Human Immunotoxicity of Developmental PCB Exposure

发育过程中接触 PCB 的人体免疫毒性

• 批准号: 10348766
• 负责人: Todd Jusko
• 金额: $ 55.19万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-25 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10348766
• 关键词: 16 year old; Activities of Daily Living; Acute bronchitis; Address; Adolescence; Adolescent; Affect; Age; Age Months; Antibodies; Antibody Response; Antibody-mediated protection; B-Lymphocytes; BCG Live; BCG Vaccine; Bacille Calmette-Guerin vaccination; Biological Response Modifiers; Birth; Categories; Cells; Chemicals; Child; Childhood; Clinical; Collection; Communicable Diseases; Data; Developed Countries; Development; Developmental Process; Diagnosis; Environment; Environmental Exposure; Exogenous Factors; Exposure to; Flow Cytometry; Food Chain; Frequencies; Future; Health; Human; Immune; Immune system; Immunity; Immunoglobulin A; Immunoglobulin G; Immunologic Markers; Immunosuppression; Individual; Infant; Infection; Invaded; Knowledge; Life; Lower Respiratory Tract Infection; Lymphocyte; Lymphocyte Subtypings; Measurement; Measures; Memory; Memory B-Lymphocyte; Methods; Mycobacterium bovis; Nose; Outcome; Peripheral; Pharyngeal structure; Phase; Physicians; Polychlorinated Biphenyls; Population; Predisposition; Prevention strategy; Primary Prevention; Process; Public Health; Research; Respiratory Tract Infections; Serum; Shapes; Slovakia; T cell response; T memory cell; T-Lymphocyte; T-Lymphocyte Subsets; Th1 Cells; Thymus Gland; Time; Tissues; Umbilical Cord Blood; Vaccination; Vaccines; Work; bioaccumulation; cohort; early childhood; early life exposure; emerging adult; environmental agent; exposed human population; fighting; follow-up; immune function; immune system function; immunotoxicity; in utero; infancy; innovation; pathogen; pharmacokinetic model; physiologically based pharmacokinetics; pollutant; postnatal; prenatal; prenatal exposure; public health relevance; respiratory morbidity; respiratory pathogen; response; vaccine efficacy; vaccine response

Emerging experimental and observational data suggest that the immune system is susceptible to the influence of early life exposure to exogenous factors. The immune system begins to develop in utero, and continues to undergo tightly regulated developmental processes through adolescence and early adulthood. However, knowledge remains scant regarding how environmental exposures earlier in life modify susceptibility of immune cells to functional deficits throughout childhood and into adolescence, especially for the human immune system. Current evidence that environmental exposures perturb human immune function during early life is primarily limited to infants and young children. Presently, there is almost no information about how these observations relate to immune function during other critical developmental stages, such as adolescence. The objective of this project is to define how exposure to a specific category of environmental agents, polychlorinated biphenyls (PCBs), during key developmental periods, affects immune functions throughout childhood and into adolescence. The proposed work builds directly on findings that higher infant PCB levels are strongly associated with lower vaccine responses and greater respiratory morbidity in a birth cohort in eastern Slovakia. The proposed work will examine adaptive immune function and infection in 400 adolescents from this cohort. Building on our finding that 6-month PCB levels were inversely associated with anti-BCG specific antibody levels, our first aim will determine IgG- and IgA-specific anti-BCG and -MMR levels at 45 months, and 7 and 16 years of age. Leveraging extensive pre- and postnatal exposure data, this will allow the estimation of age-specific PCB- antibody associations, as well as permit the estimation of vaccine response trajectory over time. This aim is particularly important since vaccines administered in infancy are intended to create durable responses that contribute to protection as children age. Our second aim examines PCB exposure in relation to functionality of distinct B cell and T cell subsets. Higher PCB concentrations are associated with lower antibody levels to vaccination in several studies. However, the mechanism is not known, and specific lymphocyte sub-types and functional capacity remain poorly characterized: data from this aim will help fill this knowledge gap. In the third aim, we will use PCR-based methods to measure the frequency of 22 common respiratory pathogens over a 1- year period of follow-up, including asymptomatic and symptomatic collections. We will also abstract physician- diagnosed lower respiratory tract infections (LRTIs) from birth through 16 years. With these measured endpoints, associations between pre- and postnatal PCB concentrations and symptomatic and asymptomatic respiratory infection will be assessed. By extending research with this established cohort from birth to adolescence, we will obtain new information about how this category of common pollutants impacts the human immune system.

新兴的实验和观察数据表明，免疫系统易受影响 早期生命暴露于外源性因素。免疫系统开始在子宫内发展，并继续 通过青春期和成年早期经历严格调节的发展过程。然而， 知识仍然很少了解环境暴露在生活中如何改变免疫的敏感性 细胞在整个儿童期到青春期的功能缺陷，尤其是对于人类免疫系统。 当前的证据表明，环境暴露在早期生命中的人类免疫功能主要是 仅限于婴儿和幼儿。目前，几乎没有关于这些观察如何的信息 在其他关键发育阶段（例如青春期）中与免疫功能有关。这个目的 项目是定义如何暴露于特定类别的环境药物，多氯联苯 （PCB）在关键的发育期间，会影响整个儿童期的免疫功能 青春期。拟议的工作直接建立在较高婴儿PCB水平密切相关的发现上 在斯洛伐克东部的出生队列中，疫苗反应较低，呼吸道发病率更高。这 拟议的工作将检查该队列中400名青少年的适应性免疫功能和感染。建筑 关于我们发现6个月的PCB水平与抗BCG特异性抗体水平成反比 第一个目标将确定45个月时IgG和IgA特异性抗BCG和-MMR水平，以及7和16年 年龄。利用大量的产前和产后暴露数据，这将允许估计年龄特异性的PCB- 抗体关联，并允许估计疫苗反应轨迹随着时间的流逝。这个目标是 特别重要 随着儿童的年龄，有助于保护。我们的第二个目标研究了与PCB有关的功能 不同的B细胞和T细胞子集。较高的PCB浓度与较低的抗体水平有关 在几项研究中疫苗接种。但是，该机制尚不清楚，特定的淋巴细胞亚型和 功能能力的表征仍然很差：此目标的数据将有助于填补这一知识差距。在第三 目的，我们将使用基于PCR的方法来测量1-- 随访的年度，包括无症状和有症状的收集。我们还将抽象医师 - 从出生到16年，被诊断出的下呼吸道感染（LRTI）。通过这些测得的端点， 产前和产后PCB浓度以及有症状和无症状呼吸道的关联 感染将被评估。通过扩展该既定队列的研究从出生到青春期，我们将 获取有关该类别的常见污染物如何影响人免疫系统的新信息。