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

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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).