Early-life metal exposures, mitochondrial heteroplasmy, and child antibody response to vaccination

生命早期的金属暴露、线粒体异质性和儿童抗体对疫苗接种的反应

• 批准号: 10701076
• 负责人: Elena Colicino
• 金额: $ 57万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-08 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10701076
• 关键词: 15 year old; 4 year old; 5 year old; Adaptive Immune System; Affect; Age; Animals; Antibodies; Antibody Formation; Antibody Repertoire; Antibody Response; Antigens; Arsenic; Attenuated; Attenuated Vaccines; B-Lymphocytes; Bacterial Antigens; Biological Markers; Birth; Blood; Cadmium; Cell physiology; Chemical Exposure; Child; Childhood; Data; Development; Diet; Diphtheria; Dose; Elderly; Environment; Environmental Exposure; Environmental Risk Factor; Exposure to; Goals; Growth; Health; Immune; Immune response; Immune system; Immunization; Immunologic Memory; Immunosuppression; Individual; Infection; Innate Immune System; Intervention; Knowledge; Lead; Lead levels; Life; Life Style; Manganese; Measles; Measures; Mediating; Mediator; Metal exposure; Metals; Mexican; Mitochondria; Mitochondrial DNA; Mumps; Obesity; Oxidative Stress; Oxidative Stress Induction; Pertussis; Play; Predisposition; Pregnancy; Public Health; Reactive Oxygen Species; Research; Risk; Role; Rubella; Schedule; Second Pregnancy Trimester; Somatic Cell; Systems Development; T-Lymphocyte; Tetanus; Time; Tooth structure; Toxoids; Urine; Vaccination; Vaccines; Viral Antigens; Work; causal model; cohort; critical period; current pandemic; early life exposure; experience; future pandemic; heteroplasmy; immune function; immune system function; immunotoxicity; in utero; individual response; innovation; lead exposure; mitochondrial DNA mutation; novel; novel marker; oxidative damage; prenatal; prevent; programs; response; social stressor; theories; vaccine formulation; vaccine response

SUMMARY Individual responses to vaccinations are a critical public health issue and mounting evidence suggests that early life environmental factors may program immune dysregulation that manifests years later. This developmental origins of health and development (DOHaD) theory posits that dose and timing of early life immunotoxic environmental exposures can have long-lasting consequences on the trajectory of immune system function. The immune system begins to develop in utero and, as children age and experience infections and vaccinations, an ever-expanding repertoire of antibodies become part of their lifelong immune memory. Yet research on child immune function and its response to ubiquitous immunotoxic metal exposures—experienced in utero and early in life (0–5 years)—has been largely overlooked.We will address this knowledge gap in the Mexican PROGRESS study, which has measures of immunotoxic metal exposures [arsenic (As), cadmium (Cd), manganese (Mn), and lead (Pb)] at several key developmental time windows and from multiple biomatrices (tooth, blood, and urine). We will assess child immune function by measuring antibody levels at 4, 6, 8, 10–11, and 13–15 years of age in response to scheduled childhood vaccinations (i.e., measles, mumps, rubella, diphtheria, tetanus, and pertussis). Our preliminary data show that (i) exposure to individual metals (Cd, Pb) and a metal mixture (As, Cd, Mn, Pb) may result in poorer antibody responses at age 4 years and that (ii) there are critical windows of susceptibility to As, Mn, and Pb exposures. Additionally, metal exposures induce systemic oxidative stress (OS) leading to suboptimal immune system function. Given the pro-oxidant role of metals, we will also quantify cumulative OS via a novel biomarker—mitochondrial DNA (mtDNA) heteroplasmy, which reflects OS-induced mtDNA mutation counts accumulating over time. Our initial data show that prenatal metal exposures are associated with mtDNA heteroplasmy counts at birth. We will measure mtDNA heteroplasmy at birth and at 8 and 13–15 years of age as a predictor and mediator of antibody responses. In Aim 1, we will determine the association between exposure to individual metals and metal mixtures with child antibody responses to vaccination at specific ages and antibody response trajectories over time. In Aim 2, we will determine critical windows of susceptibility to immunotoxic metals exposure on child immune system at specific ages and over time. In Aim 3, we will investigate associations between mtDNA heteroplasmy levels and (i) exposure to individual metals and metal mixtures and (ii) child antibody response to vaccination at specific ages and antibody response trajectories. We will apply statistical causal modeling strategies to evaluate the mediating role of mitochondrial biomarkers on the metal–immune system relationship. Completion of these aims will drive interventions that may help prevent lifelong immune system dysregulation and related adverse health consequences.

总结 个人对疫苗接种的反应是一个关键的公共卫生问题，越来越多的证据表明， 早期的生活环境因素可能会导致免疫失调，并在多年后显现出来。这 健康和发展的发展起源（DOHaD）理论认为，早期生命的剂量和时间 免疫毒性环境暴露可能对免疫系统的轨迹产生长期影响。 系统功能免疫系统在子宫内就开始发育，随着儿童年龄的增长和经历 感染和接种疫苗，不断扩大的抗体库成为他们终身免疫的一部分， 记忆儿童免疫功能及其对普遍存在的免疫毒性金属反应的研究 子宫内和生命早期（0-5岁）经历的流产在很大程度上被忽视了。 墨西哥PROGRESS研究中的这一知识空白，该研究测量了免疫毒性金属暴露 [砷（As）、镉（Cd）、锰（Mn）和铅（Pb）]， 从多种生物基质（牙齿、血液和尿液）中提取。我们将评估儿童的免疫功能， 4、6、8、10-11岁和13-15岁儿童接种计划疫苗后的抗体水平 (i.e.,麻疹、腮腺炎、风疹、白喉、破伤风和百日咳）。我们的初步数据显示，（i）暴露 个别金属（镉，铅）和金属混合物（砷，镉，锰，铅）可能会导致较差的抗体反应， 年龄4年，（ii）有敏感性的砷，锰，铅暴露的关键窗口。此外，本发明还 金属暴露诱导全身氧化应激（OS），导致次优的免疫系统功能。给定 金属的促氧化作用，我们还将通过一种新的生物标志物-线粒体DNA定量累积OS （mtDNA）异质性，其反映OS诱导的mtDNA突变计数随时间积累。我们最初 数据显示，产前金属暴露与出生时mtDNA异质性计数有关。我们将 在出生时以及8岁和13-15岁时测量mtDNA异质性作为预测和介导因素， 抗体反应。在目标1中，我们将确定暴露于单个金属和 金属混合物与特定年龄儿童对疫苗接种的抗体反应和抗体反应轨迹 随着时间在目标2中，我们将确定免疫毒性金属暴露敏感性的临界窗口， 儿童免疫系统在特定年龄和随着时间的推移。在目标3中，我们将研究线粒体DNA之间的关联 异质性水平和（i）暴露于个别金属和金属混合物和（ii）儿童抗体反应， 特定年龄的疫苗接种和抗体反应轨迹。我们将应用统计因果模型 评估线粒体生物标志物在金属免疫系统中介导作用的策略 关系这些目标的实现将推动可能有助于预防终身免疫系统疾病的干预措施。 失调和相关的不良健康后果。