Human Immunotoxicity of Developmental PCB Exposure

发育过程中接触 PCB 的人体免疫毒性

• 批准号: 9899989
• 负责人: Todd Jusko
• 金额: $ 55.02万
• 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 2024-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9899989
• 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; 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; base; 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; public health relevance; respiratory; respiratory morbidity; 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.

新出现的实验和观察数据表明，免疫系统很容易受到影响 早年暴露于外源因素。免疫系统在子宫内开始发育，并持续发展 在青春期和成年早期经历严格调控的发育过程。然而， 关于生命早期的环境暴露如何改变免疫敏感性的知识仍然很少 细胞在整个童年和青春期的功能缺陷，尤其是人类免疫系统。 目前的证据表明，环境暴露会扰乱生命早期的人类免疫功能，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进行的信息 与其他关键发育阶段（例如青春期）的免疫功能有关。此举的目的 该项目的目的是定义如何接触特定类别的环境物质，即多氯联苯 （多氯联苯）在关键发育时期会影响整个儿童期和成年后的免疫功能 青春期。拟议的工作直接建立在婴儿 PCB 水平较高与 斯洛伐克东部出生队列中的疫苗反应较低，呼吸道疾病发病率较高。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情况。建筑 根据我们发现 6 个月 PCB 水平与抗 BCG 特异性抗体水平呈负相关，我们 第一个目标是确定 45 个月、7 岁和 16 岁时的 IgG 和 IgA 特异性抗 BCG 和 -MMR 水平。 年龄。利用广泛的产前和产后暴露数据，这将有助于估计特定年龄的 PCB- 抗体关联，以及允许随着时间的推移估计疫苗反应轨迹。这个目标是 尤其重要的是，因为在婴儿期接种疫苗的目的是产生持久的反应， 随着儿童年龄的增长，为保护做出贡献。我们的第二个目标是检查 PCB 暴露与功能的关系 不同的 B 细胞和 T 细胞亚群。较高的 PCB 浓度与较低的抗体水平相关 多项研究中的疫苗接种。然而，其机制尚不清楚，特定的淋巴细胞亚型和 职能能力的特征仍然不明确：来自该目标的数据将有助于填补这一知识空白。在第三个 目标是，我们将使用基于 PCR 的方法来测量 1 年内 22 种常见呼吸道病原体的频率 一年的随访期，包括无症状和有症状的收集。我们还将抽象医生- 诊断出从出生到 16 岁的下呼吸道感染 (LRTI)。有了这些测量的终点， 产前和产后 PCB 浓度与有症状和无症状呼吸道疾病之间的关联 将评估感染情况。通过将这个既定队列的研究从出生延伸到青春期，我们将 获取有关此类常见污染物如何影响人体免疫系统的新信息。