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: 7628144
• 负责人: Wyndham Kent ANGER
• 金额: $ 59.92万
• 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/7628144
• 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。来自人类和动物研究的证据清楚地将神经毒性确定为主要关注终点。然而，很难预测重复低剂量暴露于OP对人类造成的风险，因为：1）OP剂量和神经行为缺陷之间的关系尚未在人类中建立; 2）可靠预测OP诱导的神经行为缺陷的生物标志物不可用; 3）遗传变异改变暴露敏感性的潜力尚未得到彻底研究。拟议的研究将测试的假设，OP诱导的神经行为缺陷是剂量相关的，氧化应激和炎症的措施是更好的预测神经行为缺陷比胆碱酯酶抑制。这些假设将通过研究一组农药应用工人在埃及的Menoufia省以前报告显示，在OP暴露后，人类神经行为缺陷的范围最广的。这一埃及队列特别适合这些研究，因为与大多数农药接触不同，接触很简单（一种OP，毒死蜱），在工作类别内是一致的，但在工作类别之间有很大的差异。在目标1中，将使用在应用周期内从255名埃及工人中收集的尿OP代谢物数据的PBPK/PD建模来估计OP剂量。还将对这些工作人员进行OP代谢关键酶（CYP 2B 6、CYP 2C 19和PON 1）多态性的基因分型，以评价遗传变异改变体内剂量的可能性。在目标2中，将在表现出一系列OP暴露的工人的子集中确定行为缺陷。将整合目标1和2的数据，以确定OP剂量与神经行为缺陷之间的关系。将平行进行大鼠研究（目的3），以检测候选生物标志物作为OP诱导的神经行为缺陷的预测因子。将检查的特定生物标志物包括胆碱酯酶抑制、作为氧化应激指标的尿异前列腺素以及作为炎症指标的C反应蛋白和炎性细胞因子的血清水平。在目标4中，将测试预测OP诱导的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的行为表现缺陷。拟议的研究将提供开发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。这种生物标志物的提供将有助于查明有风险的个人以及测试干预和治疗战略，有证据表明，人类广泛接触到OP，OP作为恐怖主义化学剂的可信威胁，突出表明有必要制定这些战略。项目摘要/摘要-相关性拟议研究的目标是确定暴露和影响的生物标志物，这些生物标志物可预测暴露于有机磷农药（OP）的人类的神经行为缺陷。此外，我们还将研究影响OP代谢的酶CYP 2B 6和CYP 2C 19的人类遗传变异，不仅为OP暴露数据的解释提供信息，还为调节OP神经毒性反应的遗传易感性提供见解。这些研究将提供识别风险个体所急需的数据，并将提供工具，以促进干预和治疗策略的开发和评估，不仅暴露于OP农药，这是美国和世界范围内最常用的农药，而且还暴露于被认为是可信的恐怖主义威胁的神经毒剂。