Grantee Research Project Results

2007 Progress Report: PON1 as a Predictor of Differential Susceptibility of Children to Organophosphate Pesticides

EPA Grant Number: R832734
Title: PON1 as a Predictor of Differential Susceptibility of Children to Organophosphate Pesticides
Investigators: Eskenazi, Brenda , Barr, Dana Boyd , Holland, Nina T. , Hubbard, Alan , Bradman, Asa , Harley, Kim
Current Investigators: Eskenazi, Brenda , Barr, Dana Boyd , Bradman, Asa , Holland, Nina T. , Harley, Kim , 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 Period Covered by this Report: March 20, 2007 through March 19,2008
Project Amount: $749,987
RFA: Early Indicators of Environmentally Induced Disease (2004) RFA Text | Recipients Lists
Research Category: Children's Health , Chemical Safety for Sustainability

Objective:

There has been no change to the specific aims of this study, which are as follows:

1. To determine PON1 genotype and enzyme activity levels in a cohort of 5-year-old Mexican-American children.

2. To determine whether PON1 activity and genotype are associated with child neurodevelopment.

3. To determine whether PON1 genotype/activity modifies the relationship of OP exposure and neurodevelopment.

Progress Summary:

This study examines genetic susceptibility to organophosphate (OP) pesticides among children living in an agricultural community. We have previously reported that OP pesticide exposure in this population is associated with poorer neurodevelopment in children. However, individual susceptibility to the adverse effects of OPs may differ according to the genetic expression of enzymes that detoxify OPs. Single nucleotide polymorphisms (SNPs) in the PON1 gene affect the expression of the enzyme paraoxonase, which appears to be involved in OP metabolism and detoxification. In particular, SNPs at position -192 of the coding region and position -108 in the promoter region of the gene may affect paraxonase levels and activity and may make some individuals more sensitive to the adverse effects of OPs.

A number of goals were accomplished in the past year, including the following.

Genotyping of PON₁₉₂ and PON₁₀₈ was completed for 325 5-year-olds.
Measurement of substrate-specific PON1 enzymes (paraoxonase, arylesterase, chlorpyrifos oxonase, and diazoxonase) was completed for 215 5-year-olds.
PON1 enzyme activities of 5-year-olds was found to be lower than that of their mothers, suggesting that at 5 years of age children still have lower PON1 status than adults, contributing to increased vulnerability to the adverse effects of OP pesticide exposure at this age.
Neurodevelopmental assessments of 328 5-year-olds were entered into our database and the data were cleaned, and we began preliminary analyses of these data.
Children with the most susceptible PON₁₀₈ genotype (TT genotype, indicating lower paraoxonase levels) were found to have poorer mental development as measured by the Bayley Scales of Infant Development at age 2 years than children with the more protective wildtype (CC) genotype.
Children whose mothers had the PON₁₀₈ TT genotype also had significantly lower mental development at age 2. These findings were presented at the International Society of Environmental Epidemiology in September, 2007.
These findings suggest that some children may be genetically more susceptible to the neurotoxic effects of OP pesticides.
The CDC Division of Laboratory Sciences completed a pilot study of parent OP pesticide compounds in CHAMACOS cord blood samples and is continuing with additional analyses.

Future Activities:

Submit a manuscript for publication describing the ontogeny of PON1 activity.
Complete analyses of the association of PON1 genotype and activity with neurodevelopment at 5 years of age. We will present these findings at conferences and prepare a manuscript for publication in the fall.
Complete analysis of child blood for OP pesticides.
Analyze whether PON1 genotype and activity modify the effect of OP pesticides on neurodevelopment.

Journal Articles on this Report : 4 Displayed | Download in RIS Format

Publications Views
Other project views:	All 91 publications	22 publications in selected types	All 22 journal articles

Publications
Type	Citation	Project	Document Sources
Journal Article	Eskenazi B, Rosas LG, Marks AR, Bradman A, Harley K, Holland N, Johnson C, Fenster L, Barr DB. Pesticide toxicity and the developing brain. Basic & Clinical Pharmacology & Toxicology 2008;102(2):228-236.	R832734 (2007) R832734 (Final) R831710 (2005) R831710 (Final)	Abstract from PubMed Full-text: Wiley Online-Full Text HTML Exit Abstract: Wiley Online-Abstract Exit Other: Wiley Online-Full Text PDF Exit
Journal Article	Holland N, Furlong C, Bastaki M, Richter R, Bradman A, Huen K, Beckman K, Eskenazi B. Paraoxonase polymorphisms, haplotypes, and enzyme activity in Latino mothers and newborns. Environmental Health Perspectives 2006;114(7):985-991.	R832734 (2006) R832734 (2007) R832734 (Final) R831709 (2005) R831709 (2006) R831709 (2007) R831709 (Final) R831709C002 (2006) R831710 (2004) R831710 (2005) R831710 (Final) R831710C001 (2007) R831710C003 (2006)	Full-text from PubMed Abstract from PubMed Associated PubMed link
Journal Article	Neri M, Bonassi S, Knudsen LE, Sram RJ, Holland N, Ugolini D, Merlo DF. Children’s exposure to environmental pollutants and biomarkers of genetic damage:I. Overview and critical issues. Mutation Research-Reviews in Mutation Research 2006;612(1):1-13.	R832734 (2006) R832734 (2007) R832734 (Final) R831710 (Final) R831710C003 (2006)	Abstract from PubMed Full-text: ScienceDirect-Full Text HTML Exit Abstract: ScienceDirect-Abstract Exit Other: ScienceDirect-Full Text PDF Exit
Journal Article	Vose SC, Holland NT, Eskenazi B, Casida JE. Lysophosphatidylcholine hydrolases of human erythrocytes, lymphocytes, and brain:sensitive targets of conserved specificity for organophosphorus delayed neurotoxicants. Toxicology and Applied Pharmacology 2007;224(1):98-104.	R832734 (2007) R832734 (Final) R831710 (2005) R831710 (Final)	Full-text from PubMed Abstract from PubMed Associated PubMed link Full-text: ScienceDirect-Full Text HTML Exit Abstract: ScienceDirect-Abstract Exit Other: ScienceDirect-Full Text PDF Exit

Supplemental Keywords:

Health effects, children, susceptibility, enzyme, genetic predisposition, genetic polymorphisms, pesticides, organophosphates, neurodevelopment, paraoxonase, arylesterase, PON1, RFA, Health, Scientific Discipline, INTERNATIONAL COOPERATION, ENVIRONMENTAL MANAGEMENT, Genetics, Health Risk Assessment, Biochemistry, Children's Health, Environmental Policy, Risk Assessment, farmworkers, pesticide exposure, developmental neurotoxicity, gene-environment interaction, Human Health Risk Assessment, human enzyme paraoxonase, assessment of exposure, children's vulnerablity, genetic polymorphisms, susceptibility, developmental disorders

Relevant Websites:

http://www.chamacos.org

http://ehs.sph.berkeley.edu/Holland/Genomics/genomics.html

Progress and Final Reports:

Original Abstract

The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.