Epigenomic Effects of Perinatal Exposure to Environmental Estrogens Promote the Development of Allergic Asthma

University Of Texas Med Br Galveston, Galveston TX

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Abstract

DESCRIPTION (provided by applicant): The prevalence of asthma, particularly among children in industrialized countries, has been increasing rapidly over the last 2-3 decades. We reported that exposure of mouse dams to the environmental estrogen (EE) bisphenol A (BPA) promotes the development of an asthma-like phenotype in their pups. The potential importance of our findings in mice for human asthma is supported by two recent birth cohort studies and an analysis of national survey data, each indicating an association between pre- or postnatal exposure to BPA and the prevalence of wheezing in children. Preliminary mechanistic studies on spleen cells from our mouse model suggest that perinatal exposure to BPA, followed by postnatal allergic sensitization, results in altered methylation of a key CpG motif in the promoter region of the IFN? gene in splenic DNA and over expression of IFN? mRNA and protein in both CD4+T and CD8+T cells. We also found that the effect of BPA exposure on asthma persisted through at least three matrilineal generations, suggesting that these epigenetic alterations of immune development are heritable. Initial relevance studies indicated that exogenous IFN? stimulates human cord (neonatal) blood basophils to increase their expression of major histocompatibility complex class II and inducible costimulatory-ligand, both of which are crucial for effective antigen-presenting activity, which can promote the development of T helper (Th) type 2. In this exploratory project, our observations on the epigenetic effects of BPA will be corroborated and extended to the whole DNA methylomes of several immune cell types, thereby providing a road map of the effects of BPA on asthma-related pathways. Our central hypothesis for this project is that fetal exposure to BPA induces epigenetic modulation of the developing immune systems, which promotes the development of childhood asthma and that these epigenetic effects can persists into adulthood and be passed to future generations. Based on our and others' recent findings, we will focus this project on the effects of a single EE, BPA on the DNA methylome of three populations of mouse splenocytes. Bioinformatics analyses of our findings will predict patterns of gene expression in CD4+T, CD8+T and antigen presenting cell (APC)s and define pathways and interactions that could promote the development of childhood asthma. We will test this central hypothesis in our mouse model by testing two specific hypotheses: Aim 1. Fetal exposure to BPA enhances postnatal allergic sensitization and promotes the development of an asthma-like phenotype, by causing epigenetic alterations in key genes in the CD4+T, CD8+T and/or APCs, and Aim 2. Key BPA-related alterations of DNA methylation patterns are transferred to subsequent generations. The outcomes of this exploratory project will provide a new understanding of the molecular basis by which exposure to BPA promotes the development of allergic asthma. Future studies will indicate whether similar mechanisms are also altered by other EEs, as well as developing programs to prevent or reverse these EE effects on the development of asthma.