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

摘要 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编程免疫失调，这种失调会在几年后显现。这 健康与发展的发育起源(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会对免疫的轨迹产生长期的影响 系统功能。免疫系统在子宫中开始发育，随着孩子的年龄和经历 感染和疫苗接种，不断扩大的抗体库成为它们终身免疫的一部分 记忆。儿童免疫功能及其对无处不在的免疫毒性金属反应的研究 在子宫和生命早期(0-5岁)经历的暴露在很大程度上被忽视了。我们将解决 墨西哥进展研究中的这一知识差距，该研究有免疫毒性金属暴露的测量 [砷(As)、镉(Cd)、锰(Mn)和铅(Pb)]在几个关键的发育时间窗口和 来自多种生物特征(牙齿、血液和尿液)。我们将通过测量来评估儿童的免疫功能 4岁、6岁、8岁、10-11岁和13-15岁儿童接种疫苗后的抗体水平 (即麻疹、腮腺炎、风疹、白喉、破伤风和百日咳)。我们的初步数据显示：(I)暴露于 对单个金属(Cd、Pb)和金属混合物(As、Cd、Mn、Pb)可能导致较差的抗体反应 (2)存在对砷、锰和铅暴露的临界易感性窗口。另外， 金属暴露导致全身氧化应激(OS)，导致免疫系统功能不佳。vt.给出 除了金属的助氧化作用外，我们还将通过一种新的生物标志物-线粒体DNA来量化累积的OS (MtDNA)异质性，反映OS诱导的mtDNA突变计数随时间积累。我们最初的 数据显示，出生前接触金属与出生时线粒体DNA异质性计数有关。我们会 在出生时和8岁和13-15岁时检测线粒体DNA异质性作为预测和调节 抗体反应。在目标1中，我们将确定接触个别金属和 含儿童抗体的金属混合物对特定年龄接种疫苗的反应和抗体反应轨迹 随着时间的推移。在目标2中，我们将确定免疫毒性金属暴露的关键窗口 儿童免疫系统在特定的年龄和随着时间的推移。在目标3中，我们将研究线粒体DNA与 异质性水平和(I)接触个别金属和金属混合物和(Ii)儿童抗体反应 在特定年龄接种疫苗和抗体反应轨迹。我们将应用统计因果模型 评价线粒体生物标记物在金属免疫系统中的中介作用的策略 两性关系。这些目标的实现将推动可能有助于预防终身免疫系统的干预措施 调节失调和相关的不利健康后果。

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.