Grantee Research Project Results
2004 Progress Report: Genetic Susceptibility to Pesticides
EPA Grant Number: R831709C002Subproject: 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: Center for Air, Climate, and Energy Solutions
Center Director: Robinson, Allen
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, 2003 through October 31, 2004
RFA: Centers for Children's Environmental Health and Disease Prevention Research (2003) RFA Text | Recipients Lists
Research Category: Children's Health , Human Health
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 the neurobehavioral assessment of mice developmentally exposed to chlorpyrifos-oxon (CPO). Paraoxonase (PON1)-knockout mice were treated subcutaneously with CPO (0.15, 0.18, and 0.25 mg/kg) or vehicle from postnatal day (PND) 4 to 21. At these doses, brain acetylcholinesterase (AChE) was inhibited at PND 4 by 10, 20, and 50 percent, respectively. No significant changes in the behavioral parameters assessed (radial arm maze, Morris maze, rotarod, open field, and contextual fear conditioning) were found between controls and CPO-treated animals, although there was an unexpected effect of chronic CPO exposure on the acute sensitivity of mice to CPO.
CPO-treated mice, however, displayed significant histopathological changes in the neocortex. This pathology was observed only in animals treated with 0.18 and 0.25 mg/kg dose regimens and was characterized by perinuclear vacuolization, with alterations of the endoplasmic reticulum. These changes were observed in mice at PND 22 and persisted, though to a lesser degree, in PND 90 animals. There also was a chronic inhibition of cholinesterase activity in the brains of the exposed mice. At doses of CPO too low to inhibit brain cholinesterase in PND 21 mice when administered acutely (0.15, 0.18, and 0.25 mg/kg), chronic CPO exposure resulted in a dose-related depression of the baseline cholinesterase activity in the brains of PON1-knockout mice but not wild-type mice.
Significance
A potentially most important finding is the presence of histopathological changes in the neocortex of mice following postnatal exposure to CPO. The effect appeared to be dose-dependent and persistent into adulthood. This observation will be investigated further in the next year.
Future Activities:
In the next year, we will continue our studies on the observed neuropathological changes seen in PON1-knockout mice exposed to CPO on PND 4 to 21. We will expose wild-type mice to CPO (at the same dosage levels) and will assess neuropathology at PND 22 and 90. Our hypothesis is that changes would be less severe in wild-type animals exposed to CPO than those observed in PON1-knockout mice. We also will assess the possible presence of apoptotic changes in CPO-treated mice by means of caspase staining, as the observed changes are suggestive of abnormal apoptosis in specific brain regions following developmental CPO exposure.
We will initiate studies in developing hPON1Q192 and hPON1R192 mice. These are mice that express either the Q192 or R192 alloform of human PON1 on a knockout background. The initial studies of this research project aim to establish a dosage regiment for CPO and diazoxon (DZO) that will cause a 10, 25, and 40 percent inhibition of brain AChE activity. First, we will carry out dose-response courses for CPO and DZO (single subcutaneous injection) on PND 4, 10, 15, and 21 and will measure AChE activity in the brain, diaphragm, and plasma. We then will select three dose levels for a study involving treatment between PND 4 and 20, to provide the desired degree of brain AChE inhibition.
