Exploring epigenetic mechanisms of developmental immunology

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DESCRIPTION (provided by applicant): The overall goal of the proposed project is to obtain a mechanistic understanding of how developmental exposure to the pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) leads to permanent functional changes in the immune system. TCDD represents a large family of pollutants to which humans are currently exposed. The detection of dioxins and related chemicals in human breast milk and umbilical cord blood has aroused considerable public concern about negative health outcomes from exposure In utero and via lactation. In models using adult animals, TCDD is one of the most immunotoxic compounds known. Dioxin-like compounds are also developmental toxicants; however, very little is known about the mechanisms by which they cause these effects. TCDD and related compounds bind to and activate an orphan receptor, the aryl hydrocarbon receptor (AhR). The AhR is a ligand-activated transcription factor, therefore, alterations in gene expression are believed to underlie the toxicity resulting from fetal exposure to AhR agonists, however this has not been experimentally tested. The overall hypothesis for the proposed studies is that inappropriate activation of the AhR during development interferes with the normal programming of the immune system via epigenetic mechanisms, resulting in permanent defects in gene expression that lead to immune dysfunction later in life. We have preliminary data that support this hypothesis. Specifically, exposure of pregnant mice to TCDD leads to multiple defects in immune function in the adult offspring, including suppressed lymphocyte expansion and differentiation, altered cytokine production, and increased inflammation in the lung. These effects on function occur at developmental doses of TCDD that cause no detectable change in hematopoiesis (i.e., the tissues appear normal, but upon antigenic challenge respond in an abnormal manner). These observations suggest that the effects of TCDD on immune function are long-lasting and may be imprinted by maternal exposure. The proposed studies utilize resources and expertise provided by the Genomics and Bio-Informatics Core Laboratories associated with the Center for Reproductive Biology (CRB). The Principal Investigator has expertise in immunology, toxicology and prior experience with the design and conduct of developmental immunotoxicology research. Collaboration with Dr. Michael Griswold (WSU School of Molecular Biosciences), combined with CRB core facilities brings expertise and technical support in epigenetics, molecular biology, and genomics. Using these resources, the studies described in this application seek to address specific gaps in our knowledge about how chemical exposure at levels below those that are overtly toxic to the fetus result in defects in immune function later in life. Specifically, studies conducted in Aim 1 will determine the role of DNA methylation in defective expression of IFNy. In Aim 2, we will identify the specific cell population(s) responsible for the deregulated T cell function in developmentally exposed mice. Once this critical information is obtained, we will use gene expression profiling to further characterize changes in gene expression within the affected cells, and determine the contribution of epigenetic mechanisms to alterations in the expression of selected genes (Aim 3). Findings from these studies will improve our understanding of the mechanisms that underlie the fetal programming of adult diseases of the immune system.