Biomarkers of Organophosphorus Pesticide-Induced Neurotoxicity

有机磷农药引起的神经毒性的生物标志物

• 批准号: 7845891
• 负责人: Wyndham Kent ANGER
• 金额: $ 6.25万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7845891
• 关键词: Address; Adult; Agricultural Workers; Agriculture; Air; Anger; Animals; Behavioral; Biological; Biological Markers; Blood; Brain; Buffaloes; C-reactive protein; CYP2B6 gene; CYP2C19 gene; Categories; Chemical Agents; Chlorpyrifos; Cholinesterases; Cognitive; Cohort Studies; Collaborations; Control Groups; Data; Dermal; Development; Dose; Drug Kinetics; Egypt; Enzymes; Equipment; Erythrocytes; Evaluation; Exhibits; Exposure to; Fostering; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Variation; Genotype; Goals; Health; Health Sciences; Human; Human Genetics; Individual; Inflammation; Inflammatory; Intervention; Isoprostanes; Link; Measures; Metabolism; Modeling; Motor; O,O-diethyl O-3,5,6-trichloro-2-pyridyl phosphate; Occupations; Oregon; Oxidative Stress; Performance; Pesticides; Plasma; Population; Rattus; Reporting; Research; Risk; Sampling; Science; Scientist; Seasons; Serum; Severities; Simulate; Terrorism; Testing; Toxicology; Universities; Urine; Validation; Washington; Work; abstracting; base; cognitive function; cohort; cytokine; exposed human population; gene environment interaction; genetic variant; insight; nerve agent; neurobehavioral; neurotoxic; neurotoxicity; novel; pesticide exposure; pesticide induced neurotoxicity; pharmacodynamic model; response; tool; treatment strategy; urinary

DESCRIPTION (provided by applicant): Organophosphorus pesticides (OPs) are the most commonly used pesticides in the U.S. and worldwide. Evidence from human and animal studies clearly identifies neurotoxicity as the primary endpoint of concern. However, it has been difficult to predict the risk that repeated low-dose exposure to OPs pose to humans because: 1) a relationship between OP dose and neurobehavioral deficits has yet to be established in humans; 2) biomarkers that reliably predict OP-induced neurobehavioral deficits are not available: and 3) the potential for genetic variation to modify exposure sensitivity has not been thoroughly investigated. The proposed studies will test the hypotheses that OP-induced neurobehavioral deficits are dose-related and that measures of oxidative stress and inflammation are better predictors of neurobehavioral deficit than cholinesterase inhibition. These hypotheses will be tested by studying a cohort of pesticide application workers in Egypt's Menoufia Governorate previously reported to exhibit the broadest range of neurobehavioral deficits in humans following OP exposure. This Egyptian cohort is uniquely suited for these studies because, unlike most pesticide exposures, the exposure is simple (a single OP, chlorpyrifos) and consistent within job categories, but with substantial differences between job categories. In aim 1, OP doses will be estimated using PBPK/PD modeling of urinary OP metabolite data collected from 255 Egyptian workers over the application cycle. These workers will also be genotyped for polymorphisms of key enzymes involved in OP metabolism (CYP2B6, CYP2C19 and PON1) to evaluate the potential for genetic variation to modify internal dose. In aim 2, behavioral deficits will be determined in a subset of workers exhibiting a range of OP exposures. Data from aims 1 and 2 will be integrated to determine the relationship between OP dose and neurobehavioral deficits. Rat studies will be conducted in parallel (aim 3) to test candidate biomarkers as predictors of OP-induced neurobehavioral deficits. The specific biomarkers that will be examined include cholinesterase inhibition, urinary isoprostanes as a measure of oxidative stress, and serum levels of C-reactive protein and inflammatory cytokines as measures of inflammation. In aim 4, those biomarkers that predict OP-induced neurobehavioral deficits in rats will be tested to determine if they similarly predict deficits in behavioral performance in Egyptian pesticide workers. The proposed studies will provide critical data needed to develop effective biomarkers of OP exposure, biological response and genetic susceptibility. The availability of such biomarkers would facilitate the identification of at-risk individuals as well as the testing of intervention and treatment strategies, and the need to develop these strategies is underscored by evidence of widespread human exposure to OPs and the credible threat of OPs as chemical agents of terrorism. Project Summary/Abstract - Relevance The goal of the proposed studies is to identify biomarkers of exposure and effect that are predictive of neurobehavioral deficits in humans exposed to organophosphorus pesticides (OPs). In addition, we will examine human genetic variants of the enzymes CYP2B6 and CYP2C19 that influence OP metabolism to not only inform interpretation of OP exposure data, but also provide insights into genetic susceptibilities that modulate neurotoxic responses to OPs. These studies will provide data critically needed to identify at-risk individuals and will provide tools to facilitate the development and evaluation of intervention and treatment strategies for exposure to not only OP pesticides, which are the most commonly used pesticides in the U.S. and worldwide, but also to nerve agents that are considered a credible terrorist threat.

