Influence of Exposure to a Mixture of PFAS and Metals on the developing immune system

项目2：总结/摘要 出生前和幼儿期的早期暴露可导致发育中的持久后果。 健康与疾病贯穿整个生命过程。两大类无处不在的化学物质几乎被检测到 在人类群体中普遍存在的是金属和合成全氟烷基和多氟烷基物质（PFAS）。 金属和准金属，如铅和砷，是已知的有害物质，产前暴露 已被证明可以调节发育中的免疫系统。同样，暴露于PFAS一直是 与对重要的儿童免疫接种（如破伤风）的免疫反应下降有关， 白喉疫苗。然而，我们对这两类化学品的综合影响的理解， 发育中的免疫系统和免疫反应仍然有限。虽然儿童免疫仍然存在， 我们对生命早期化学品暴露如何影响免疫系统的理解是公共卫生预防的基石 系统的发展和反应仍然极为有限。更有限的是我们对 在生命早期多次接触化学品对免疫系统的共同作用。当前风险评定 对这些化合物的评估是以成人为终点，并对单一化学品的暴露进行估计。我们 建议全面系统地调查产前和生命早期暴露于 金属混合物和PFAS对免疫系统发育的影响及其对疫苗诱导免疫的影响。 我们正在利用来自Viva项目的标本，这是一个在马萨诸塞州波士顿招募的前瞻性出生队列， 确定妊娠早期金属和PFAS的产前混合物是否单独或联合相关， 出生时与脐带血细胞因子和淋巴细胞增殖的混合物; 2）定量产前 金属/PFAS混合物与破伤风、白喉和百日咳（TDAP）以及麻疹、腮腺炎有关， 风疹（MMR）疫苗在儿童中期（~7岁）的滴度，并评估出生后 儿童期金属和PFAS暴露有助于这种关系;以及3）测试DNA甲基化特征 出生时测量的白细胞介导产前化学品暴露与TDAP降低之间的关联 和儿童期MMR疫苗抗体应答。在这个项目中，我们将测试纵向协会在一个大的 具有详细混杂因素信息和现有高质量数据和样本的母子配对队列。我们 将采用新的统计方法来测试不同的产前和产后环境混合物， 全面量化化学品暴露对免疫系统和疫苗发育的影响- 诱导免疫。该项目将提供有关PFAS发育免疫毒性的关键知识， 金属，单独和作为混合物，在环境相关的浓度为美国人口。的 这项研究的免疫参数具有临床相关性，将有助于为个人的风险评估提供信息 以及旨在保护儿童的公共卫生准则。

PROJECT 2: SUMMARY/ABSTRACT Early-life exposures, both prenatally and in early childhood, can lead to lasting consequences in the development of health and disease throughout the life-course. Two major classes of ubiquitous chemicals detected almost universally across human populations are metals and synthetic per- and polyfluoroalkyl substances (PFAS). Metals and metalloids, such as lead and arsenic, are known hazardous substances and prenatal exposure has been shown to modulate the developing immune system. Similarly, exposure to PFAS consistently has been associated with decreased immune response to important childhood immunizations like the tetanus and diphtheria vaccines. However, our understanding of the combined impact of these two classes of chemicals on the developing immune system and immune response remains limited. While childhood immunization remains a cornerstone for public health prevention our understanding on how early-life chemical exposures affect immune system development and response remains extremely limited. Even more limited is our understanding of the joint contribution of multiple chemical exposures in early life on the immune system. Current risk assessments for these compounds are performed with adult endpoints and estimates of exposure to a single chemical. We propose to comprehensively and systematically investigate the influence of prenatal and early-life exposure to a mixture of metals and PFAS on the developing immune system and their influence on vaccine-induced immunity. We are leveraging specimens from Project Viva, a prospective birth cohort recruited in Boston, MA to 1) Determine if a prenatal mixture of first trimester metals and PFAS are individually and jointly associated as a mixture with cord blood cytokines and lymphocyte proliferation at birth; 2) Quantify the extent to which a prenatal metal/PFAS mixture is associated with Tetanus, Diphtheria and Pertussis (TDAP) and Measles, Mumps, and Rubella (MMR) vaccine titers in mid-childhood (~7 years of age) and evaluate the extent to which postnatal childhood metal and PFAS exposure contributes to this relationship; and 3) Test if DNA methylation signatures at birth measured in leukocytes mediate associations between prenatal chemical exposure and reduced TDAP and MMR vaccine antibody response in childhood. In this project we will test longitudinal associations in a large cohort of mother-child pairs with detailed confounder information and existing high-quality data and samples. We will implement novel statistical methodology to test different prenatal and postnatal environmental mixtures to comprehensively quantify the impact of chemical exposures on the developing immune system and vaccine- induced immunity. This project will provide critical knowledge on the developmental immunotoxicity of PFAS and metals, individually and as a mixture, at environmentally relevant concentrations for the U.S. population. The immune parameters of this research are clinically relevant and will help inform risk assessments for individuals as well as public health guidelines with the goal of protecting children.