This highly innovative project addresses the role of epigenetic changes in the pathogenesis of childhood asthma. There is growing evidence, some from our own research, that prenatal exposure to polycyclic aromatic hydrocarbons (PAH), common urban pollutants from traffic and other combustion sources, may be a risk factor for asthma in childhood. Following up on a recent pilot study that demonstrated proof of principle, the proposed research will determine whether epigenetic changes related to prenatal PAH exposure are involved in the pathogenic process of childhood asthma. The first study will utilize banked human cord white blood cells, paired placental tissue, and clinical outcome data from children, now aged 9/10 years) who are participants in a prospective cohort study in minority communities in New York City (CCCEH cohort). Analysis of DNA methylation in cord blood DMA and gene expression in placental tissue from these children will be used to identify candidate genes that may be involved in the mechanistic pathway between prenatal PAH exposure and childhood asthma at age 9-10 (i.e., that are differentially methylated and expressed in the high vs. low PAH exposure groups). The set of candidate genes will then be tested as potential biologic markers predictive of childhood asthma in this study sample. Those genes that are found to be predictive will then comprise a "candidate epigenome" to be confirmed in a closely linked animal model. In this complementary animal model, pregnant mice will be exposed to a PAH mixture of similar composition to that measured in air samples from the CCCEH cohort. Blood, placenta and target tissue (lung and spleen) collected from offspring at delivery will be examined for PAH-related changes in gene methylation and gene expression, respectively. A group of offspring prenatally exposed will be followed for 4 weeks to determine asthma-like phenotype. Criteria for selecting the final biomarker(s) will be a) high concordance between gene methylation in white blood cells and gene expression in target tissue and b) significant association with asthma-like phenotype. It is anticipated that this research will provide valuable new data on the role of epigenetic changes in the pathogenesis of childhood asthma. If specific methylation changes induced in utero are found to predict asthma and ultimately validated, we will have identified clinically relevant biomarkers for predicting asthma risk in children. ExpandCollapse Abstract