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: 10337281
• 负责人: PHILIPPE ADAM GRANDJEAN
• 金额: $ 53.18万
• 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 2022-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10337281
• 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; 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; vaccine-induced antibodies; 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，发育性暴露于全氟烷基化物质（PFA）是 与对常规儿童疫苗的抗体反应相关。我们最近的发现 建议母乳喂养可以将PFA转移到婴儿身上，并导致血清PFA的大幅度升高 浓度，可能对免疫系统发展产生不利影响。作为来自 在先前的研究中，我们无法使用婴儿期，我们对早期血清PFA的浓度进行了建模 并表明早期产后血清PFA水平与抗体浓度成反比 在5岁时测量，比在18个月或更晚时测得的血清浓度更重要。 目前的建议将获得婴儿期和母乳中的血液样本，以分析PFA以改善 在婴儿期间血清PFA的轮廓建模。这将允许检验早期生活的假设 暴露于免疫毒性PFA会损害自适应免疫系统的发展，并对 常规儿童疫苗的效率。血清PFA的扩展模型将用于估计 来自以前队列的> 1000名儿童在婴儿期的PFA暴露，血清样本来自 未收集婴儿期。除了在新队列中的3和12个月的3个月和12个月的血液采样外，我们还将 使用新颖的手机技术，让母亲记录母乳喂养，发生传染病， 抗生素治疗和其他相关研究参数每两周一次。我们对疫苗的关注包括 毒素（白喉和tetanius），因为这些新蛋白疫苗是最可靠的临床疫苗 免疫抑制的指标。母乳喂养的持续时间将被视为曝光 途径和主持人，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，那里的条件极佳 可用于招募出生队列并确保高参与率和最小的社会经济 混淆。 PFA的暴露主要起源于海鲜，而平均序列有很大差异 浓度与美国水平相似。可以在16个月内招募600个队列的大小，并将 提供适当的统计能力，作为迄今为止该领域最大的统计能力之一。在3个月和12个月大时， 将评估疫苗抗体，胸腺大小和高级差异细胞计数。统计数据 分析将包括多元分析，调解和/或调制的评估，结构方程 PFA与免疫功能的暴露关联组合暴露与基准建模 剂量计算。传统上，对免疫毒理学的研究集中在不利影响上 成熟的有机体，该提案旨在表征从发育暴露中的免疫毒性风险 早期最脆弱的发育阶段的优先污染物。