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.

Public Health Relevance

Paraoxonase (PON1) has been linked to changes in neurodevelopment in children as well as other adverse health outcomes in adults. For the first time, we propose to study the role of genetic and novel epigenetic factors on PON1 in relation to attention, motor function, and cognition in Mexican-American children. This proposed interdisciplinary study will provide new insight on the molecular mechanisms affecting susceptibility to impaired neurodevelopment in a well characterized minority birth cohort and beyond neurodevelopment will inform studies of other PON1 related conditions with high public health significance such as heart disease and obesity.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project (R01)
Project #
Application #
Study Section
Neurological, Aging and Musculoskeletal Epidemiology Study Section (NAME)
Program Officer
Gray, Kimberly A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Berkeley
Public Health & Prev Medicine
Schools of Public Health
United States
Zip Code
Tindula, Gwen; Murphy, Susan K; Grenier, Carole et al. (2018) DNA methylation of imprinted genes in Mexican-American newborn children with prenatal phthalate exposure. Epigenomics 10:1011-1026
Felix, Janine F; Joubert, Bonnie R; Baccarelli, Andrea A et al. (2018) Cohort Profile: Pregnancy And Childhood Epigenetics (PACE) Consortium. Int J Epidemiol 47:22-23u
Huen, Karen; Solomon, Olivia; Kogut, Katherine et al. (2018) PON1 DNA methylation and neurobehavior in Mexican-American children with prenatal organophosphate exposure. Environ Int 121:31-40
Holland, Nina (2017) Future of environmental research in the age of epigenomics and exposomics. Rev Environ Health 32:45-54
Solomon, Olivia; Yousefi, Paul; Huen, Karen et al. (2017) Prenatal phthalate exposure and altered patterns of DNA methylation in cord blood. Environ Mol Mutagen 58:398-410
Volberg, Vitaly; Yousefi, Paul; Huen, Karen et al. (2017) CpG Methylation across the adipogenic PPAR? gene and its relationship with birthweight and child BMI at 9 years. BMC Med Genet 18:7
Rahmani, Elior; Shenhav, Liat; Schweiger, Regev et al. (2017) Genome-wide methylation data mirror ancestry information. Epigenetics Chromatin 10:1
Breton, Carrie V; Marsit, Carmen J; Faustman, Elaine et al. (2017) Small-Magnitude Effect Sizes in Epigenetic End Points are Important in Children's Environmental Health Studies: The Children's Environmental Health and Disease Prevention Research Center's Epigenetics Working Group. Environ Health Perspect 125:511-526
Lizarraga, Daneida; Huen, Karen; Combs, Mary et al. (2016) miRNAs differentially expressed by next-generation sequencing in cord blood buffy coat samples of boys and girls. Epigenomics 8:1619-1635
Huen, Karen; Harley, Kim; Kogut, Katherine et al. (2016) DNA methylation of LINE-1 and Alu repetitive elements in relation to sex hormones and pubertal timing in Mexican-American children. Pediatr Res 79:855-62

Showing the most recent 10 out of 16 publications