Biomarkers of Organophosphorus Pesticide-Induced Neurotoxicity

描述（由申请人提供）：有机磷农药（OPs）是美国和全世界最常用的农药。来自人类和动物研究的证据清楚地表明，神经毒性是关注的主要终点。然而，很难预测反复低剂量暴露于有机磷农药对人类造成的风险，因为：1)有机磷农药剂量与人类神经行为缺陷之间的关系尚未建立；2)目前还没有能够可靠预测op诱导的神经行为缺陷的生物标志物；3)基因变异改变暴露敏感性的可能性尚未得到彻底的研究。拟议的研究将验证op诱导的神经行为缺陷与剂量相关的假设，以及氧化应激和炎症的测量比胆碱酯酶抑制更能预测神经行为缺陷。这些假设将通过对埃及Menoufia省一群农药施用工人的研究进行检验，此前有报道称，这些工人在接触OP后表现出最广泛的神经行为缺陷。这个埃及队列特别适合这些研究，因为与大多数农药接触不同，接触是简单的（单一的OP，毒死蜱），并且在工作类别内是一致的，但在工作类别之间存在实质性差异。在目标1中，将使用从255名埃及工人收集的尿液OP代谢物数据的PBPK/PD建模来估计OP剂量。这些工人还将对参与OP代谢的关键酶（CYP2B6， CYP2C19和PON1）的多态性进行基因分型，以评估遗传变异改变内剂量的可能性。在目标2中，行为缺陷将在表现出一系列OP暴露的工人中确定。将综合目标1和目标2的数据，以确定OP剂量与神经行为缺陷之间的关系。大鼠研究将同时进行（目标3），以测试候选生物标志物作为op诱导的神经行为缺陷的预测因子。将被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反应蛋白和炎症细胞因子的血清水平。在目标4中，将测试那些预测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、生物反应和遗传易感性的有效生物标志物所需的关键数据。这些生物标记物的可用性将有助于识别高危个体，以及对干预和治疗策略的测试。有证据表明，人类广泛接触有机磷化合物，以及有机磷化合物作为恐怖主义化学制剂的可信威胁，这就强调了制定这些策略的必要性。项目摘要/摘要-相关性本研究的目的是确定暴露于有机磷农药（OPs）的生物标志物及其影响，以预测人类暴露于有机磷农药（OPs）的神经行为缺陷。此外，我们将研究影响OP代谢的CYP2B6和CYP2C19酶的人类遗传变异，不仅为OP暴露数据的解释提供信息，而且还为调节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高危人群所需的关键数据，并将提供工具，以促进干预和治疗策略的发展和评估，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。

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.