Perinatal Lead (Pb) Exposure's Effect on DNA Methylation and Hydroxymethylation and Risk of Adverse Neurodevelopmental Outcomes
Creators: name: Rygiel, Christine
Publisher: name: My University
Year: 2021
Subjects: subject: epigenetics
subject: lead (Pb)
subject: environmental exposure
subject: developmental programming
subject: neurodevelopment
subject: DNA methylation (5mC) and hydroxymethylation (5hmC)
subject: Public Health
subject: Health Sciences

description: The health impacts of prenatal Pb exposure can be framed with the Developmental Origins of Health and Disease (DOHaD) theory, which postulates that exposure to environmental factors (i.e., diet, chemicals, stress, etc.) during sensitive periods of development (i.e., pre-conception, gestation, neonatal, etc.) alters an organism’s molecular biology, physiology, and metabolism, potentially leading to myriad effects on cognition, growth, and maturation. Around the world, exposure to lead (Pb) continues to be a persistent problem. A particularly vulnerable population includes pregnant women, where Pb from both current and past exposures can affect their developing fetuses. Disruptions in normal epigenetic processes during gestation impact gene regulation and subsequent outcomes. Accumulating evidence for DOHaD includes potential mechanisms such as epigenetic reprogramming via DNA methylation (5mC) and, less studied, DNA hydroxymethylation (5hmC), linking developmental exposures to later-life outcomes. This dissertation aims to examine whether Pb exposure influences DNA 5mC and 5hmC and susceptibility to early cognitive delays. A human longitudinal cohort, Early Life Exposure in Mexico to Environmental Toxicants (ELEMENT), was used to investigate whether developmental Pb exposure would alter epigenetics at birth and in adolescence, and if these alterations are associated with decreases in neurodevelopmental scores in early infancy. The first aim of this dissertation characterized the association between prenatal Pb exposure measured in maternal blood and bone and CpG site-specific DNA methylation at &gt;750,000 loci at birth in infant umbilical cord blood cells. Linear regression models were used to identify differentially methylated CpG sites by prenatal Pb exposure, using the false discovery rate method to correct for multiple testing. In the second aim, we evaluated both gene-specific DNA 5mC and 5hmC in adolescent whole blood from the same cohort to determine whether the association of prenatal Pb exposure and epigenetics persisted into adolescence and determine if 5hmC is associated with the exposure. Finally, in the third aim we assessed whether DNA methylation at birth mediates the association between prenatal Pb exposure and adverse neurodevelopmental outcomes at 12- and 24-months of age. In Aim 1, we found that trimester-specific developmental Pb exposures were associated with gene-specific DNA methylation changes at birth, and most changes were identified in genes related to neurodevelopment. Next, we showed that some of these Pb-induced DNA methylation changes were stable into adolescence, particularly those associated with first trimester exposure. This potentially suggests that perturbations occurring during the first trimester are reprogramming the epigenome and these changes remain into adolescence. Within Aim 2, we observed widespread, variable 5hmC levels in adolescent whole blood. We also revealed that prenatal Pb exposure has independent associations with both 5mC and 5hmC. These associations were also sex-specific at some loci, indicating a sexually dimorphic effect on the epigenome. Finally, the Aim 3 mediation analysis showed DNA methylation mediated the association between second trimester Pb exposure and cognition scores at 24-months of age at multiple neurodevelopmental measures. Overall, this dissertation illustrates that prenatal exposures to Pb can modulate epigenetics, and this may be one mechanism linking exposure to persistent effects on development and offspring health. Additional studies in larger cohorts or animal studies are needed in order to confirm these findings. These results emphasize the importance of distinguishing between 5mC and 5hmC during epigenetic studies, thus presenting a new conceivable mechanism describing the underlying biology behind the association between exposure and outcome, 5hmC