Genetic and Epigenetic Mechanisms of Susceptibility to Exposures in Children

Children are more susceptible to exposures to environmental toxicants than adults, and in utero exposures may result in developmental problems and chronic diseases. Some children can be particularly vulnerable due to their genetic makeup which can affect their bodies’ abilities to detoxify pesticides and other environmental chemicals.  Epigenetic changes, particularly DNA methylation, play a significant role in the mediation of the effects of environmental exposure on human health and are hypothesized to be major contributing factors to the early-life origins of adult disease.  Results from the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) birth cohort study will be presented to illustrate complex relationships of the effects of prenatal exposure to pesticides and other environmental toxicants with genetic and epigenetic factors on children’s health.  The CHAMACOS longitudinal birth cohort study (N=601) investigates exposure to pesticides in low-income Mexican-American farmworker families; mothers and their children were followed from early pregnancy to 9 years of age. We have previously found that trans-placental exposures to several of these pollutants are associated with adverse birth outcomes including shorter gestational duration as well as abnormal reflexes in children at different ages, higher risk of attention disorders, and decreased IQ at age 7.  Paraoxonase 1 (PON1), which can detoxify OPs, provides an example of a metabolic enzyme whose broad variability within populations may confer differential susceptibility to environmental exposures.  Someone with low PON1 levels may be less protected from OP exposures than people with higher PON1 levels. We determined PON1 genotypes and three PON1 enzyme activities in more than 450 mothers and their children from pregnancy through age 9 and found that both age and genetics were strong determinants of PON1 variability and thus susceptibility to pesticides.  We also used cutting edge technology including lllumina 450K BeadChip arrays and pyrosequencing to investigate global and site-specific DNA methylation in CHAMACOS children.  Unlike genetics, epigenetic mechanisms can be reversible and an enhanced understanding of their role may lead to better protection of pregnant women and children, and improved public health.