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：摘要/摘要 早期接触，无论是在产前还是在童年早期，都会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 在人类群体中普遍存在的是金属以及合成的全氟烷基和多氟烷基物质(PFAS)。 金属和类金属，如铅和砷，是已知的危险物质，产前暴露于 已被证明可以调节发育中的免疫系统。同样，接触全氟辛烷磺酸的风险一直是 与对破伤风和破伤风等重要儿童免疫接种的免疫反应降低有关 白喉疫苗。然而，我们对这两类化学品共同影响的理解是 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 作为公共卫生预防的基石，我们对早期接触化学物质如何影响免疫的理解 系统开发和反应仍然极其有限。更有限的是我们对 早期生命中多次接触化学物质对免疫系统的共同作用。当前风险评估 这些化合物是在成年终点和估计接触单一化学品的情况下进行的。我们 建议全面、系统地调查产前和早期接触a的影响。 金属和全氟辛烷磺酸混合物对发育中免疫系统的影响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预期出生队列1) 确定妊娠早期金属和全氟辛烷磺酸的产前混合物是否单独和共同关联为 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 金属/全氟辛烷磺酸混合物与破伤风、白喉和百日咳(TDAP)以及麻疹、腮腺炎和 儿童中期(~7岁)风疹(MMR)疫苗效价，并评估出生后 儿童时期接触金属和PFAS有助于这种关系；以及3)测试DNA甲基化特征 出生时白细胞测定在产前化学暴露与Tdap降低之间的调节作用 和儿童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 具有详细混杂信息和现有高质量数据和样本的母子对队列。我们 将实施新的统计方法来测试不同的产前和出生后环境混合物，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。该项目将提供关于全氟辛烷磺酸的发育免疫毒性的关键知识和 金属，无论是单独的还是混合的，对美国人口来说都是与环境相关的浓度。这个 这项研究的免疫参数具有临床相关性，并将有助于为个体的风险评估提供信息 以及旨在保护儿童的公共卫生指南。