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University of Washington

Superfund Research Program

Biomarkers of Susceptibility to Environmentally-Induced Diseases

Project Leader: Clement E. Furlong
Grant Number: P42ES004696
Funding Period: 2009-2023
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Project Summary (2009-2015)

The paraoxonase family of genes (PON1, PON2 and PON3) is located on human chromosome 7. HDL associated PON1 metabolizes organophosphorus (OP) compounds, oxidized lipids, drugs and quorum sensing factors. PON1 polymorphisms affect catalytic efficiency and plasma levels. The consequences of the two PON2 coding region polymorphisms are unknown. PON1 is synthesized in liver and secreted into plasma, whereas PON2 is ubiquitously expressed in tissues, including the brain. PON2 does not hydrolyze OPs but has strong antioxidant properties. PON1 status was found to be altered in male Parkinson's patients compared with male control subjects. This project aims to increase knowledge of PON1, PON2 and PON3 functions in determining susceptibility to environmentally-induced neurotoxicity and neurodegenerative diseases. The first objective follows up on the project’s studies on the relationship of PON1 status and susceptibility to OP toxicity in a cohort of Washington State pesticide handlers. In addition to monitoring plasma cholinesterase levels, researchers include a novel quantitative mass spectrometric (MS) analysis of protein biomarkers modified by exposures in OP handlers and airline incidents. The second objective is to investigate the interplay of PON1 and carboxylesterase in modulating the toxicity of insecticide mixtures. The third objective is to examine the role of PON1 in modulating prenatal developmental neurotoxicity of chlorpyrifos oxon, where PON1 status of dams is hypothesized to be important for fetal protection. These studies with PON1 null mice and humanized PON1 transgenic mice (tgHuPON1-Q192 & tgHuPON1-R192) include biochemical, behavioral, histopathological and molecular end-points. The fourth objective is to investigate the role of PONs 1, 2 and 3 and HDL composition in Parkinson's disease (PD). As a follow-up on the project’s previous studies that showed differences in PON1 status in male PD patients compared with controls, project researchers use an MS-based proteomic approach to examine HDL composition in PD subjects vs. matched controls. Mice lacking PON proteins are also being tested for sensitivity to the dopaminergic neurotoxin MPTP. The fifth objective involves collaboration with the Phytorermediation of Pollutants Using Transgenic Plants project to express stable rabbit PON1 in plant systems for remediating OP spills.

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