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

接触 PFAS 和金属的混合物对免疫系统发育的影响

• 批准号: 10349969
• 负责人: Andres Cardenas
• 金额: $ 28.06万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-04-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10349969
• 关键词: 7 year old; Accounting; Address; Adult; Affect; Animal Model; Antibody Formation; Antibody Response; Antibody titer measurement; Arsenic; Attenuated; Biological Markers; Birth; Blood; Boston; Chemical Exposure; Chemicals; Child; Childhood; Cohort Studies; Complex; DNA Methylation; Data; Data Science; Development; Diphtheria; Diphtheria Toxoid; Disease; Dose; Environment; Environmental Exposure; Environmental Pollution; Exposure to; First Pregnancy Trimester; Genes; Goals; Guidelines; Hazardous Substances; Health; Human; Immune; Immune response; Immune system; Immunity; Immunization; Immunologic Markers; Individual; Interleukin-10; Interleukin-13; Interleukin-6; Joints; Knowledge; Lead; Leukocytes; Life; Life Cycle Stages; Measles; Measles-Mumps-Rubella Vaccine; Measures; Mediating; Mediator of activation protein; Mercury; Metal exposure; Metals; Methodology; Methods; Mothers; Mumps; Pathway interactions; Pertussis; Plasma; Poison; Poly-fluoroalkyl substances; Population; Pregnancy; Prevention; Prevention strategy; Public Health; Reporting; Research; Risk; Risk Assessment; Rubella; S-Phase Fraction; Sampling; School-Age Population; Serology; Specimen; Systems Development; TNF gene; Testing; Tetanus; Tetanus Vaccine; Toxicology; Umbilical Cord Blood; Vaccination; Vaccines; Water Pollutants; clinically relevant; cohort; cytokine; early childhood; early life exposure; epidemiology study; epigenome; exposed human population; genome-wide; immunoregulation; immunotoxicity; lymphocyte proliferation; novel; offspring; postnatal; prenatal; prenatal exposure; prenatal influence; prospective; recruit; response; rubella antibodies; vaccine-induced immunity

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.

项目 2：总结/摘要 生命早期的暴露，无论是产前还是儿童早期，都可能对发育产生持久的影响 整个生命过程中的健康和疾病。几乎检测到两大类普遍存在的化学物质 金属和合成的全氟烷基物质和多氟烷基物质 (PFAS) 是人类普遍存在的物质。 金属和准金属，例如铅和砷，是已知的有害物质，产前接触已 已被证明可以调节发育中的免疫系统。同样，接触 PFAS 的情况也一直存在 与破伤风等重要儿童免疫接种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了解 正在发育的免疫系统和免疫反应仍然有限。虽然儿童免疫接种仍然存在 公共卫生预防的基石我们对生命早期化学品暴露如何影响免疫的理解 系统开发和响应仍然极其有限。更有限的是我们对 生命早期多次接触化学物质对免疫系统的共同影响。当前的风险评估 对于这些化合物，是根据成人终点和单一化学品暴露估计值进行的。我们 提议全面、系统地调查产前和生命早期接触某种物质的影响 金属和 PFAS 的混合物对发育中的免疫系统及其对疫苗诱导免疫的影响。 我们正在利用来自 Project Viva 的样本，该项目是在马萨诸塞州波士顿招募的一个预期出生队列 1) 确定妊娠早期金属和 PFAS 的产前混合物是否单独或共同关联为 与出生时脐带血细胞因子和淋巴细胞增殖的混合物； 2) 量化产前检查的程度 金属/PFAS 混合物与破伤风、白喉和百日咳 (TDAP) 以及麻疹、流行性腮腺炎和 儿童中期（~7 岁）的风疹 (MMR) 疫苗滴度并评估产后的程度 童年时期的金属和 PFAS 接触促成了这种关系； 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 减少之间的关联 和儿童期 MMR 疫苗抗体反应。在这个项目中，我们将在大范围内测试纵向关联 母子对队列，具有详细的混杂信息和现有的高质量数据和样本。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，以 全面量化化学品暴露对发育中的免疫系统和疫苗的影响 诱导免疫。该项目将提供有关 PFAS 的发育免疫毒性和 金属，单独和作为混合物，其浓度与美国人口的环境相关。这 这项研究的免疫参数具有临床相关性，有助于为个人进行风险评估 以及以保护儿童为目标的公共卫生准则。