Project 1 Childhood Immune Function and Exposure (Karagas)

项目1是达特茅斯儿童环境和疾病预防研究中心的核心。积累的数据表明，在胎儿发育和幼儿期的脆弱窗口期，砷暴露可能会产生各种不良影响。免疫力改变是实验研究和高暴露人群中被确定为受砷影响的关键途径之一。然而，美国并不存在与我们人口相关的水平的此类研究。感染是美国儿童最常见的疾病原因，也是全球儿童死亡的主要原因。此外，近年来，过敏和特应性已成为儿童发病率的一个更广泛的来源，原因尚不清楚。 我们从动物和流行病学研究的初步数据提供了机制和临床证据的异常免疫功能与砷暴露的婴儿。最近的研究还表明，某些环境暴露对儿童的疫苗反应有重大影响，但尚未研究砷对疫苗反应的影响。此外，新技术刚刚开始揭示生命早期肠道微生物组的建立对免疫系统成熟和能力以及金属生物转化的基本作用。 我们建议建立一个前瞻性队列研究，以确定砷的普遍暴露水平是否影响儿童的免疫反应，包括感染，过敏/特应性，疫苗反应和肠道微生物收购的风险。纵向出生队列研究包括1,000名新罕布什尔州居民的母子二人组，他们从私人威尔斯井中获得家庭用水，这是该地区砷暴露的潜在来源。我们将通过以下方式积极随访入组的婴儿：（1）每四个月与母亲进行一次间隔访谈;（2）筛选5岁以下的儿科记录。我们将与斯坦福大学的Kari Nadeau博士合作，要求婴儿在一年的健康儿童访视期间采集静脉血样，以检测对白喉/破伤风/百日咳、肺炎球菌和脊髓灰质炎疫苗的抗体反应。作为一个探索性的目标，我们将对重复粪便样本（在6周龄和12个月大时收集）中的细菌DNA进行测序，以评估子宫内和生命早期暴露于砷对发育中微生物组的影响之间的关系。据我们所知，这是美国第一个关于砷和儿童健康的前瞻性分子流行病学研究，也是美国少数几个有详细的幼儿感染信息沿着其他免疫相关变量的队列研究。

Project 1 is central to the overall Children's Environment and Disease Prevention Research Center at Dartmouth. Accumulating data suggest a variety of adverse effects that may result from arsenic exposure during the vulnerable window of fetal development and early childhood. Altered immunity is among the key pathways identified as affected by arsenic in experimental studies and in highly exposed populations. However, such studies do not exist for the US at levels relevant to our population. Infections are the most common causes of illnesses in children in US, and are the leading causes of deaths in children worldwide. Additionally, allergy and atopy have become a more widespread source of childhood morbidity in recent years for reasons as yet unknown. Our preliminary data from animal and epidemiologic studies provide both mechanistic and clinical evidence of aberrant immune function related to arsenic exposure in infants. Recent studies also suggest a significant impact of certain environmental exposures on vaccine response in children, but the effects of arsenic on vaccine response have not been investigated. Further, new technologies are just beginning to uncover the fundamental role of the establishment of the intestinal microbiome early in life on immune system maturation and competency as well as in metal biotransformation. We propose to build on a prospective cohort study to determine whether prevalent exposure levels of arsenic influence children's immune response including risk of infection, allergy/atopy, vaccine response and intestinal microbial acquisition. The longitudinal birth cohort study comprises 1,000 mother-child dyads who are residents of New Hampshire and obtain household water from private wells, a potential source of arsenic exposure in the region. We will actively follow infants enrolled in the cohort through: (1) interval interviews with the mothers every four months and (2) screening pediatric records up to age 5 years. We will request a venous blood sample from infants during their one-year.well-child visits to test for antibody response to diphtheria/tetanus/pertussis, pneumococcus and polio vaccines in collaboration with Dr. Kari Nadeau at Stanford University. As an exploratory aim, we will sequence bacterial DNA from repeated stool samples (collected at six weeks and 12 months of age) to assess the relation between in utero and early life exposure to arsenic on the developing microbiome. To our knowledge, this is among the first prospective molecular epidemiologic studies of arsenic and children's health in the US, and among the few cohorts in the US with detailed early childhood infection information along with other immune-related variables.