Grantee Research Project Results

2006 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: 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, 2005 through October 31,2006
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:

One of the primary aims of this project in the past year was to determine changes in gene expression patterns during brain development in mice exposed to chlorpyrifos oxon (CPO) throughout early postnatal development, and to determine the role of the human PON1_Q192R polymorphism in modulating gene expression changes related to CPO exposure. During the reporting period we completed data collection for our studies on the toxicogenomics of CPO exposure during postnatal development, and we are analyzing the data and confirming specific changes in gene expression by RT-PCR. In addition, we have published several papers on the importance of PON1 status as a predictor of OP pesticide sensitivity in a cohort of Latina mothers and newborns, in collaboration with the UC Berkeley Child Health Center. We have also made significant contributions to a first-of-its-kind textbook on Gene-Environment interactions and the field of ecogenetics, which was published in the last year with Dr. Costa as one of the two editors.

The collaboration between the UW CHC and the UC Berkeley CHAMACOS project has been fruitful in the last year, resulting in two new publications and a related publication. These studies examined OP insecticide sensitivity in a cohort of Latina mothers and newborns in the Salinas Valley, CA. In 2004, we had demonstrated an association between in utero OP pesticide exposure and fetal growth and length of gestation (Eskenazi et al., 2004). In the past year we followed up on this observation by examining PON1 status and specific PON1 haplotypes as predictors of OP insecticide sensitivity in this cohort (Furlong CE et al., 2006; Holland N et al., 2006). These studies in humans, together with work done in our laboratory on humanized transgenic mice, allowed us to establish a predicted range of variability in sensitivity to the OP compounds chlorpyrifos oxon (131 to 164-fold) and diazinoxon (65-fold). PON1 levels varied by 26-fold among newborns and by 14-fold among mothers, with newborns’ PON1 levels being 4-fold lower on average than those of the mothers. These findings indicated that many of the newborns and some of the mothers in this cohort would be particularly susceptible to the adverse effects of OP pesticide exposure. In a related study of this same cohort (Young et al., 2006), we demonstrated a significant association between in utero OP pesticide exposure and neurobehavioral functioning in neonates.

The experiments examining gene expression changes in the brain following chronic postnatal exposure to CPO have been completed, using both Agilent and Affymetrix microarrays. Gene expression profiles were examined following chronic postnatal (PN4-21) exposure of PON1 knockout mice, hPON1Q192 mice, and hPON1R192 mice to CPO, allowing for comparison between mice that lack PON1 and mice that express either of the two most relevant human alloforms of PON1. Other endpoints were also examined, as described previously. As discussed for the previous reporting period, the experiments with the PON1 knockout mice had to be repeated due to differences in RNA quality between these mice and the transgenic mice. These experiments have been completed. All RNA samples have now been processed in an identical manner at the same facility, and the new data from both Affymetrix and Agilent microarrays is being analyzed in conjunction with Rosetta Inpharmatics. As with other endpoints following postnatal exposure to CPO, gene expression changes in the transgenic animals exposed to CPO were less severe than those observed in PON1-knockout mice, and hPON1Q192 mice were significantly more sensitive than hPON1R192 mice. Thus, multiple endpoints point to increased OP sensitivity of individuals carrying the Q192 alloform of PON1.

SIGNIFICANCE: These studies are providing information on the genomic consequences of OP exposure, and on the role of the human PON1₁₉₂ isoforms in modulating these consequences. The establishment of a predicted range of variability in sensitivity to OP pesticides in mothers and newborns is of great significance, and together with our related studies indicates that PON1 status plays an important role in determining sensitivity to the OP pesticides chlorpyrifos and diazinon. These results are relevant to OP sensitivity in humans, since half of the human population has the Q192 allele.

Future Activities:

In the next year we will complete our data analysis of the effects of CPO on gene expression in the brain, and confirm changes in the expression of specific genes, using quantitative RT-PCR on independently-generated samples that we already have in hand. Of particular interest are modulators of glutamatergic and GABAergic neurotransmission, proteins involved in protection against oxidative damage, and components of the mitochondrial respiratory chain, all of which appear to be affected in the Q192 transgenic mice. Data analysis will include correlating PON1 levels in the plasma of individual mice with effects on changes in gene expression, with the hypothesis that higher levels of PON1 will be more protective against the effects of CPO. We will be able to compare results on the two platforms and also to determine the inter-individual variability within pools, by assessing gene expression patterns in individual animals exposed to CPO. We will continue the collaborative efforts with the UC Berkeley group by examining whether PON Status is associated with the developmental effects of OP pesticide exposure during gestation.

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

Publications Views
Other subproject views:	All 32 publications	29 publications in selected types	All 19 journal articles
Other center views:	All 333 publications	157 publications in selected types	All 133 journal articles

Publications
Type	Citation	Sub Project	Document Sources
Journal Article	Furlong CE, Holland N, Richter RJ, Bradman A, Ho A, Eskenazi B. PON1 status of farmworker mothers and children as a predictor of organophosphate sensitivity. Pharmacogenetics and Genomics 2006;16(3):183-190.	R831709 (2005) R831709 (2006) R831709 (2007) R831709 (Final) R831709C002 (2006) R831710 (2004) R831710 (2005) R831710 (Final) R831710C001 (2007) R831710C003 (2006) R831710C003 (2007)	Abstract from PubMed Abstract: Pharmacogenetics and Genomics-Abstract Exit Other: National Center for Farmworker Health-Full Text PDF Exit
Journal Article	Guizzetti M, Pathak S, Giordano G, Costa LG. Effect of organophosphorus insecticides and their metabolites on astroglial cell proliferation. Toxicology 2005;215(3):182-190.	R831709 (2005) R831709 (2006) R831709 (2007) R831709 (Final) R831709C001 (2005) R831709C001 (2006) R831709C002 (2006)	Abstract from PubMed Full-text: Science Direct-Full Text HTML Exit Abstract: Science Direct-Abstract Exit Other: Science Direct- 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.	R831709 (2005) R831709 (2006) R831709 (2007) R831709 (Final) R831709C002 (2006) R831710 (2004) R831710 (2005) R831710 (Final) R831710C001 (2007) R831710C003 (2006) R832734 (2006) R832734 (2007) R832734 (Final)	Full-text from PubMed Abstract from PubMed Associated PubMed link
Journal Article	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) R831709 (Final) R831709C002 (2004) R831709C002 (2006) R831710 (2004) R831710 (2005) R831710 (Final)	Abstract from PubMed Full-text: ScienceDirect-Full Text HTML Exit Abstract: ScienceDirect-Abstract Exit Other: ScienceDirect-Full Text PDF Exit

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, Environmental Management, Scientific Discipline, Health, RFA, Risk Assessment, Health Risk Assessment, Children's Health, Biochemistry, Environmental Chemistry, health effects, children's environmental health, assessment of exposure, developmental neurotoxicity, agricultural community, community-based intervention, pesticide exposure, genetic polymorphisms, biological response, environmental health, environmental risks, children's vulnerability
, 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 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

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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.