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

描述（由申请人提供）：最近的数据表明双酚A （BPA）可能与哮喘有关，可能是通过炎症加剧和T调节细胞功能障碍。初步数据显示，早期BPA暴露与儿童后期喘息和呼出一氧化氮分数浓度（FeNO，气道炎症的标志）之间存在剂量依赖关系。双酚a是一种普遍存在于食品和饮料容器衬里的环境雌激素。慢性低剂量暴露对儿童的影响在很大程度上是未知的。我们建议建立一项正在进行的纵向出生队列研究，以评估产前和早期生活暴露于BPA是否与7-10岁儿童的喘息、FeNO和哮喘（通过标准化医师评估测量）增加有关。这项研究将在330名儿童中进行，这些儿童从怀孕开始就被纳入哥伦比亚儿童环境健康中心（CCCEH）的预期出生队列。另一个目的是探索BPA暴露是否通过改变T调节性（Treg）细胞数量和功能或改变抗原提呈细胞（APCs）上抑制分子的表达而与哮喘有机械联系。双酚a浓度将通过认可的实验室检测从母亲产前和3-5岁儿童收集的尿液样本，以及7-10岁儿童新收集的尿液样本。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双酚a暴露与父母在年度问卷中报告儿童喘息、医生诊断哮喘、FeNO和7至10岁时免疫球蛋白（Ig）E水平之间的关系。BPA对T调节细胞通路的影响将通过从7-10岁儿童的血液样本中收集的Treg细胞计数、记忆T细胞与记忆T细胞的比率和辅助性T细胞因子的产生水平来研究。双酚a对抗原提呈细胞通路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的产生水平进行测试。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对发育中的免疫系统和哮喘风险的影响。我们汇集了一个经验丰富和富有成效的多学科研究科学家团队，他们在解决BPA暴露是否与哮喘和气道炎症的发展有关方面处于独特的地位。此外，该团队可以探索与环境暴露于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）以及哮喘表型因素相关的新假设。GO的资助将确保在两年内通过在同行评审文献中发表的手稿向公众公布本提案中的结果。

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).