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

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 新生儿期细菌感染导致高发病率和死亡率, 占死亡人数的26%。已知怀孕期间存在的环境因素 影响新生儿的危及生命的感染,包括葡萄球菌。金黄色葡萄球菌感染,虽然机制是 不清楚四氯二苯并对二恶英(TCDD)是一种环境污染物,它通过细胞质中的 芳香烃受体(AhR)。虽然AhR在调节毒性方面的作用已得到充分表征, 最近,AhR活化被证明可调节T细胞分化为T细胞亚群或Th 17 细胞我们已经产生了令人兴奋的初步数据,表明TCDD激活AhR抑制T细胞增殖。 对葡萄球菌肠毒素B(SE B)的反应,这是由表观遗传途径介导的,包括 在活化的T细胞中,微RNA(miR)表达、DNA甲基化和组蛋白修饰的失调。 更重要的是,我们的研究表明,TCDD可能对T细胞产生跨代表观遗传效应, 细胞基于上述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TCDD对Vβ8+ T细胞的AhR活化在降低T细胞凋亡中起着至关重要的作用。 促炎性Th 1/Th 17细胞以及增加抗炎性T细胞及其亚群, 调节miR表达,这可能取决于DNA甲基化,组蛋白修饰和 染色质重塑可以通过跨代传递。由于SEB可以激活Vβ8+, T细胞占外周血T细胞的约30%,我们的研究旨在确定TCDD诱导的T细胞 在妊娠期间母体暴露于TCDD后,F0、F1、F2和F3代的变化持续存在,或 交配前母体/父体暴露(F0)。在目标1中,我们将确定 TCDD对SEB诱导的CD 4 + T细胞分化的影响我们将测试TCDD对TCR克隆性的影响, Vβ8+ CD 4 + T细胞对SEB应答的多样性。在目标2中,我们将研究特定的 miR在F0-F3代中的CD 4 + T细胞分化中的作用。此外,用特异性miR转染T细胞, 将进行模拟或逆转TCDD诱导的T细胞分化, 这种影响会持续几代人。在目标3中,我们将确定基因组范围和基因座特异性的作用。 调节Th/Treg差异表达的特异性miR启动子CpG位点的DNA甲基化 对几代人的SEB的回应。目的4将阐明组蛋白修饰的容许性和抑制性 TCDD介导的CD 4 + T细胞中miR跨代失调中的染色质可及性 分化最后,将评估这些变化是否通过雄性或雌性生殖系印记。 这些研究具有重要意义,因为TCDD介导的免疫毒性的新表观遗传途径 几代人之间的关系将得到确认。此外,了解AhR配体如何通过以下途径介导差异效应: 表观遗传途径将导致创新的预防和治疗方式的发展。

项目成果

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Mitzi Nagarkatti其他文献

Mitzi Nagarkatti的其他文献

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{{ truncateString('Mitzi Nagarkatti', 18)}}的其他基金

Targeting early ceramide elevation in pre-symptomatic eczema
针对症状前湿疹的早期神经酰胺升高
  • 批准号:
    10665481
  • 财政年份:
    2022
  • 资助金额:
    $ 48.12万
  • 项目类别:
Silybin as an anti-inflammatory and anti-fibrotic agent in cancer cachexia
水飞蓟宾作为癌症恶病质的抗炎和抗纤维化剂
  • 批准号:
    10665485
  • 财政年份:
    2022
  • 资助金额:
    $ 48.12万
  • 项目类别:
Role of the environmental sensor, AhR on colitis
环境传感器 AhR 对结肠炎的作用
  • 批准号:
    10390988
  • 财政年份:
    2021
  • 资助金额:
    $ 48.12万
  • 项目类别:
Role of the environmental sensor, AhR on colitis
环境传感器 AhR 对结肠炎的作用
  • 批准号:
    10494130
  • 财政年份:
    2021
  • 资助金额:
    $ 48.12万
  • 项目类别:
Role of the environmental sensor, AhR on colitis
环境传感器 AhR 对结肠炎的作用
  • 批准号:
    10757110
  • 财政年份:
    2021
  • 资助金额:
    $ 48.12万
  • 项目类别:
Role of the environmental sensor, AhR on colitis
环境传感器 AhR 对结肠炎的作用
  • 批准号:
    10685372
  • 财政年份:
    2021
  • 资助金额:
    $ 48.12万
  • 项目类别:
Role of the environmental sensor, AhR on colitis
环境传感器 AhR 对结肠炎的作用
  • 批准号:
    10774364
  • 财政年份:
    2021
  • 资助金额:
    $ 48.12万
  • 项目类别:
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
  • 批准号:
    10440259
  • 财政年份:
    2019
  • 资助金额:
    $ 48.12万
  • 项目类别:
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
  • 批准号:
    10023261
  • 财政年份:
    2019
  • 资助金额:
    $ 48.12万
  • 项目类别:
AhR ligands in epigenetic dysregulation of T cells
AhR 配体在 T 细胞表观遗传失调中的作用
  • 批准号:
    10075626
  • 财政年份:
    2017
  • 资助金额:
    $ 48.12万
  • 项目类别:

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