Early-life bisphenol A, immune dysregulation, and inner-city pediatric asthma

描述（由申请人提供）：该基金是对最近数据的回应，这些数据表明双酚A（BPA）可能会导致哮喘，可能是通过加剧炎症和T调节细胞功能障碍。初步数据显示，早期生活中BPA暴露与儿童后期喘息和呼出的一氧化氮（FeNO，气道炎症的标志物）分数浓度之间存在剂量依赖性关联。BPA是一种普遍存在的环境雌激素，用于食品和饮料容器衬里。儿童长期低剂量接触的影响基本上是未知的。我们建议在一项正在进行的纵向出生队列研究的基础上，评估产前和生命早期暴露于BPA是否与7-10岁儿童喘息、FeNO和哮喘（通过标准化医生评估测量）增加相关。这项研究将在哥伦比亚儿童环境健康中心（CCCEH）的330名前瞻性出生队列儿童中进行，这些儿童自怀孕以来一直接受随访。另一个目的是探索BPA暴露是否通过改变调节性T细胞（Treg）数量和功能或改变抗原呈递细胞（APC）上抑制分子的表达与哮喘发生机制性联系。BPA浓度将通过经认证的实验室在储存的尿液样本中进行测定，这些样本是从产前母亲和3-5岁儿童以及7-10岁儿童新收集的尿液中收集的。在控制相关协变量后，将使用多元线性或逻辑回归分析来确定BPA暴露与父母在年度问卷中报告的儿童喘息、医生对哮喘的诊断、FeNO和7至10岁时的免疫球蛋白（IG）E水平之间的相关性。BPA对T调节细胞通路的影响将通过Treg细胞计数，记忆与幼稚T细胞的比率以及从7-10岁儿童收集的血液样本中的T辅助细胞（Th）细胞因子产生水平进行研究。BPA对抗原呈递细胞途径的影响将通过抗原特异性淋巴细胞增殖试验、共刺激和抑制分子的表达水平以及促炎细胞因子产生水平进行检测。这项工作将服务于NIEHS的目标：确定产前和生命早期暴露于BPA对免疫系统发育和哮喘风险的影响。我们汇集了一支经验丰富、富有成效的多学科研究科学家团队，他们具有独特的优势，可以解决BPA暴露是否与哮喘和气道炎症的发展相关。此外，该团队可以探索关于环境暴露于BPA，特异性免疫失调（包括对T调节细胞功能和抗原呈递的影响）以及哮喘表型元素之间联系的新假设。GO赠款资金将确保该提案中发现的结果在两年内通过同行评审文献中发表的手稿向公众公布。 公共卫生相关性：该提案旨在建立在一项正在进行的纵向出生队列研究的基础上，以评估产前和生命早期暴露于BPA是否与7-10岁儿童喘息、FeNO和哮喘（通过标准化医生评估测量）增加相关。这项研究将在哥伦比亚儿童环境健康中心（CCCEH）的330名前瞻性出生队列儿童中进行，这些儿童自怀孕以来一直接受随访。另一个目的是探索BPA暴露是否通过改变调节性T细胞（Treg）数量和功能或改变抗原呈递细胞（APC）上抑制分子的表达与哮喘发生机制性联系。

DESCRIPTION (provided by applicant): This grant is responsive to recent data suggesting that bisphenol A (BPA) may contribute to asthma, possibly through heightened inflammation and T regulatory cell dysfunction. Preliminary data show a dose-dependent association between early-life BPA exposure and later childhood wheeze and fractional concentration of exhaled nitric oxide (FeNO, a marker of airway inflammation). BPA is a ubiquitous environmental estrogen used in food and beverage container linings. Effects of chronic, low-dose exposure in children are largely unknown. We propose to build on an ongoing longitudinal birth cohort study to evaluate whether prenatal and early-life exposure to BPA will be associated with increased wheeze, FeNO, and asthma (as measured by standardized physician evaluation) in children ages 7-10 years. The study will be undertaken among 330 children enrolled in the prospective birth cohort of the Columbia Center for Children's Environmental Health (CCCEH) who have been followed since pregnancy. An additional aim is to explore whether BPA exposure is mechanistically linked to asthma via altered T regulatory (Treg) cell number and function or altered expression of inhibitory molecules on antigen presenting cells (APCs). BPA concentrations will be assayed via an accredited laboratory in stored urine samples collected from mothers prenatally and children at ages 3-5 years and, in newly collected urine at child ages 7-10 years. Multiple linear or logistic regression analyses will be used to determine associations between BPA exposure and parental report of child wheeze on annual questionnaires, physician diagnosis of asthma, FeNO, and immunoglobulin (Ig)E levels at age 7 to 10 years after controlling for relevant covariates. Effects of BPA on T regulatory cell pathways will be investigated via Treg cell counts, ratio of memory to na¿ve T cells, and T helper (Th) cytokine production levels in blood samples collected from the children at ages 7-10 years. Effects of BPA on antigen presenting cell pathways will be tested via antigen-specific lymphoproliferation assays, expression levels of costimulatory and inhibitory molecules, and proinflammatory cytokine production levels. This work will serve the goals of NIEHS: to identify the impact of prenatal and early-life exposure to BPA on the developing immune system and risk of asthma. We bring together a highly experienced and productive team of multidisciplinary research scientists who are uniquely positioned to address whether BPA exposure is associated with the development of asthma and airway inflammation. Further, this team can explore novel hypotheses regarding links with environmental exposure to BPA, specific immune dysregulation that includes effects on T regulatory cell function and antigen presentation, and elements of the asthma phenotype. GO grant funding would ensure that results discovered in this proposal reach the public within two years via manuscripts published in the peer reviewed literature. PUBLIC HEALTH RELEVANCE: This proposal seeks to build on an ongoing longitudinal birth cohort study to evaluate whether prenatal and early-life exposure to BPA will be associated with increased wheeze, FeNO, and asthma (as measured by standardized physician evaluation) in children ages 7-10 years. The study will be undertaken among 330 children enrolled in the prospective birth cohort of the Columbia Center for Children's Environmental Health (CCCEH) who have been followed since pregnancy. An additional aim is to explore whether BPA exposure is mechanistically linked to asthma via altered T regulatory (Treg) cell number and function or altered expression of inhibitory molecules on antigen presenting cells (APCs).