Transgenerational exposures as modifiers of host defense against infection

描述(由申请人提供)：本项目的目标是确定由于环境暴露而发生的哺乳动物免疫系统功能改变的跨代遗传所涉及的关键参数。免疫系统对公众和个人的健康至关重要，即使它的功能稍有改变，也会对健康和疾病产生深远的负面影响。例如，流感病毒感染对全球健康构成重大威胁，每年感染人数超过10亿。有证据表明，产前和早期接触污染物是流感和其他呼吸道感染后临床结果较差的被忽视的因素。有证据表明发育中暴露会影响人类和动物模型免疫系统功能的一类环境制剂是芳香烃受体(AhR)配体。例如，早期接触原型AhR配体2，3，7，8-四氯二苯并-对二恶英(TCDD)会深刻扰乱F1代特定淋巴细胞亚群对感染的反应，令人兴奋的试点数据显示，F2代的淋巴细胞功能受到影响。其他初步数据支持这样的观点，即这些变化至少部分是由于DNA甲基化的变化。此外，TCDD引起跨代(F3)效应，并改变其他器官系统的DNA甲基化。使用与疾病结局直接相关的当代、灵敏的分析方法，我们将进一步确定F3代中一组疾病特异性T细胞反应的特征，并将这些变化与在F2和F1后代中观察到的改良的抗病毒免疫反应进行直接比较。这一全面的分析将包括确定T细胞功能跨代影响的剂量依赖性质，以及建立跨代免疫功能变化的配体特异性性质。我们还将定义易感性的发育窗口，性别差异的基础，以及父母来源在病毒感染免疫改变的跨代遗传中的作用。此外，我们将研究AhR配体暴露将异常免疫功能从一代传递到下一代的机制。我们将使用遗传学、路径特异性和基因组范围的方法识别以跨代方式改变的基因和基因网络，并将这些改变与DNA甲基化和其他表观遗传调控机制的改变联系起来。产生的新科学信息将对公众健康产生巨大影响。很少有关于环境暴露影响的跨代遗传的研究考虑到免疫系统，或者直接评估一种每年至少影响1/7人的疾病的潜在后果。鉴于TCDD和其他AhR配体在其他组织中引起发育和跨代影响，我们的研究结果将对更好地预测AhR及其众多配体对人类发育和健康的许多方面的潜力产生广泛影响。

DESCRIPTION (provided by applicant): The objective of this project is to define key parameters involved in transgenerational inheritance of alterations in the function of the mammalian immune system that occur as a result of environmental exposure. The immune system is fundamentally important to public and individual health, and even slight modifications in its function can have a profoundly negative impact on health and disease. For instance, influenza virus infections pose significant global health threats, infecting over 1 billion people annually. Evidence points to prenatal and early life exposure to pollutants as overlooked contributors to poorer clinical outcomes following influenza and other respiratory infections. One family of environmental agents for which there is evidence that developmental exposure affects the function of the immune system in humans and animal models is aryl hydrocarbon receptor (AhR) ligands. For instance, early life exposure to the prototype AhR ligand, 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) profoundly disrupts the response of specific lymphocyte subsets to infection in the F1 generation, and exciting pilot data reveal that lymphocyte function is affected in F2 offspring. Other preliminary data support the idea that these changes are due, at least in part, to alterations in DNA methylation. Moreover, TCDD causes transgenerational (F3) effects and altered DNA methylation in other organ systems. Using contemporary, sensitive assays that directly relate to disease outcome, we will further characterize an integrated set of disease-specific T cell responses in the F3 generation, and directly compare these changes to the modified anti-viral immune response observed in F2 and F1 offspring. This comprehensive analysis will include defining the dose-dependent nature of transgenerational effects on T cell functions, and establishing the ligand-specific nature of immune function changes across generations. We will also define the developmental window of susceptibility, basis of sex differences, and role of parental origin in transgenerational inheritance of altered immunity to viral infection. Moreover, we will investigate the mechanism by which AhR ligand exposure transmits aberrant immune function from one generation to the next. We will identify genes and gene networks that are altered in a transgenerational manner using genetic, pathway-specific and genome-wide approaches, and link these changes to alterations in DNA methylation and other epigenetic regulatory mechanisms. The new scientific information generated will have a tremendous impact on public health. Few studies of transgenerational inheritance of the effects of environmental exposures have considered the immune system, or directly evaluated the potential consequences to a disease that affects at least 1 in 7 people each year. Given that TCDD and other AhR ligands cause developmental and transgenerational effects in other tissues, findings from our studies will have a broad impact on efforts to better predict the potential for AhR and its myriad ligands to impinge on many facets of human development and health.