Vulnerability During Infancy to Immunotoxic Contaminant Exposures

婴儿期对免疫毒性污染物暴露的脆弱性

• 批准号: 9885685
• 负责人: PHILIPPE ADAM GRANDJEAN
• 金额: $ 53.85万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9885685
• 关键词: 5 year old; Adaptive Immune System; Address; Adult; Adverse effects; Affect; Age; Age-Months; Algorithms; American; Antibiotic Therapy; Antibodies; Antibody Formation; Antibody Response; Antigens; Attenuated; Attenuated Vaccines; Benchmarking; Birth; Blood specimen; Breast Feeding; Cell Count; Cellular Phone; Child; Childhood; Clinical; Cohort Studies; Communicable Diseases; Consensus; Data; Development; Dioxins; Diphtheria; Dose; Ensure; Environmental Risk Factor; Equation; Exposure to; Faeroe Islands; Frequencies; Guidelines; Haemophilus Vaccines; Human; Human Milk; Immune system; Immunization; Immunologics; Immunosuppression; Immunotoxicology; Impairment; Incidence; Individual; Infant; Infection; Lead; Leukocytes; Life; Link; Lymphocyte Subset; Maternal antibody; Measures; Mediating; Mediation; Milk; Modeling; Monitor; Mothers; Multivariate Analysis; Organism; Pneumococcal vaccine; Polychlorinated Biphenyls; Population Study; Prevention; Proteins; Public Health; Reporting; Research; Resistance; Risk; Risk Assessment; Role; Sampling; Seafood; Serum; Statistical Data Interpretation; Structure; Study models; System; Systems Development; T-Lymphocyte; Technology; Testing; Tetanus; Thymus Gland; Time; Toxic Environmental Substances; Toxoids; Translating; United States Environmental Protection Agency; Vaccination; Vaccines; World Health Organization; antigen challenge; cohort; contaminated water; drinking water; early life exposure; exposure pathway; immune function; immune system function; immunotoxicity; improved; infancy; insight; maternal serum; negative affect; novel; pathogen; pollutant; postnatal; prenatal; prospective; recruit; response; socioeconomics; vaccine efficacy; virtual

Abstract Our studies have demonstrated that developmental exposure to perfluorinated alkylate substances (PFAS) are associated with attenuated antibody responses to routine childhood vaccines. Our most recent findings suggest that breastfeeding can transfer PFAS to the infant and lead to substantial elevations of serum-PFAS concentrations, with possible adverse implications for immune system development. As blood samples from infancy were not available to us in previous studies, we modeled the concentrations of early-life serum-PFAS and showed that levels of early postnatal serum-PFAS are inversely associated with antibody concentrations measured at age 5 years, more so than serum concentrations measured at age 18 months or later. The present proposal will obtain blood samples in infancy and maternal milk for analysis of PFAS to improve the modeling of profiles of serum-PFAS during infancy. This will allow testing of the hypothesis that early-life exposure to immunotoxic PFAS impair the development of the adaptive immune system and negatively affects the efficacy of routine childhood vaccines. The extended model of serum-PFAS will be used for estimation of exposures of PFAS in infancy among >1,000 children from previous cohorts, where serum samples from infancy were not collected. In addition to blood sampling at ages 3 and 12 months in the new cohort, we will use novel cell phone technology to allow mothers to record breastfeeding, occurrence of infectious disease, antibiotic treatment, and other relevant study parameters every two weeks. Our focus on vaccines will include toxoids (diphtheria and tetanus), as these de novo protein vaccines are known to be the most reliable clinical indicators of immune suppression. The duration of breastfeeding will be considered both as an exposure pathway and a moderator, as breastfeeding is considered to be advantageous for the child’s immune system development. The proposed study will be carried out at the Faroe Islands, where excellent conditions are available to recruit the birth cohort and to ensure a high participation rate and minimal socioeconomic confounding. Exposures of PFAS mainly originate from seafood and vary substantially, while average serum concentrations are similar to U.S. levels. A cohort size of 600 can be recruited within 16 months and will provide appropriate statistical power as one of the largest so far in the field. At 3 and 12 months of age, vaccine antibodies, thymus size, and advanced differential white cell counts will be assessed. Statistical data analysis will include multivariate analysis, assessment of mediation and/or modulation, structural equation modeling of combined exposure of exposure associations of PFAS with immune functions, and benchmark dose calculations. While research on immunotoxicology has traditionally focused on adverse effects in the mature organism, this proposal aims to characterize immunotoxic risks from developmental exposure to these priority pollutants at the most vulnerable developmental stages in early life.

抽象的 我们的研究表明，发育过程中接触全氟烷基化物 (PFAS) 的影响 与常规儿童疫苗的抗体反应减弱有关。我们的最新发现 表明母乳喂养可以将 PFAS 转移给婴儿并导致血清 PFAS 大幅升高 浓度，可能对免疫系统发育产生不利影响。作为血液样本 在之前的研究中，我们无法获得婴儿期的数据，因此我们模拟了生命早期血清 PFAS 的浓度 并表明出生后早期血清 PFAS 水平与抗体浓度呈负相关 5 岁时测量的血清浓度高于 18 个月或以后测量的血清浓度。这 目前的提案将获取婴儿和母乳中的血液样本进行 PFAS 分析，以改善 婴儿期血清 PFAS 谱的建模。这将允许检验早期生命的假设 接触具有免疫毒性的 PFAS 会损害适应性免疫系统的发育并对 常规儿童疫苗的功效。血清-PFAS的扩展模型将用于估计 来自先前队列的超过 1,000 名儿童在婴儿期接触 PFAS，其中血清样本来自 婴儿期未收集。除了在新队列中 3 个月和 12 个月时进行血液采样外，我们还将 利用新颖的手机技术让妈妈记录母乳喂养、传染病的发生、 每两周一次抗生素治疗和其他相关研究参数。我们对疫苗的关注将包括 类毒素（白喉和破伤风），因为这些从头蛋白疫苗被认为是最可靠的临床疫苗 免疫抑制指标。母乳喂养的持续时间将被视为暴露 途径和调节剂，因为母乳喂养被认为对孩子的免疫系统有利 发展。拟议的研究将在法罗群岛进行，那里条件优越 可用于招募出生队列并确保高参与率和最低的社会经济条件 令人困惑。 PFAS 的暴露主要来自海鲜，且差异很大，而平均血清 浓度与美国水平相似。 16 个月内可招募 600 人的队列，并将 作为该领域迄今为止最大的统计能力之一，提供了适当的统计能力。在 3 个月和 12 个月大时， 将评估疫苗抗体、胸腺大小和高级白细胞分类计数。统计数据 分析将包括多变量分析、中介和/或调节评估、结构方程 PFAS 暴露与免疫功能关联的联合暴露模型和基准 剂量计算。虽然免疫毒理学研究传统上侧重于不良反应 成熟的有机体，该提案旨在描述发育暴露于这些成熟有机体的免疫毒性风险 生命早期最脆弱发育阶段的优先污染物。