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

生命早期的双酚 A、免疫失调和市中心小儿哮喘

• 批准号: 7854582
• 负责人: Robin Marjorie Whyatt
• 金额: $ 72万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7854582
• 关键词: Accounting; Address; African American; Age; Allergens; Antigen Presentation; Antigen-Presenting Cells; Antigens; Asthma; Beverages; Biological Assay; Biometry; Birth; Blood specimen; Cell Count; Cell physiology; Cells; Child; Childhood; Childhood Asthma; Chronic; Cohort Studies; Data; Development; Diagnosis; Disease; Dominican; Dose; Elements; Endocrine Disruptors; Enrollment; Ensure; Environmental Estrogen; Environmental Exposure; Environmental Health; Environmental Risk Factor; Epidemiologic Studies; Ethnic Origin; Evaluation; Exhalation; Exposure to; Food; Functional disorder; Funding; Goals; Grant; Hospitalization; Hypersensitivity; IgE; Immune; Immune system; Immunoglobulins; Immunology; Inflammation; Interdisciplinary Study; Laboratories; Life; Link; Logistic Regressions; Manuscripts; Measures; Memory; Molecular Epidemiology; Mothers; National Institute of Environmental Health Sciences; Nitric Oxide; Parents; Pathway interactions; Peer Review; Pharmaceutical Preparations; Phenotype; Physicians; Positioning Attribute; Predisposition; Pregnancy; Prevalence; Production; Public Health; Publications; Publishing; Pulmonology; Questionnaires; Recording of previous events; Regression Analysis; Reporting; Research; Research Personnel; Respiratory physiology; Review Literature; Risk; Sampling; Schools; Scientist; Serum; T-Cell Activation; T-Lymphocyte; Testing; Time; United States National Institutes of Health; Universities; Urine; Wheezing; Work; airway inflammation; bisphenol A; cohort; cost; cytokine; experience; health care service utilization; inner city; multidisciplinary; novel; postnatal; prenatal; prospective; public health relevance; response; sex; standardize measure; urinary

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).

描述（由申请人提供）：这项资助是对最近数据的回应，这些数据表明双酚 A (BPA) 可能通过加剧炎症和 T 调节细胞功能障碍而导致哮喘。初步数据显示，生命早期接触 BPA 与儿童后期喘息和呼出一氧化氮（FeNO，气道炎症标志物）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内衬。长期、低剂量接触对儿童的影响在很大程度上尚不清楚。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接触 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）增加有关。这项研究将在哥伦比亚儿童环境健康中心 (CCCEH) 前瞻性出生队列中的 330 名儿童中进行，这些儿童自怀孕以来一直受到跟踪。另一个目的是探讨 BPA 暴露是否通过改变 T 调节 (Treg) 细胞数量和功能或改变抗原呈递细胞 (APC) 上抑制分子的表达而与哮喘发生机制相关。 BPA 浓度将通过认可的实验室对产前母亲和 3-5 岁儿童收集的储存尿液样本以及新收集的 7-10 岁儿童尿液样本进行测定。在控制相关协变量后，将使用多重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 岁时免疫球蛋白 (Ig)E 水平之间的关联。 BPA 对 T 调节细胞通路的影响将通过从 7-​​10 岁儿童采集的血液样本中的 Treg 细胞计数、记忆 T 细胞与幼稚 T 细胞的比率以及辅助性 T (Th) 细胞因子的产生水平来研究。 BPA 对抗原呈递细胞途径的影响将通过抗原特异性淋巴增殖测定、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接触 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，他们在研究 BPA 暴露是否与哮喘和气道炎症的发展相关方面具有独特的优势。此外，该团队还可以探索有关 BPA 环境暴露、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）以及哮喘表型要素之间关系的新假设。 GO 拨款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。 公共健康相关性：该提案旨在以一项正在进行的纵向出生队列研究为基础，评估产前和生命早期接触 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) 前瞻性出生队列中的 330 名儿童中进行，这些儿童自怀孕以来一直受到跟踪。另一个目的是探讨 BPA 暴露是否通过改变 T 调节 (Treg) 细胞数量和功能或改变抗原呈递细胞 (APC) 上抑制分子的表达而与哮喘发生机制相关。