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：
10658858
负责人：
Mitzi Nagarkatti
金额：
$ 48.12万
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 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10658858
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 Induction Cell Differentiation process Cells Cessation of life Chromatin Complex DNA DNA Methylation DNA Modification Methylases Data Developing Countries Development Dioxins Down-Regulation Endocrine Disruptors Environmental Pollutants 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-4 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 S-Adenosylmethionine Site Staphylococcal Enterotoxin B Staphylococcal Infections Staphylococcus aureus Superantigens System T cell clonality T cell differentiation T cell response T-Cell Activation 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 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 innovation insight male mortality novel overexpression permissiveness polarized cell pregnant promoter reproductive 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.

抽象的新生儿期的细菌感染会导致高发病率和死亡率，并在发展中国家造成26％的死亡。已知怀孕期间存在的环境因素影响新生儿（包括葡萄球菌）的威胁生命的感染。金黄色的感染，尽管机制是不清楚。 Tetrachlorodibenzo-p-Dioxin（TCDD）是一种环境污染物，它通过胞质起作用芳基碳氢化合物受体（AHR）。虽然AHR因其在调节毒性中的作用而被很好地描述最近，由TCDD介导的，最近，AHR激活可调节T细胞分化为T Regs或Th17 细胞。我们已经生成了令人兴奋的初步数据，表明TCDD激活AHR会抑制T细胞对葡萄球菌肠毒素B（SEB）的反应，这是由表观遗传途径介导的激活T细胞中microRNA（miR）表达，DNA甲基化和Hisstone修饰的失调。更重要的是，我们的研究表明，TCDD可能对T的转化表观遗传作用细胞。基于上面讨论的葡萄球菌感染的重要性，我们将使用SEB作为抗原测试中心假设，即通过TCDD对Vβ8+ T细胞的AHR激活在还原中起着至关重要的作用促炎性TH1/TH17细胞以及增加抗炎Treg及其子集调节miR表达，这可能取决于DNA甲基化，Hisstone的修饰和染色质重塑，可以通过跨金融传输。 AS SEB可以激活Vβ8+ 构成周围T细胞约30％的T细胞，我们的研究旨在确定TCDD诱导的在怀孕期间，Mater暴露于TCDD或交配之前的母亲/父亲暴露（F0）。在AIM 1中，我们将确定 TCDD在SEB诱导的CD4+ T细胞分化上。我们将测试TCDD对TCR克隆性的影响 Vβ8+ CD4+ T细胞反应的多样性（Th1、2、17，Tregs）对SEB。在AIM 2中，我们将研究特定的作用 F0-F3代的CD4+ T细胞分化中的miR。此外，用特定miR的T细胞翻译将进行模拟或antagomirs，以逆转TCDD诱导的T细胞分化，并确定是否是否这些效果持续存在。在AIM 3中，我们将确定全基因组和基因座特异性的作用在调节Th/treg的差异表达的特定miR启动子上的CpG位点上的DNA甲基化对SEB的响应。 AIM 4将阐明允许和反射性组蛋白的修饰 TCDD介导的CD4+ T细胞中MIR的转化失调中的染色质可及性转化失调分化。最后，将评估这些变化是否通过男性或女性种系印刷。拟议的研究非常重要，因为TCDD介导的免疫毒性的新型表观遗传途径将确定几代人。此外，了解AHR配体如何通过表观遗传途径将导致创新的预防和治疗方式的发展。