Vulnerability During Infancy to Immunotoxic Contaminant Exposures

摘要 我们的研究表明，全氟烷基化物（PFAS）的发育暴露 与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转移给婴儿，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， 在以前的研究中，我们无法获得婴儿期，我们模拟了早期生活血清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 在5岁时测量，高于在18个月或更大时测量的血清浓度。的 目前的建议将获得婴儿和母乳中的血液样本，用于PFAS分析，以改善 婴儿期血清PFAS谱的建模。这将有助于检验早期生命 暴露于免疫毒性PFAS会损害适应性免疫系统的发育， 常规儿童疫苗的有效性。血清-PFAS的扩展模型将用于估计 来自先前队列的> 1，000名儿童在婴儿期的PFAS暴露，其中来自 未收集婴儿。除了在新的队列中在3岁和12个月大时采集血样外，我们还将 利用新型手机技术，让母亲记录母乳喂养，传染病的发生， 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已知是最可靠的临床 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，那里条件优越， 确保高参与率和最低的社会经济收入， 真让人困惑PFAS的暴露主要来源于海产品，并且变化很大，而平均血清 浓度与美国相似。600人的队列规模可以在16个月内招募， 提供适当的统计功效，是该领域迄今为止最大的统计功效之一。在3个月和12个月大的时候， 将评估疫苗抗体、胸腺大小和晚期分类白色细胞计数。统计数据 分析将包括多变量分析、中介和/或调节的评估、结构方程 PFAS暴露与免疫功能的联合暴露模型和基准 剂量计算。虽然免疫毒理学的研究传统上集中在免疫系统的不良反应上， 成熟的生物体，该提案旨在描述发育暴露于这些 在生命早期最脆弱的发育阶段优先处理污染物。

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.