Journal Articles on this Report : 11 Displayed | Download in RIS Format
| Other subproject views: | All 32 publications | 29 publications in selected types | All 19 journal articles |
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| Other center views: | All 175 publications | 127 publications in selected types | All 107 journal articles |
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Costa LG, Richter RJ, Li W-F, Cole T, Guizzetti M, Furlong CE. Paraoxonase (PON1) as a biomarker of susceptibility for organophosphate toxicity. Biomarkers 2003;8(1):1-12. |
R831709 (2005) R831709 (2007) R831709C002 (2004) R826886 (2000) R826886C002 (2002) |
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Costa LG, Cole TB, Jarvik GP, Furlong CE. Functional genomics of the paraoxonase (PON1) polymorphisms: effects on pesticide sensitivity, cardiovascular disease, and drug metabolism. Annual Review of Medicine 2003;54:371-392. |
R831709 (2005) R831709 (2007) R831709C002 (2004) R826886 (2000) R826886C002 (2002) |
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Costa LG, Cole TB, Furlong CE. Polymorphisms of paraoxonase (PON1) and their significance in clinical toxicology of organophosphates. Clinical Toxicology 2003;41(1):37-45. |
R831709 (2005) R831709 (2007) R831709C002 (2004) |
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Costa LG, Vitalone A, Cole TB, Furlong CE. Modulation of paraoxonase (PON1) activity. Biochemical Pharmacology 2005;69(4):541-550. |
R831709 (2005) R831709 (2007) R831709C002 (2004) |
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Costa LG, Cole TB, Vitalone A, Furlong CE. Measurement of paraoxonase (PON1) status as a potential biomarker of susceptibility to organophosphate toxicity. Clinica Chimica Acta 2005;352(1-2):37-47. |
R831709 (2005) R831709 (2007) R831709C002 (2004) |
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Eskenazi B, Harley K, Bradman A, Weltzien E, Jewell NP, Barr DB, Furlong CE, Holland NT. Association of in utero organophosphate pesticide exposure and fetal growth and length of gestation in an agricultural population. Environmental Health Perspectives 2004;112(10):1116-1124. |
R831709 (2007) R831709C002 (2004) R831710 (2004) R831710 (2005) R831710 (Final) R831710C001 (2004) |
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Furlong CE, Cole TB, Jarvik GP, Pettan-Brewer C, Geiss GK, Richter RJ, Shih DM, Tward AD, Lusis AJ, Costa LG. Role of paraoxonase (PON1) status in pesticide sensitivity:genetic and temporal determinants. Neurotoxicology 2005;26(4):651-659. |
R831709 (2005) R831709 (2007) R831709C002 (2004) |
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Jarvik GP, Jampsa R, Richter RJ, Carlson CS, Rieder MJ, Nickerson DA, Furlong CE. Novel paraoxonase (PON1) nonsense and missense mutations predicted by functional genomic assay of PON1 status. Pharmacogenetics 2003;13(5):291-295. |
R831709 (2005) R831709 (2007) R831709C002 (2004) |
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Kelada SN, Costa-Mallen P, Checkoway H, Viernes HA, Farin FM, Smith-Weller T, Franklin GM, Costa LG, Longstreth Jr WT, Furlong CE, Javrik GP, Swanson PD. Paraoxonase 1 promoter and coding region polymorphisms in Parkinson's disease. Journal of Neurology, Neurosurgery, and Psychiatry 2003;74(4):546-547. |
R831709 (2005) R831709 (2007) R831709C002 (2004) |
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Tiffany-Castiglioni E, Venkratraj V, Qian Y. Genetic polymorphisms and mechanisms of neurotoxicity:overview. Neurotoxicology 2005;26(4):641-649. |
R831709 (2007) R831709C002 (2004) |
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Young JG, Eskenazi B, Gladstone EA, Bradman A, Pedersen L, Johnson C, Barr DB, Furlong CE, Holland NT. Association between in utero organophosphate pesticide exposure and abnormal reflexes in neonates. NeuroToxicology 2005;26(2):199-209. |
R831709 (2005) R831709 (2006) R831709 (2007) R831709C002 (2004) R831709C002 (2006) R831710 (2004) R831710 (2005) R831710 (Final) |
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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 exposureRelevant Websites:
http://depts.washington.edu/chc Exit
Progress and Final Reports:
Original AbstractMain Center Abstract and Reports:
R831709 Center for Air, Climate, and Energy Solutions 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
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.
Project Research Results
19 journal articles for this subproject
Main Center: R831709
175 publications for this center
107 journal articles for this center