TLR Ligand and Pesticide Exposure in Farms: Role in Atopic Immune Responses
农场中 TLR 配体和农药暴露:在特应性免疫反应中的作用
基本信息
- 批准号:7895212
- 负责人:
- 金额:$ 19.63万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-09-20 至 2012-08-31
- 项目状态:已结题
- 来源:
- 关键词:2,4-Dichlorophenoxyacetic AcidA MouseAdverse effectsAgricultural WorkersAgricultureAirAllergensApplications GrantsArtsAttentionBacterial DNAC57BL/6 MouseCellsChildCollectionCountyDependenceDepositionDevelopmentDoseDustEndotoxinsEnvironmental ExposureExposure toExtrinsic asthmaFarming environmentFemaleForce of GravityHealthHerbicidesHygieneHypersensitivityImmune responseImmunityInsecticidesInterdisciplinary StudyInvestigationKnowledgeLaboratory StudyLigandsMediatingMethodologyMicrobeModelingMolecularMusNational Institute of Environmental Health SciencesOhioOvalbuminParticle SizeParticulatePathogenesisPatternPeptidoglycanPesticide ResiduesPesticidesPredispositionProductionProspective StudiesRegulatory T-LymphocyteReportingResearch PersonnelRiskRoleSamplingSoilSourceStagingSurfaceSystemTLR4 geneTestingToll-like receptorsWomanair samplingallergic responsebaseclinically relevantcytokineenvironmental endotoxinfarmerglyphosatemalemetam sodiummicrobialmicroorganismmouse modelnovelparticlepesticide exposureprotective effectpublic health relevancerespiratoryresponse
项目摘要
DESCRIPTION (provided by applicant): The recent Agricultural Health Study among 25,814 farm women conducted by the researchers from NIEHS, NIOSH, and NCI reported a highly significant association between any use of pesticides in farms and atopic asthma in 282 subjects. This association was strongest among women who grew up on a farm. Growing up on farms and application of pesticides were jointly associated with higher overall risk for atopic asthma in contrary to the protective effect of farm environment (as expected based on the Hygiene Hypothesis); which was in the same study demonstrated for women who grew up on farms and never applied pesticides. Another recent study showed that the production of several cytokines induced by endotoxin was suppressed in pesticide treated mice. Exposures to toll like receptor (TLR) ligands in farm environment including MAMPs (microbe-associated molecular patterns) from microorganisms and microbial products have significant influence on the suppression of allergic response. This suppressive response was implicated to the induction of regulatory T cells (Treg) by recent revisions of the Hygiene Hypothesis. Therefore we propose to explore and determine how combined airway exposures to TLR ligands and pesticides influence immune responses associated with atopic asthma in farm environments. In the first specific aim we will characterize exposures of environmental TLR ligands (endotoxin, peptidoglycan, and bacterial DNA) and two conventional pesticides relevant to atopic asthma in 10 farms of Ohio before and after pesticide application. A state-of-the-art bioaerosol sampling methodology will be used. It includes an inhalable sampler and a NIOSH-developed size- selective sampling system with two-stage cyclone (three particle size fractions: <1.0 5m, 1 - 1.8 5m, and >1.8 5m), for the collection of airborne TLR ligands and pesticides and a novel microbial source strength tester for the collection of aerosolizable TLR ligands and pesticides from soil surface. We will determine the respiratory deposition potential of particulate TLR ligands and pesticides for male, female, and children subjects using the LUDEP ICRP respiratory deposition model. Results from the first specific aim will thus allow us to understand the real world simultaneous exposure levels to inhalable TLR ligands and pesticides in farms. In second specific aim we will determine how unpurified but clinically relevant air and surface sample extracts from above-mentioned farms analogous to real world exposures influence host susceptibility towards ovalbumin induced hypersensitivity and induction of Tregs. The TLR4 dependence of these influences will be determined by using ovalbumin-sensitized wild type and TLR4 -/- C57BL/6 mice. The findings will provide vital preliminary information on the relationship between adverse effects of pesticide exposure versus protective effects of TLR ligand exposure in the development of atopic asthma among agricultural workers.
