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

• 批准号: 8145597
• 负责人: ATIN ADHIKARI
• 金额: $ 23.31万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-20 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8145597
• 关键词: 2,4-Dichlorophenoxyacetic Acid; Adverse effects; Agricultural Workers; Agriculture; Air; Allergens; Applications Grants; Attention; Bacterial DNA; C57BL/6 Mouse; Cells; Child; Collection; County; Dependence; Deposition; Development; Dose; Dust; Endotoxins; Environmental Exposure; Exploratory/Developmental Grant; Exposure to; Extrinsic asthma; Farming environment; Female; Force of Gravity; Health; Herbicides; Hygiene; Hypersensitivity; Immune response; Immunity; Insecticides; Interdisciplinary Study; Investigation; Laboratory Study; Ligands; Mediating; Methodology; Microbe; Modeling; Molecular; Mus; National Institute of Environmental Health Sciences; Ohio; Ovalbumin; Particle Size; Particulate; Pathogenesis; Pattern; Peptidoglycan; Pesticide Residues; Pesticides; Predisposition; Production; Prospective Studies; Regulatory T-Lymphocyte; Reporting; Research Personnel; Risk; Role; Sampling; Soil; Source; Staging; Surface; System; TLR4 gene; Testing; Toll-like receptors; Woman; air sampling; allergic response; base; clinically relevant; cytokine; environmental endotoxin; farmer; glyphosate; male; metam sodium; microbial; microorganism; mouse model; novel; particle; pesticide exposure; protective effect; public health relevance; respiratory; response

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）：NIEHS、NIOSH和NCI的研究人员最近在25，814名农场妇女中进行的农业健康研究报告称，在282名受试者中，农场中任何农药的使用与特应性哮喘之间存在高度显著的相关性。在农场长大的妇女中，这种联系最为强烈。在农场长大和使用杀虫剂与特应性哮喘的总体风险较高相关，这与农场环境的保护作用相反（根据卫生假说的预期）;这在同一项研究中证明了在农场长大且从未使用杀虫剂的女性。另一项最近的研究表明，在农药处理的小鼠中，内毒素诱导的几种细胞因子的产生受到抑制。在农场环境中暴露于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），对过敏反应的抑制具有显著影响。这种抑制性反应与最近修订的卫生假说（Hygiene Hypothesis）中调节性T细胞（Treg）的诱导有关。因此，我们建议探索和确定如何结合气道暴露TLR配体和农药影响免疫反应与过敏性哮喘在农场环境中。在第一个具体的目标，我们将描述暴露的环境TLR配体（内毒素，肽聚糖，和细菌DNA）和两个传统的农药相关的过敏性哮喘在俄亥俄州的10个农场之前和之后的农药应用。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开发的两级旋风分离器的尺寸选择性采样系统（三个粒径级：<1.05m，1 - 1.85m和> 1.85m），用于收集空气中TLR配体和农药，和一个新的微生物源强度测试仪，用于收集可气溶胶化的TLR配体和农药从土壤表面。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配体和农药的呼吸沉积潜力。因此，第一个具体目标的结果将使我们能够了解真实的世界农场中可吸入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品提取物（类似于真实的暴露）如何影响宿主对卵清蛋白诱导的超敏反应和THBE诱导的易感性。这些影响的TLR 4依赖性将通过使用卵清蛋白致敏的野生型和TLR 4-/-C57 BL/6小鼠来确定。这些发现将提供重要的初步信息农药暴露的不良影响与TLR配体暴露的保护作用之间的关系，在农业工人特应性哮喘的发展。 公共卫生相关性：农药的使用可以显着相关的过敏性哮喘的农民，因此，农业环境可能不会提供传统的卫生假说的基础上预测的保护作用。广泛的免疫刺激物质和农药存在于农业环境中，传统的调查与纯化的材料和农药可能无法提供精确的信息农药暴露的不良影响与TLR配体在农民中发展特应性哮喘的保护作用之间的关系。在这个R21项目中，我们将探讨未纯化的，但临床相关的环境样品收集在农场（农药应用前后）在卵清蛋白过敏原致敏小鼠的免疫活性。