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Extramural Research

Genetic Susceptibility

EPA Grant Number: R834514C004
Subproject: this is subproject number 004 , established and managed by the Center Director under grant R834514
(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 (2010)
Center Director: Faustman, Elaine
Title: Genetic Susceptibility
Investigators: Faustman, Elaine
Institution: University of Washington
EPA Project Officer: Callan, Richard
Project Period: October 1, 2010 through September 30, 2015
RFA: Children's Environmental Health and Disease Prevention Research Centers (with NIEHS) (2009)
Research Category: Children's Health



The proposed studies aim to develop high throughput protocols for assessing OP exposures by characterizing specific biomarker proteins in blood, and to make use of these more accurate measures of exposure to investigate gene/environment interactions related to genetic variability in the paraoxonase (PONI) gene, particularly with respect to OP exposures that occur during early development. Specific Aim 1 is to validate high throughput immunomagnetic bead (1MB) based isolation protocols for rapid purification and analysis of the active site peptides of two proteins, red cell acyl peptide hydrolase (APH) and plasma butyrylcholinesterase (BChE), as biomarkers of exposure to OP compounds. A targeted proteomics strategy based on microcapillary liquid chromatography-selected reaction monitoring-mass spectrometry (uLC-SRM-MS) will be validated and used to quantify the percentage modification of BChE and APH in archived samples from the Community Based Participatory Research Project. Data from the biomarker experiments will be correlated with other data available on urinary metabolite levels, inhibition of APH and/or BChE, and PONI status. Specific Aims 2 and 3 use knockout and humanized mouse models to determine the importance of PONI status for OP exposures that occur during critical periods of early development. Specific Aim 2 is to determine the extent to which APH and BChE are covalently modified following test exposure of pregnant mice to chlorpyrifos (CP) or CPO. Specific Aim 3 is to determine the extent to which BChE and APH are covalently modified following exposure of neonatal mice to CP or CPO.

Expected Results:

These aims will evaluate interactions among biomarkers of sensitivity, exposure and response in an in vivo system, allowing us to determine full dose responses of the OP compounds and generate quantitative biomarker data.

Supplemental Keywords:

RFA, Health, Scientific Discipline, INTERNATIONAL COOPERATION, ENVIRONMENTAL MANAGEMENT, Biochemistry, Environmental Monitoring, Children's Health, Environmental Policy, Biology, Risk Assessment, pesticide exposure, age-related differences, pesticides, children's vulnerablity, biological markers, agricultural community

Progress and Final Reports:
2011 Progress Report

Main Center Abstract and Reports:
R834514    University of Washington Center for Child Environmental Health Risks Research (2010)

Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
R834514C001 Community-Based Participatory Research
R834514C002 Pesticide Exposure Pathways
R834514C003 Molecular Mechanisms
R834514C004 Genetic Susceptibility

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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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