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）：在NIEHS，NIOSH和NCI的研究人员进行的25,814名农场妇女中，最近的农业健康研究报告了282名受试者在农场中使用农药的任何使用与特应性哮喘之间存在着显着的关联。在农场长大的妇女中，这种协会是最强大的。与农场环境的保护作用相反（基于卫生假设的预期，与农药的应用一起长大，并且农药的应用与较高的特应性哮喘的总体风险共同关联；在同一研究中，这是针对在农场长大且从未施用农药的妇女。最近的另一项研究表明，在农药处理的小鼠中抑制了内毒素诱导的几种细胞因子的产生。从微生物和微生物产物中的农场环境中，包括妈妈（与微生物相关的分子模式）在农场环境中对收费（TLR）配体的接触暴露对抑制过敏反应具有重大影响。通过卫生假说的最新修订，这种抑制反应与调节T细胞（TREG）的诱导有关。因此，我们建议探索并确定气道对TLR配体和农药的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。在第一个具体目的中，我们将表征环境TLR配体（内毒素，肽聚糖和细菌DNA）的暴露，以及在俄亥俄州10个农药之前和之后的10个农场中与特应性哮喘相关的传统农药。将使用最先进的生物Aerosol抽样方法。 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.我们将使用LUDEP ICRP呼吸沉积模型来确定男性，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，第一个特定目标的结果将使我们能够同时了解农场中可吸入的TLR配体和农药的现实接触水平。在第二个特定目的中，我们将确定与现实世界暴露类似的上述农场中未育种但与临床相关的空气和表面样品提取物会影响宿主对卵巢蛋白诱导的超敏性和Treg诱导的易感性。这些影响的TLR4依赖性将通过使用卵蛋白敏化的野生型和TLR4 - / - C57BL/6小鼠来确定。这些发现将提供有关农药暴露与TLR配体暴露在农业工人之间特应性哮喘发展的不利影响之间的关系的重要初步信息。 公共卫生相关性：农药的使用可能与农民之间的特征性哮喘有显着相关性，因此农业环境可能无法提供基于传统卫生假设所预测的保护作用。在农业环境中存在广泛的免疫刺激材料和农药，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配体在农民中发展原性哮喘的不利影响之间的关系。在这个R21项目中，我们将探索在卵巢过敏原敏化小鼠中，在农场（农药施用之前和之后）收集的未繁殖但临床相关的环境样本的免疫学活动。