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.

摘要 我们的研究表明，发育过程中暴露于全氟烷化物质(PFAS)是 与对常规儿童疫苗的抗体反应减弱有关。我们最新的发现 提示母乳喂养可将PFAS传递给婴儿，并导致血清PFAS显著升高 浓度，可能对免疫系统发育产生不利影响。作为血液样本来自 在以前的研究中，我们无法获得婴儿期的数据，我们模拟了早期血清-PFAS的浓度 研究表明，出生后早期的血清-pfas水平与抗体浓度呈负相关。 在5岁时测量，比在18个月或更长时间测量的血清浓度更高。这个 目前的建议将采集婴儿和母亲母乳的血液样本进行全氟辛烷磺酸分析，以改善 婴儿期血清全氟辛烷酸谱的模拟。这将允许对早期生命的假设进行检验 暴露于免疫毒性全氟辛烷磺酸会损害适应性免疫系统的发育，并产生负面影响。 常规儿童疫苗的效力。扩展的血清-PFAS模型将用于估计 来自以前队列的1000名儿童在婴儿期暴露于PFAS，其中血清样本来自 婴儿没有被收集。除了在新的队列中对3岁和12个月大的婴儿进行血液采样外，我们还将 使用新颖的手机技术，让母亲可以记录母乳喂养，传染病的发生， 抗生素治疗，以及其他相关研究参数每两周一次。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是已知的最可靠的临床疫苗 免疫抑制的指标。母乳喂养的持续时间将被视为 途径和调节剂，因为母乳喂养被认为对儿童的免疫系统有利 发展。拟议的研究将在法罗群岛进行，那里的条件很好 可用于招募出生队列，并确保高参与率和最低社会经济 令人困惑。全氟辛烷磺酸的暴露主要来自海鲜，差异很大，而平均血清 浓度与美国的水平相似。可以在16个月内招募600人的队列，并将 提供适当的统计力量，作为该领域迄今最大的之一。在3个月和12个月大的时候， 将对疫苗抗体、胸腺大小和高级分类白细胞计数进行评估。统计数据 分析将包括多变量分析、调节和/或调节的评估、结构方程 全氟辛烷磺酸暴露与免疫功能和基准的联合暴露模型 剂量计算。虽然免疫毒理学的研究传统上集中在 成熟的生物体，这项建议旨在表征发育过程中暴露于这些物质的免疫毒性风险 优先考虑生命早期最脆弱的发育阶段的污染物。