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.

Public Health Relevance

Asthma and allergic rhinitis are major public health problems, and are the most common chronic diseases of childhood in the United States. Fetal life exposures to dietary antioxidants and modifiable sources of oxidative stress (overweight, cigarette smoke, traffic pollution or acetaminophen) may have long-term effects on risk of these diseases, and risk may be further reduced or amplified by later childhood exposures. This study will contribute to development of targeted treatments and public health measures to prevent or control asthma and allergic disease.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Infectious Diseases, Reproductive Health, Asthma and Pulmonary Conditions Study Section (IRAP)
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Minnicozzi, Michael
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Brigham and Women's Hospital
United States
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Sen, S; Rifas-Shiman, S L; Shivappa, N et al. (2017) Associations of prenatal and early life dietary inflammatory potential with childhood adiposity and cardiometabolic risk in Project Viva. Pediatr Obes :
Fleisch, Abby F; Rifas-Shiman, Sheryl L; Rokoff, Lisa B et al. (2017) Associations of maternal prenatal smoking with umbilical cord blood hormones: the Project Viva cohort. Metabolism 72:18-26
Blomberg, Maria; Rifas-Shiman, Sheryl L; Camargo Jr, Carlos A et al. (2017) Low Maternal Prenatal 25-Hydroxyvitamin D Blood Levels Are Associated with Childhood Atopic Dermatitis. J Invest Dermatol 137:1380-1384
Trivedi, Michelle K; Sharma, Sunita; Rifas-Shiman, Sheryl L et al. (2017) Folic Acid in Pregnancy and Childhood Asthma: A US Cohort. Clin Pediatr (Phila) :9922817729482
Wright, Lakiea S; Rifas-Shiman, Sheryl L; Oken, Emily et al. (2017) Prenatal and Early-Life Fructose, Fructose-Containing Beverages, and Mid-Childhood Asthma. Ann Am Thorac Soc :
Sen, Sarbattama; Rifas-Shiman, Sheryl L; Shivappa, Nitin et al. (2016) Dietary Inflammatory Potential during Pregnancy Is Associated with Lower Fetal Growth and Breastfeeding Failure: Results from Project Viva. J Nutr 146:728-36
Harris, Maria H; Gold, Diane R; Rifas-Shiman, Sheryl L et al. (2016) Prenatal and childhood traffic-related air pollution exposure and childhood executive function and behavior. Neurotoxicol Teratol 57:60-70
Bunyavanich, Supinda; Rifas-Shiman, Sheryl L; Platts-Mills, Thomas A et al. (2016) Prenatal, perinatal, and childhood vitamin D exposure and their association with childhood allergic rhinitis and allergic sensitization. J Allergy Clin Immunol 137:1063-1070.e2
Tse, Sze Man; Rifas-Shiman, Sheryl L; Coull, Brent A et al. (2016) Sex-specific risk factors for childhood wheeze and longitudinal phenotypes of wheeze. J Allergy Clin Immunol 138:1561-1568.e6
Harris, Maria H; Gold, Diane R; Rifas-Shiman, Sheryl L et al. (2015) Prenatal and Childhood Traffic-Related Pollution Exposure and Childhood Cognition in the Project Viva Cohort (Massachusetts, USA). Environ Health Perspect 123:1072-8

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