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: 10512528
• 负责人: Elena Colicino
• 金额: $ 60.98万
• 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/10512528
• 关键词: 15 year old; 4 year old; 5 year old; Adaptive Immune System; Address; 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; Future; Goals; Gold; Growth; Health; Immune; Immune response; Immune system; Immunization; Immunologic Memory; Individual; Infection; Intervention; Knowledge; Lead; Lead levels; Life; Life Style; Manganese; Measles; Measures; Mediating; Mediator of activation protein; Metal exposure; Metals; Mexican; Mitochondria; Mitochondrial DNA; Mumps; Obesity; Oxidative Stress; 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; early life exposure; experience; heteroplasmy; immune function; immune system function; immunotoxicity; in utero; individual response; innovation; lead exposure; mitochondrial DNA mutation; novel; novel marker; oxidative damage; pandemic disease; prenatal; prevent; programs; response; social stressor; theories; vaccine formulation; vaccine response; 15 year old; 4 year old; 5 year old; Adaptive Immune System; Address; 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; Future; Goals; Gold; Growth; Health; Immune; Immune response; Immune system; Immunization; Immunologic Memory; Individual; Infection; Intervention; Knowledge; Lead; Lead levels; Life; Life Style; Manganese; Measles; Measures; Mediating; Mediator of activation protein; Metal exposure; Metals; Mexican; Mitochondria; Mitochondrial DNA; Mumps; Obesity; Oxidative Stress; 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; early life exposure; experience; heteroplasmy; immune function; immune system function; immunotoxicity; in utero; individual response; innovation; lead exposure; mitochondrial DNA mutation; novel; novel marker; oxidative damage; pandemic disease; 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.

概括 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 早期生命环境因素可能会在几年后针对体现的免疫失调。这 健康与发展的发展起源（DOHAD）理论认为早期的剂量和时机 免疫毒性环境暴露会对免疫轨迹产生长期的后果 系统功能。免疫系统开始在子宫内发展，随着儿童的年龄和经验 感染和疫苗接种，这是一种不断扩展的抗体曲目，成为其终身免疫的一部​​分 记忆。然而，对儿童免疫术功能的研究及其对无处不在的免疫毒性金属的反应 曝光 - 在子宫里经历过，并在生命的早期（0-5岁）被忽略了。我们将解决 墨西哥进度研究中的这种知识差距，该研究具有免疫毒性金属暴露的测量 [砷（AS），镉（CD），锰（MN）和铅（PB）]在几个关键的发展时间窗口和 来自多个生物因素（牙齿，血液和尿液）。我们将通过测量来评估儿童免疫功能 响应于计划的儿童疫苗接种的4、6、8、10-11和13-15岁的抗体水平 （即麻疹，腮腺炎，风疹，白喉，破伤风和百日咳）。我们的初步数据表明（i）曝光 对于单个金属（CD，Pb）和金属混合物（AS，CD，MN，Pb）可能会导致较差的抗体反应 年龄4岁，（ii）有关键的AS，MN和PB暴露的易感性。此外， 金属暴露诱导全身氧化应激（OS），导致免疫系统功能。给出 金属的促氧化作用，我们还将通过新型生物标志物 - 蒙上角色DNA来量化累积OS （mtDNA）异质，反映了OS诱导的mtDNA突变会随着时间的推移积累。我们的最初 数据表明，产前金属暴露与MTDNA出生时的杂质计数有关。我们将 测量出生时MTDNA异质性，并在8岁和13-15岁时作为预测和中介 抗体反应。在AIM 1中，我们将确定接触各个金属与 具有儿童抗体对特定年龄疫苗接种的金属混合物和抗体反应轨迹 随着时间的推移。在AIM 2中，我们将确定对免疫毒性金属暴露易感性的关键窗口 儿童免疫系统在特定年龄和随着时间的流逝。在AIM 3中，我们将研究mtDNA之间的关联 异质水平和（i）暴露于单个金属和金属混合物以及（ii）儿童抗体反应 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建模 评估线粒体生物标志物在金属 - 免疫系统上的中介作用的策略 关系。这些目标的完成将推动干预措施，以防止终身免疫系统 失调和相关的不良健康后果。