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Extramural Research

2005 Progress Report: Genetic Susceptibility to Pesticides

EPA Grant Number: R831709C002
Subproject: this is subproject number 002 , established and managed by the Center Director under grant R831709
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).

Center: University of Washington Center for Child Environmental Health Risks Research
Center Director: Faustman, Elaine
Title: Genetic Susceptibility to Pesticides
Investigators: Faustman, Elaine
Institution: University of Washington
EPA Project Officer: Callan, Richard
Project Period: November 1, 2003 through October 31, 2008 (Extended to October 31, 2010)
Project Period Covered by this Report: November 1, 2004 through October 31, 2005
RFA: Centers for Children's Environmental Health and Disease Prevention Research (2003)
Research Category: Children's Health , Health Effects

Description:

Objective:

The objective of this research project is to identify susceptibility factors for developmental neurotoxicity of pesticides, including genetic polymorphisms.

Progress Summary:

During the reporting period, we completed our studies on histopathological changes in the neocortex of mice following postnatal exposure to chlorpyrifos-oxon (CPO).  In paraoxonase (PON1)-knockout mice exposed to 0.18 or 0.25 mg/kg/day CPO from postnatal day (PND) 4 to 21, we had observed histopathology in the neocortex, characterized by perinuclear vacuolization and alteration of the endoplasmic reticulum.  We followed up on this observation by exposing hPON1Q192 and hPON1R192 transgenic mice to CPO at the same dosage levels, and assessing neuropathology at PND 13, 22, and 90.  As we had hypothesized, changes in the transgenic animals exposed to CPO were less severe than those observed in PON1-knockout mice, and hPON1Q192 mice were more sensitive than hPON1R192 mice (Table 1).

Table 1.  Perinuclear Vacuoles in Neocortex of PON1 Mice Exposed to CPO During Postnatal Development

Table 1.  Perinuclear Vacuoles in Neocortex of PON1 Mice Exposed to CPO During Postnatal Development

 

We are nearing completion of studies of acute organophosphorus pesticide (OP) toxicity in developing hPON1Q192 and hPON1R192 mice.  These studies involved a single subcutaneous injection of CPO followed by measurement of acetylcholinesterase activity in the brain, diaphragm, and plasma.  Dose-response curves have been completed for CPO and chlorpyrifos (CPS) at PND 13, 21, and 40.  Currently, we are repeating the CPO dose-response curve at PND 4 and beginning experiments with diazinon (DZ) and diazoxon (DZO).  

Significance

A potentially important finding is the presence of histopathological changes in the neocortex of mice following postnatal exposure to CPO, with greater protection afforded by hPON1R192 compared to hPON1Q192.

Future Activities:

In the next year, we will continue our studies assessing the possible presence of apoptotic changes in CPO-treated mice, using caspase staining.  The observed changes are suggestive of abnormal apoptosis in specific brain regions following developmental CPO exposure.  Our neurobehavioral studies in the previous reporting period had revealed no behavioral changes following chronic CPO exposure.  In the next year, we will test CPO-exposed mice in an open field/emergence/novel object test designed to measure complex behavior and memory.  There is some suggestion from the literature that these behaviors may be more likely to be affected by OP exposure.  We will finish the studies of acute CPO and CPS exposure in developing mice and focus on the effects of DZ and DZO exposures.


Journal Articles on this Report : 2 Displayed | Download in RIS Format

Other subproject views: All 32 publications 29 publications in selected types All 19 journal articles
Other center views: All 175 publications 127 publications in selected types All 107 journal articles

Type Citation Sub Project Document Sources
Journal Article Cole TB, Walter BJ, Shih DM, Tward AD, Lusis AJ, Timchalk C, Richter RJ, Costa LG, Furlong CE. Toxicity of chlorpyrifos and chlorpyrifos oxon in a transgenic mouse model of the human paraoxonase (PON1) Q192R polymorphism. Pharmacogenetics and Genomics 2005;15(8):589-598. R831709 (2005)
R831709C002 (2005)
  • Abstract from PubMed
  • Abstract: Pharmacogenetics and Genomics-Abstract
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  • Journal Article Furlong CE, Cole TB, Walter BJ, Shih DM, Tward A, Lusis AJ, Timchalk C, Richter RJ, Costa LG. Paraoxonase 1 (PON1) status and risk of insecticide exposure. Journal of Biochemical and Molecular Toxicology 2005;19(3):182-183. R831709 (2005)
    R831709 (2007)
    R831709C002 (2005)
  • Abstract from PubMed
  • Abstract:
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  • Supplemental Keywords:

    children’s health, epidemiology, genetics, health risk assessment, risk assessment, assessment of exposure, asthma, children’s environmental health, diesel exhaust, environmental risks, exposure assessment, genetic mechanisms, genetic risk factors, genetic susceptibility, maternal exposure, nutritional risk factors,, RFA, Health, Scientific Discipline, ENVIRONMENTAL MANAGEMENT, Health Risk Assessment, Biochemistry, Children's Health, Risk Assessment, health effects, pesticide exposure, environmental health, community-based intervention, developmental neurotoxicity, environmental risks, biological response, Human Health Risk Assessment, genetic polymorphisms, children's vulnerablity, assessment of exposure

    Relevant Websites:

    http://depts.washington.edu/chc Exit

    Progress and Final Reports:
    Original Abstract
    2004 Progress Report
    2006 Progress Report
    2007 Progress Report


    Main Center Abstract and Reports:
    R831709    University of Washington Center for Child Environmental Health Risks Research

    Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
    R831709C001 Molecular Mechanisms of Pesticide-Induced Developmental Toxicity
    R831709C002 Genetic Susceptibility to Pesticides
    R831709C003 Community-Based Participatory Research Project
    R831709C004 Pesticide Exposure Pathways Research Project

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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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