The Fetal and Childhood Environment, Oxidative Balance, Inflammation and Asthma

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DESCRIPTION (provided by applicant): Asthma and allergic rhinitis, the most common chronic diseases of childhood in the United States, are major public health problems. Characterized by variable airflow obstruction and airway inflammation, childhood asthma is thought to have its origins in fetal and infant development. Environmental exposures influencing oxidative balance during critical time windows may have long-lasting effects on child airway and immune function, epigenetic programming of inflammation, and consequent risk of symptomatic asthma. In Project Viva, increased wheeze risk in the first two years of life was associated with higher fetal life exposures to sources of oxidative stress/inflammation (adiposity, cigarette smoke, traffic pollution, and acetaminophen). Conversely, higher prenatal maternal antioxidant dietary intake reduced early-life wheeze risk. With 12 years of longitudinal data, Project Viva has the best design to assess whether these fetal exposures have long-lasting adverse or, in the case of antioxidants, protective effects against asthma or airway inflammation that persist into adolescence. We hypothesize the following: (1) At age 12, lower fetal life exposure to dietary antioxidants and higher fetal life/early childhood exposure to these sources of oxidative stress/inflammation will (a) increase risk of allergic rhinitis and active asthma; and (b) be relatd to intermediate age 12 phenotypes including differential DNA methylation of nasal cells, fractional exhaled nitric oxide (FeNO), and airflow obstruction. (2) Differential DNA methylation of nasal cells will relate, not only to allergic rhinitis, but also to FeNO and active asthma. Finaly, (3) The relation of fetal life maternal dietary antioxidants and sources of oxidative stress/inflammation with nasal and pulmonary outcomes at age 12 will be captured by the following biomarkers in cord blood (a) Pro- and anti-inflammatory biomarkers in innate- and adiposity-related pathways [soluble TNF-¿ receptor-II, IL-6, and C-reactive protein; leptin and insulin-like growth factors I and II] and (b) Differential methylation of cord blood in genome-scal scans by the Illumina 450K BeadChip. We will validate the function of top nasal cell methylation marks on gene expression in the same nasal cell specimens. As well as performing external replication, we will externally validate the function of the top methylation marks in cord blood and nasal cells on gene expression in the Asthma BRIDGE project - a biorepository with methylation and gene expression data from blood, pulmonary macrophages and bronchial epithelium. By defining the longitudinal progression of epigenetic, inflammatory, and heterogeneous clinical respiratory responses to modifiable exposures influencing oxidative balance, this study will make a unique contribution to development of strategies for prevention and targeted treatment of asthma and allergic disease.