This highly innovative project addresses the role of epigenetic changes in the pathogenesis of childhoodasthma. There is growing evidence, some from our own research, that prenatal exposure to polycyclicaromatic hydrocarbons (PAHs), common urban pollutants from traffic and other combustion sources, may bea risk factor for asthma in childhood. Following up on a recent pilot study that demonstrated proof oforinciple, the proposed research will determine whether epigenetic changes related to prenatal PAHexposure are involved in the pathogenic process of childhood asthma. The first study will utilize bankedhuman cord white blood cells, paired placental tissue, and clinical outcome data from children, now aged9/10 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 tissuefrom these children will be used to identify candidate genes that may be involved in the mechanistic pathwaybetween prenatal PAH exposure and childhood asthma at age 9-10 (i.e., that are differentially methylatedand expressed in the high vs. low PAH exposure groups). The set of candidate genes will then be tested aspotential biologic markers predictive of childhood asthma in this study sample. Those genes that are foundto be predictive will then comprise a 'candidate epigenome' to be confirmed in a closely linked animalmodel. In this complementary animal model, pregnant mice will be exposed to a PAH mixture of similarcomposition 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 genemethylation and gene expression, respectively. A group of offspring prenatally exposed will be followed for 4weeks to determine asthma-like phenotype. Criteria for selecting the final biomarker(s) will be a) highconcordance 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 valuablenew data on the role of epigenetic changes in the pathogenesis of childhood asthma. If specific methylationchanges induced in utero are found to predict asthma and ultimately validated, we will have identifiedclinically relevant biomarkers for predicting asthma risk in children.
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