PUBLIC HEALTH RELEVANCE: Pesticide usage can be significantly associated with atopic asthma among the farmers and therefore farming environment may not provide the protective effect predicted based on the traditional Hygiene Hypothesis. Wide range of immunostimulatory materials and pesticides are present in farming environments and traditional investigations with purified materials and pesticides may not provide precise information on relationship between adverse effect of pesticide exposures versus protective effect of TLR ligands in developing atopic asthma among farmers. In this R21 project we will explore immunological activities of unpurified but clinically relevant environmental samples collected in farms (before and after pesticide application) in ovalbumin allergen sensitized mice.
描述(由申请人提供):最近由 NIEHS、NIOSH 和 NCI 的研究人员对 25,814 名农场妇女进行的农业健康研究报告显示,农场使用农药与 282 名受试者的特应性哮喘之间存在高度显着的关联。这种关联在农场长大的女性中最为强烈。在农场长大和使用杀虫剂与较高的特应性哮喘总体风险相关,这与农场环境的保护作用相反(正如基于卫生假说的预期);同一项研究也针对在农场长大且从未使用过杀虫剂的女性进行了证明。最近的另一项研究表明,经过农药处理的小鼠体内由内毒素诱导的几种细胞因子的产生受到抑制。农场环境中暴露于 Toll 样受体 (TLR) 配体,包括来自微生物和微生物产品的 MAMP(微生物相关分子模式),对抑制过敏反应具有显着影响。最近对卫生假说的修订表明,这种抑制反应与调节性 T 细胞 (Treg) 的诱导有关。因此,我们建议探索并确定 TLR 配体和杀虫剂的气道联合暴露如何影响农场环境中与特应性哮喘相关的免疫反应。在第一个具体目标中,我们将描述俄亥俄州 10 个农场在施用农药之前和之后环境 TLR 配体(内毒素、肽聚糖和细菌 DNA)和两种与特应性哮喘相关的常规农药的暴露情况。将使用最先进的生物气溶胶采样方法。它包括一个可吸入采样器和一个 NIOSH 开发的带有两级旋风分离器的尺寸选择性采样系统(三种粒径级分:<1.0 5m、1 - 1.8 5m 和 >1.8 5m),用于收集空气中的 TLR 配体和农药以及一种新型微生物源强度测试仪,用于从土壤表面收集可雾化的 TLR 配体和农药。我们将使用 LUDEP ICRP 呼吸沉积模型确定男性、女性和儿童受试者的颗粒 TLR 配体和杀虫剂的呼吸沉积潜力。因此,第一个具体目标的结果将使我们能够了解现实世界中农场中可吸入 TLR 配体和农药的同时暴露水平。在第二个具体目标中,我们将确定来自上述农场的未纯化但临床相关的空气和表面样本提取物(类似于现实世界的暴露)如何影响宿主对卵清蛋白诱导的超敏反应和 Tregs 诱导的敏感性。这些影响的 TLR4 依赖性将通过使用卵清蛋白致敏的野生型和 TLR4 -/- C57BL/6 小鼠来确定。这些发现将为农业工人中特应性哮喘的发展提供重要的初步信息,了解农药接触的不利影响与 TLR 配体接触的保护作用之间的关系。
公共卫生相关性:农药的使用可能与农民的特应性哮喘显着相关,因此农业环境可能无法提供根据传统卫生假说预测的保护作用。农业环境中存在多种免疫刺激材料和农药,对纯化材料和农药的传统研究可能无法提供有关农药暴露的不利影响与 TLR 配体对农民患特应性哮喘的保护作用之间关系的准确信息。在这个 R21 项目中,我们将探索在农场(施用农药之前和之后)收集的未纯化但临床相关的环境样本对卵清蛋白过敏原致敏小鼠的免疫活性。
项目成果
期刊论文数量(0)
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ATIN ADHIKARI其他文献
ATIN ADHIKARI的其他文献
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Traffic-related air pollutants and respiratory tract microbiome in children
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农场中 TLR 配体和农药暴露:在特应性免疫反应中的作用
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