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Epigenetic mechanisms in Transgenerational Effects of an Environmental Pollutant

环境污染物跨代效应的表观遗传机制

基本信息

批准号：
10023261
负责人：
Mitzi Nagarkatti
金额：
$ 49.94万
依托单位：
UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-24 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10023261
关键词：
ATAC-seq Adult Affect Anti-Inflammatory Agents Antigens Aryl Hydrocarbon Receptor Azacitidine Bacterial Infections Biological Assay Biosensor CD4 Positive T Lymphocytes Cell Differentiation process Cells Centers for Disease Control and Prevention (U.S.)Cessation of life Chromatin Complex DNA DNA Methylation DNA Modification Methylases Data Developing Countries Development Dioxins Down-Regulation Endocrine Disruptors Environmental Pollutants Environmental Pollution Environmental Risk Factor Enzymes Epigenetic Process Exposure to FOXP3 gene Female Fertilization GATA3 gene Gene Expression Generations Genes Genomic Imprinting Genomics Histones IL17 gene Immune response Infection Inflammation Inflammatory Interferon Type II Interleukin-10 Interleukin-17 Interleukin-4 Lead Life Ligands Maternal Exposure Mediating Methylation Methyltransferase MicroRNAs Modality Modeling Morbidity - disease rate Mothers Mus Neonatal Newborn Infant Parents Partner in relationship Paternal Exposure Pathway interactions Peripheral Phase Phenotype Play Pregnancy Preventive Receptor Activation Regulatory T-Lymphocyte Resistance Role S-Adenosylhomocysteine Site Staphylococcal Enterotoxin B Staphylococcus aureus Superantigens System T cell clonality T cell differentiation T cell response T-Cell Receptor T-Lymphocyte T-cell diversity T-cell receptor repertoire Testing Tetrachlorodibenzodioxin Th1 Cells Therapeutic Time Toxic Shock Syndrome Toxic effect Transfection Transforming Growth Factor beta Up-Regulation aryl hydrocarbon receptor ligand base chromatin remodeling complementarity-determining region 3 cytokine cytokine release syndrome demethylation differential expression endocrine disruptor exposure epigenome genome-wide histone methylation histone modification immunoregulation immunotoxicity imprint inhibitor/antagonist innovation insight male mortality novel overexpression pregnant promoter reproductive response restriction enzyme transcription factor transmission process

项目摘要

Abstract Bacterial infections during neonatal phase cause high rates of morbidity and mortality, and in developing countries are responsible for 26% of deaths. Environmental factors present during pregnancy are known to impact life-threatening infections in newborns, including Staph. aureus infections, although the mechanisms are unclear. Tetrachlorodibenzo-p-dioxin (TCDD) is an environmental pollutant, which acts through the cytosolic aryl hydrocarbon receptor (AhR). While AhR has been well characterized for its role in regulating toxicity mediated by TCDD, recently, AhR activation was shown to regulate T cell differentiation into T regs or Th17 cells. We have generated exciting preliminary data indicating that AhR activation by TCDD suppresses T cell response to Staphylococcal enterotoxin B (SEB) and that this is mediated by epigenetic pathways including dysregulation in microRNA (miR) expression, DNA methylation, and histone modifications in activated T cells. More importantly, our studies have suggested that TCDD may exert transgenerational epigenetic effects on T cells. Based on the importance of Staph infections discussed above, we will use SEB as an antigen to test the central hypothesis that AhR activation of Vβ8+ T cells by TCDD, plays a crucial role in reducing pro-inflammatory Th1/Th17 cells as well as increasing anti-inflammatory Tregs and its subsets by modulating miR expression, and that this may depend on DNA methylation, histone modifications and chromatin remodeling that could be transmitted transgenerationally. Inasmuch as, SEB can activate Vβ8+ T cells which constitute ~30% of peripheral T cells, our studies are aimed at determining whether TCDD-induced changes persist in F0, F1, F2, and F3 generations following maternal exposure during pregnancy to TCDD or maternal/paternal exposure prior to mating (F0). In Aim 1, we will determine the transgenerational effects of TCDD on SEB-induced CD4+ T cell differentiation. We will test the effect of TCDD on the TCR clonality and diversity of the Vβ8+ CD4+ T cell response (Th1, 2, 17, Tregs) to SEB. In Aim 2, we will study the role of specific miRs in CD4+ T cell differentiation in F0-F3 generations. Furthermore, transfection of T cells with specific miR mimics or antagomirs will be performed to reverse T cell differentiation induced by TCDD and determine whether the effects persist across generations. In Aim 3, we will determine the role of genome-wide and locus-specific DNA methylation on CpG sites on promoters of specific miR that regulate differential expression of Th/Treg response to SEB across the generations. Aim 4 will elucidate the permissive and repressive histone modification and chromatin accessibility in TCDD-mediated transgenerational dysregulation of miR involved in CD4+ T cell differentiation. Lastly, whether these changes are imprinted through male or female germline will be assessed. The proposed studies are highly significant in that novel epigenetic pathways of TCDD-mediated immunotoxicity across generations will be identified. Also, understanding how AhR ligands mediate differential effects through epigenetic pathways would lead to development of innovative preventive and therapeutic modalities.

摘要