Transgenerational exposures as modifiers of host defense against infection

描述（由申请人提供）：本项目的目的是定义环境暴露导致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健康至关重要，即使其功能发生轻微变化，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，每年感染超过10亿人。有证据表明，产前和生命早期暴露于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因素。有证据表明发育暴露影响人类和动物模型免疫系统功能的一类环境因子是芳烃受体（AhR）配体。例如，早期生活中暴露于原型AhR配体，2，3，7，8-四氯二苯并对二恶英（TCDD）深刻地破坏了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后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甲基化的改变。此外，TCDD会引起跨代（F3）效应，并改变其他器官系统中的DNA甲基化。使用与疾病结果直接相关的当代敏感检测方法，我们将进一步表征F3代中疾病特异性T细胞应答的综合集，并将这些变化与F2和F1后代中观察到的改良抗病毒免疫应答进行直接比较。这种全面的分析将包括定义对T细胞功能的跨代效应的剂量依赖性，并建立跨代免疫功能变化的配体特异性。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力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，途径特异性和全基因组方法识别以跨代方式改变的基因和基因网络，并将这些变化与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共卫生产生巨大影响。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，或直接评估每年至少影响七分之一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代际效应，我们的研究结果将对更好地预测AhR及其无数配体对人类发育和健康的许多方面的影响产生广泛影响。

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.