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

基本信息

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
项目类别：
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

项目摘要

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.

概括个人对疫苗接种的反应是一个重要的公共卫生问题，越来越多的证据表明生命早期的环境因素可能会导致免疫失调，并在数年后显现出来。健康与发育的发育起源（DOHaD）理论认为，生命早期的剂量和时间免疫毒性环境暴露可能对免疫轨迹产生长期影响免疫系统在子宫内开始发育，并且随着儿童年龄的增长和经验的增长。感染和疫苗接种，不断扩大的抗体库成为他们终生免疫系统的一部分然而，关于儿童免疫功能及其对普遍存在的免疫毒性金属的反应的研究。在子宫内和生命早期（0-5岁）经历的暴露在很大程度上被忽视了。我们将解决墨西哥 PROGRESS 研究中的这一知识差距，该研究测量了免疫毒性金属暴露 [砷 (As)、镉 (Cd)、锰 (Mn) 和铅 (Pb)] 在几个关键的发育时间窗口和我们将通过测量来评估儿童的免疫功能。 4、6、8、10-11 和 13-15 岁时针对计划的儿童疫苗接种的抗体水平（即麻疹、腮腺炎、风疹、白喉、破伤风和百日咳）。对单个金属（Cd、Pb）和金属混合物（As、Cd、Mn、Pb）可能会导致抗体反应较差 4 岁，并且 (ii) 存在对砷、锰和铅暴露敏感的关键窗口。金属暴露会诱发全身氧化应激（OS），导致免疫系统功能不佳。为了了解金属的促氧化作用，我们还将通过一种新型生物标记物——线粒体 DNA 来量化累积 OS （mtDNA）异质性，反映了 OS 诱导的 mtDNA 突变计数随着时间的推移而累积。数据显示，产前金属暴露与出生时线粒体 DNA 异质性计数有关。测量出生时、8 岁和 13-15 岁时的 mtDNA 异质性作为预测和调节因素在目标 1 中，我们将确定接触各种金属与抗体反应之间的关联。含有儿童抗体的金属混合物对特定年龄的疫苗接种的反应和抗体反应轨迹随着时间的推移，我们将确定对免疫毒性金属暴露的敏感性的关键窗口。在目标 3 中，我们将研究 mtDNA 之间的关联。异质性水平和（i）接触单个金属和金属混合物以及（ii）儿童抗体反应在特定年龄和抗体反应轨迹的疫苗接种我们将应用统计因果模型。评估线粒体生物标志物对金属免疫系统介导作用的策略完成这些目标将推动可能有助于预防终身免疫系统的干预措施。失调和相关的不良健康后果。