Project 1: Biomarkers of Susceptibility to Environmentally-Induced Diseases

对氧磷酶家族基因（PON1、PON2和PONS）位于人类7号染色体上。高密度脂蛋白相关PON1代谢有机磷（OP）化合物、氧化脂质、药物和群体感应因子。PON1多态性影响催化效率和血浆水平。两种PON2编码区多态性的后果尚不清楚。PON1在肝脏中合成并分泌到血浆中，而PON2在包括脑在内的组织中普遍表达。PON2不水解OPs，但具有较强的抗氧化性能。与男性对照组相比，男性帕金森患者的PON1状态发生了改变。拟议的研究旨在增加我们对PON1， PON2和PONS在确定环境诱导的神经毒性和神经退行性疾病易感性方面的功能的了解。特异性目标1是对我们在华盛顿州农药处理者队列中PON1状态与OP毒性易感性关系的后续研究。除了监测血浆胆碱酯酶水平，我们将包括一种新的定量质谱（MS）分析

The paraoxonase family of genes (PON1, PON2 and PONS) 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 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. The proposed studies aim to increase our knowledge of PON1, PON2 and PONS functions in determining susceptibility to environmentally-induced neurotoxicity and neurodegenerative diseases. Specific Aim 1 follows up on our 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, we will include a novel quantitative mass spectrometric (MS) analysis of protein biomarkers modified by exposures in OP handlers and airline incidents. Specific Aim 2 investigates the interplay of PON1 and carboxylesterase in modulating the toxicity of insecticide mixtures. Specific Aim 3 examines 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. Specific Aim 4 investigates the role of PONs 1, 2 and 3 and HDL composition in Parkinson's disease (PD). As a follow-up on our previous studies that showed differences in PON1 status in male PD patients compared with controls, we will use an MS-based proteomic approach to examine HDL composition in PD subjects vs. matched controls. Mice lacking PON proteins will also be tested for sensitivity to the dopaminergic neurotoxin MPTP. Specific Aim 5 involves a collaboration with Project 5 to express stable rabbit PON1 in plant systems for remediating OP spills.