PON1 as a Predictor of Differential Susceptibility of Children to Organophosphate PesticidesEPA Grant Number: R832734
Title: PON1 as a Predictor of Differential Susceptibility of Children to Organophosphate Pesticides
Investigators: Eskenazi, Brenda , Barr, Dana Boyd , Bradman, Asa , Harley, Kim , Holland, Nina T. , Hubbard, Alan
Institution: University of California - Berkeley
EPA Project Officer: Callan, Richard
Project Period: March 20, 2006 through February 28, 2009 (Extended to February 28, 2011)
Project Amount: $749,987
RFA: Early Indicators of Environmentally Induced Disease (2004) RFA Text | Recipients Lists
Research Category: Health Effects , Human Health , Health
Recent studies demonstrate widespread pesticide exposures to pregnant women and children in the US. However, given the same level of pesticide exposure, some individuals may be more susceptible to the potential adverse effects of pesticides depending on their genetic makeup and expression of genes encoding key metabolic enzymes. For example, the human enzyme paraoxonase (PON1) detoxifies various organophosphate (OP) pesticides with different efficiency depending on the main single nucleotide polymorphism (SNP) at position 192 and other SNPs along promoter and coding regions. PON1 activity is very low in newborns, with the lowest levels in children with vulnerable genotypes. Thus, PON1 genotype/activity may be a marker for the differential susceptibility of children to OP exposures and their later adverse neurodevelopment.
The CHAMACOS Study is a longitudinal birth cohort study of children living in the agricultural community of the Salinas Valley, CA. and is the keystone project of the US EPA/NIEHS Center for Children’s Environmental Health Research at UC Berkeley. Initial data suggest OP exposure in this primarily Latino farmworker cohort at levels that exceed national reference data. We have collected extensive information about this population, including data on chemical exposures beyond Ops (non-persistent endocrine disrupting pesticides, organochlorines, PCB’s, PBDE), physical environment (housing quality), diet, and their psychosocial milieu (social support, depression, household structure, socioeconomic status, neighborhood characteristics, etc). For this study, we propose to investigate the role of PON1 in determining susceptible subpopulations while accounting for the complex environment that people live in. This proposal takes advantage of the existing CHAMACOS biorepository and extensive longitudinal data on children’s neurodevelopment and OP exposure. We have also completed preliminary PON1 genotyping of approximately 130 maternal and cord blood samples.
- To determine PON1 genotype for two polymorphisms (192 and –108) and measure enzyme activity levels (paraoxonase, diazoxonase, chlorpyrifos oxonase, and arylesterase) from cord and child blood for approximately 325 CHAMACOS children.
- To examine the relationship of PON1 genotype/activity on their neurodevelopment.
- To determine whether PON1 genotype/activity modifies the potential adverse effects on neurodevelopment of in utero and childhood OP exposure as measured in blood samples.
We propose to measure PON1 activity and determine the PON1 polymorphisms for 192 and -108 in all CHAMACOS children who are followed to age 5 years (n=325). Neurodevelopmental assessments of children in this cohort are currently being conducted on the children at age 5 years using a test battery that assesses cognition (verbal and visuo-spatial), language, memory, attention, school readiness, and fine and gross motor skills. Pesticide exposure has been determined by measuring levels of dialkyl phosphate metabolites in maternal urine during pregnancy and in child urine at 6 months and 1, 2, 3.5 and, currently, 5 years of age. Pesticide parent compounds will also be measured in plasma derived from blood samples collected from the cord and from the child at age 5 years.
This research will determine whether PON1 genotype/activity is associated with differential susceptibility to the adverse effects of pesticide exposure in children. It will also inform future policy decisions regarding allowable pesticide exposure to children and pregnant women necessary for the implementation of the Food Quality Protection Act of 1996.