描述（由申请人提供）：有机磷农药（OP）是美国和全球最常用的农药。人类和动物研究的证据清楚地将神经毒性确定为关注的主要终点。但是，很难预测重复暴露于OPS对人类的风险，因为：1）OP剂量与神经行为缺陷之间的关系尚未在人类中建立； 2）没有可靠地预测运行诱导的神经行为缺陷的生物标志物：3）尚未彻底研究遗传变异来改变暴露敏感性的潜力。拟议的研究将检验假设的假设，即剂量与剂量相关，氧化应激和炎症的测量比胆碱酯酶抑制是更好的预测因素。这些假设将通过研究埃及的梅努菲亚省的一系列农药施用工人来检验，此前据报道，在OP暴露后，在人类中表现出最广泛的神经行为缺陷。该埃及队列非常适合这些研究，因为与大多数农药暴露不同，这种暴露是简单的（单一OP，Chlorpyrifos），并且在工作类别中是一致的，但工作类别之间存在实质性差异。在AIM 1中，将使用PBPK/PD建模在应用周期中从255名埃及工人收集的尿OP代谢物数据进行估算。这些工人还将进行基因分型，以用于参与OP代谢的关键酶（CYP2B6，CYP2C19和PON1）的多态性，以评估遗传变异的可能性变异以改变内部剂量。在AIM 2中，将在展示一系列OP暴露的一部分工人的子集中确定行为缺陷。 AIM 1和2的数据将集成，以确定OP剂量和神经行为缺陷之间的关系。大鼠研究将并行进行（AIM 3），以测试候选生物标志物作为操作诱导的神经行为缺陷的预测指标。将要检查的特定生物标志物包括胆碱酯酶抑制作用，尿异前列腺作为氧化应激的量度，以及C反应蛋白和炎症细胞因子的血清水平作为炎症的指标。在AIM 4中，将测试那些预测大鼠神经行为缺陷的生物标志物，以确定它们是否类似地预测埃及农药工人行为表现的缺陷。拟议的研究将提供需要开发OP暴露，生物学反应和遗传易感性的有效生物标志物所需的关键数据。这种生物标志物的可用性将有助于确定处于危险中的个人以及对干预和治疗策略的测试，并且需要广泛暴露于人类对OP的证据以及对OP的可靠威胁作为恐怖主义的化学试剂的证据强调。项目摘要/摘要 - 拟议研究的目标是鉴定暴露和作用的生物标志物，这些生物标志物可预测暴露于有机磷农药（OPS）的人类中的神经行为缺陷。此外，我们将研究影响OP代谢的人类CYP2B6和CYP2C19的人类遗传变异，不仅可以为OP暴露数据解释提供解释，而且还提供了调节对OPS神经毒性反应的遗传易感性的见解。这些研究将为识别高危个人提供至关重要的数据，并将提供工具，以促进开发和评估干预措施和治疗策略，不仅是美国和全世界最常用的农药，这是美国和全世界最常用的农药，而且是为了神经被认为是可靠的恐怖威胁。