and LINE-1 (long interspersed nuclear element-1) methylation via pyrosequencing, on 103 umbilical cord blood samples from the biorepository of the Early Life Exposures in Mexico to Environmental Toxicants (ELEMENT) study group. Prenatal lead exposure had been assessed by measuring maternal bone lead levels at the mid-tibial shaft and the patella using a spot-source 109Cd K-shell X-ray fluores- cence instrument.

Results: We found an inverse dose–response relationship in which quartiles of patella lead cor- related with cord LINE-1 methylation (p for trend = 0.01) and and tibia lead correlated with Alu methylation (p for trend = 0.05). In mixed effects regression models, maternal tibia lead was nega- tively associated with umbilical cord genomic DNA methylation of Alu (β = –0.027; p = 0.01). We found no associations between cord blood lead and cord genomic DNA methylation.

Conclusions: Prenatal lead exposure is inversely associated with genomic DNA methylation in cord blood. These data suggest that the epigenome of the developing fetus can be influenced by maternal cumulative lead burden, which may influence long-term epigenetic programming and dis- ease susceptibility throughout the life course.

Key Words: blood lead, bone lead, DNA methylation, early life, epigenetics, fetal programming, genomic DNA methylation, intergenerational, lead exposure, life course, Mexico. Environ Health Perspect 117:1466–1471 (2009). doi:10.1289/ehp.0800497 available via [Online 25 March 2009]