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Extramural Research

2009 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 , 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 Period Covered by this Report: March 20, 2009 through February 28,2010
Project Amount: $749,987
RFA: Early Indicators of Environmentally Induced Disease (2004)
Research Category: Health Effects , Human Health

Description:

Objective:

There has been no basic change to the specific aims of this study. We proposed to focus on pesticide exposure, PON status assessments, and neurodevelopment analyses on 7-year-old children instead of 5-year-old children. In this report, we outline progress and challenges that we have encountered. Overall, the specific objectives are unchanged from the original proposal, and are:

  • To determine PON1 genotype and enzyme activity levels in a cohort of Mexican-American children.
  • To determine whether PON1 activity and genotype are associated with child neurodevelopment.
  • 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, individuals’ susceptibility to the adverse effects of OPs may differ according to their 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 paraoxonase levels and activity and may make some individuals more sensitive to the adverse effects of OPs.

Accomplishments/Results:

  • We have completed all the laboratory analyses defined in the proposal and have focused on data analysis and manuscript preparation.
  • We have completed genotyping of PON1192 and PON1-108 for 434 children and 431 mothers.
  • We have completed all measurements of substrate-specific PON1 enzyme activity [paraoxonase (POase), arylesterase (ARYase), chlorpyrifos oxonase (CPOase), and diazoxonase DZOase)] at 5 years (N = 225) and 7 years (N = 281)
  • We have published the first longitudinal paper describing the ontogeny of PON1 enzyme activity from birth to 7 years of age (Huen et al, EHP 2009). Although it was previously believed that PON1 activity reached adult levels by age 2 years (based on a study of 9 children), our study of 458 children shows that PON1 activity continues to increase until age 7. Additionally, at age 7, PON1 activity levels of children was still slightly, but significantly, lower than that of their mothers.
  • We first looked at outcomes in 2 year olds. We found that the PON1-108T allele in children was associated with poorer MDI and somewhat poorer Psychomotor Development Index. Children were less likely to display PDD when they or their mothers had higher ARYase and when their mothers had higher POase activities. The association between DAPs and MDI was strongest in children with PON1-108T allele but this and other interactions between DAPS and PON1 polymorphisms or enzymes were not significant.We concluded that PON1 is associated with child neurobehavioral development, but additional research is needed to confirm if it modifies the relation with in utero organophosphate exposure. This analysis has been submitted to Environmental Health Perspectives.
  • We are analyzing the association of PON1 genotype and activity with neurodevelopment at age 5. Our current analyses suggests that the findings among 2 year may persist at older ages.
  • We are examining whether there are interactive effects of PON1 genotype and OP exposure on neurodevelopment at age 5. Because of analytic difficulties with OP measurements in blood, these analyses have thus far focused on urinary dialkyl phosphates (DAPs) as the primary exposure measure.
  • We have completed neurodevelopmental assessments on 329 children at age 7. These data are currently being entered. Future activities will extend the analyses of PON and neurodevelopment at age 5 to include results at age 7.

Future Activities:

  1. Complete the analyses of the association of PON1 genotype and activity with neurodevelopment at 5 and 7 years of age. Submit for publication.
  2. Complete examination of whether PON1 genotype and activity modify the effect of OP pesticides on neurodevelopment. This analysis will utilize OP urinary metabolite measurements as an exposure biomarker. Submit for publication (possibly as one paper with above).
  3. Publish results of parent compound OPs in blood.
  4. If data allow, examine associations of parent compounds in blood with neurodevelopment, including effect modification by PON1 status


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

Other project views: All 90 publications 21 publications in selected types All 21 journal articles

Type Citation Project Document Sources
Journal Article Huen K, Richter R, Furlong C, Eskenazi B, Holland N. Validation of PON1 enzyme activity assays for longitudinal studies. Clinica Chimica Acta 2009;402(1-2):67-74.
abstract available   full text available
R832734 (2009)
R832734 (Final)
R831709 (2007)
R831710 (Final)
R834513 (2010)
R834513 (2011)
  • Full-text from PubMed
  • Abstract from PubMed
  • Associated PubMed link
  • Abstract: Science Direct - Abstract
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  • Journal Article Huen K, Harley K, Brooks J, Hubbard A, Bradman A, Eskenazi B, Holland N. Developmental changes in PON1 enzyme activity in young children and effects of PON1 polymorphisms. Environmental Health Perspectives 2009;117(10):1632-1638.
    abstract available   full text available
    R832734 (2009)
    R832734 (Final)
    R831710 (Final)
    R834513 (2010)
    R834513 (2011)
  • Full-text from PubMed
  • Abstract from PubMed
  • Associated PubMed link
  • Journal Article Huen K, Harley K, Bradman A, Eskenazi B, Holland N. Longitudinal changes in PON1 enzymatic activities in Mexican-American mothers and children with different genotypes and haplotypes. Toxicology and Applied Pharmacology 2010;244(2):181-189.
    abstract available   full text available
    R832734 (2009)
    R832734 (Final)
    R834513 (2010)
    R834513 (2011)
  • 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
  • Journal Article Sly PD Eskenazi B, Pronczuk J, Sram R, Diaz-Barriga F, Machin DG, Carpenter DO, Surdu S, Meslin EM. Ethical issues in measuring biomarkers in children’s environmental health. Environmental Health Perspectives 2009;117(8):1185-1190.
    abstract available   full text available
    R832734 (2009)
    R832734 (Final)
    R831710 (Final)
    R834513 (2010)
    R834513 (2011)
  • Full-text from PubMed
  • Abstract from PubMed
  • Associated PubMed link
  • 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, pesticide exposure, farmworkers, developmental neurotoxicity, gene-environment interaction, Human Health Risk Assessment, human enzyme paraoxonase, susceptibility, genetic polymorphisms, children's vulnerablity, assessment of exposure, developmental disorders

    Relevant Websites:

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

    Progress and Final Reports:
    Original Abstract
    2006 Progress Report
    2007 Progress Report
    Final Report

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    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.

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