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 (?mu?LC-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.
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.

Public Health Relevance

These experiments will integrate the the interactions among biomarkers of susceptibility, exposure, and response to OP compounds during critical periods of development. Using MS analysis of modified APH and BChE to examine the role of genetic variability of P0N1 in modulating gene environment interactions will provide a more detailed understanding of the role of P0N1 in modulating environmental exposures to OPs.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Program Projects (P01)
Project #
5P01ES009601-14
Application #
8381048
Study Section
Special Emphasis Panel (ZES1-LKB-G)
Project Start
Project End
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
14
Fiscal Year
2012
Total Cost
$59,907
Indirect Cost
$16,896
Name
University of Washington
Department
Type
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Gibbs, Jenna L; Yost, Michael G; Negrete, Maria et al. (2017) Passive Sampling for Indoor and Outdoor Exposures to Chlorpyrifos, Azinphos-Methyl, and Oxygen Analogs in a Rural Agricultural Community. Environ Health Perspect 125:333-341
Kim, Hee Yeon; Wegner, Susanna H; Van Ness, Kirk P et al. (2016) Differential epigenetic effects of chlorpyrifos and arsenic in proliferating and differentiating human neural progenitor cells. Reprod Toxicol 65:212-223
Holme, Francesca; Thompson, Beti; Holte, Sarah et al. (2016) The role of diet in children's exposure to organophosphate pesticides. Environ Res 147:133-40
Harley, Kim G; Engel, Stephanie M; Vedar, Michelle G et al. (2016) Prenatal Exposure to Organophosphorous Pesticides and Fetal Growth: Pooled Results from Four Longitudinal Birth Cohort Studies. Environ Health Perspect 124:1084-92
Marsillach, Judit; Costa, Lucio G; Furlong, Clement E (2016) Paraoxonase-1 and Early-Life Environmental Exposures. Ann Glob Health 82:100-10
Smith, Marissa N; Grice, Joshua; Cullen, Alison et al. (2016) A Toxicological Framework for the Prioritization of Children's Safe Product Act Data. Int J Environ Res Public Health 13:431
Furlong, Clement E; Marsillach, Judit; Jarvik, Gail P et al. (2016) Paraoxonases-1, -2 and -3: What are their functions? Chem Biol Interact 259:51-62
Peter, Beate; Wijsman, Ellen M; Nato Jr, Alejandro Q et al. (2016) Genetic Candidate Variants in Two Multigenerational Families with Childhood Apraxia of Speech. PLoS One 11:e0153864
Engel, Stephanie M; Bradman, Asa; Wolff, Mary S et al. (2016) Prenatal Organophosphorus Pesticide Exposure and Child Neurodevelopment at 24 Months: An Analysis of Four Birth Cohorts. Environ Health Perspect 124:822-30
Weldon, Brittany A; Shubin, Sara Pacheco; Smith, Marissa N et al. (2016) Urinary microRNAs as potential biomarkers of pesticide exposure. Toxicol Appl Pharmacol 312:19-25

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