PON Epigenetics and Neurodevelopment in Children

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DESCRIPTION (provided by applicant): Neurobehavior and cognition in children are affected by hereditary, environmental and social factors, but the molecular mechanisms remain largely unknown, prompting the study of the potential role of epigenetic dysregulation. Epigenetic mechanisms control gene expression without changes in DNA sequence, and DNA methylation and non-coding RNAs are two important types of epigenetic modifications. Recent studies have demonstrated associations between the multifunctional antioxidant enzyme paraoxonase (PON1) and poor neurodevelopment and adverse health outcomes in children. We previously characterized PON1 functional genomics in Mexican-American children and their mothers from the CHAMACOS study, and found a greater than 100-fold range of PON1 enzyme activities defined in part by age and genotype. Although genetics influence 25% of PON1 expression, a large portion of PON1 variability remains unexplained suggesting a role for other factors such as epigenetics. In fact, some studies have shown that epigenetic dysregulation can affect neurodevelopment and cognitive processes such as learning, memory, and neurogenesis. Among CHAMACOS children, PON1 genotype and enzyme levels were associated with changes in behavior and learning at age 2 and lower IQ scores (measure of cognitive abilities) at age 7. While no studies on the role of PON1 epigenetics on gene expression and poor cognition have been reported, our preliminary data show that DNA methylation in PON1 is strongly associated with PON1 enzyme levels. We hypothesize that epigenetic mechanisms significantly contribute to the broad variability in PON1 enzyme levels and poor neurodevelopment in children. The proposed study will take advantage of the well characterized data on PON1 genetics, rich collection of biological samples and neurobehavioral data already amassed through the CHAMACOS study. Our specific aims are to (1) determine the relationship between maternal PON1 DNA methylation profiles during pregnancy with those of their children at birth and age 7; (2) characterize expression of miRNAs that bind to PON1; (3) examine the relationship between epigenetic marks and PON1 expression; and (4) establish the effect of PON1 epigenetics on attention, motor function, and cognition in 7 year olds. The total sample size will be 315 mother-child pairs with complete neurodevelopment assessment, PON1 genetic and enzyme level data, and biological samples for all proposed analyses. This work will serve as model for studies of candidate susceptibility genes and will address several key knowledge gaps in environmental molecular epidemiology. Understanding how epigenetic mechanisms affect child neurodevelopment and PON1 variability in pregnant women and children will help to identify vulnerable sub populations. Environmental exposures can result in epigenetic alterations, thus characterization of the relationship between epigenetics and disease will establish the foundation necessary for examining mediation of gene environment interactions by epigenetics.