2005 Progress Report: Genetic Susceptibility to PesticidesEPA 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) RFA Text | Recipients Lists
Research Category: Children's Health , Health Effects , Health
The objective of this research project is to identify susceptibility factors for developmental neurotoxicity of pesticides, including genetic polymorphisms.
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
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).
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.
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|
||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.||
||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.||
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, environmental health, health effects, pesticide exposure, community-based intervention, developmental neurotoxicity, biological response, environmental risks, Human Health Risk Assessment, assessment of exposure, children's vulnerablity, genetic polymorphisms
Progress and Final Reports:Original Abstract
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