Long-term effects of developmental exposure to a mixture of thyroid disruptors associated with hydrofracking on T cell development and antimicrobial immunity

发育暴露于与水力压裂相关的甲状腺干扰物混合物对 T 细胞发育和抗菌免疫的长期影响

• 批准号: 10214619
• 负责人: JACQUES Robert
• 金额: $ 19.25万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-13 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10214619
• 关键词: Acute; Address; Adult; Affect; Amphibia; Animal Model; Antiviral Agents; Area; Biological; Biological Metamorphosis; Biological Models; Biomedical Research; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cell Death; Cell physiology; Chemicals; Comparative Biology; Data; Dependence; Development; Dose; Endocrine Disruptors; Endocrinology; Environment; Environmental Pollutants; Epidemiology; Exhibits; Exposure to; Flow Cytometry; Foundations; Frequencies; Gases; Gene Expression; Genes; Genus Mycobacterium; Goals; Goitrogens; Gonadal Steroid Hormones; Health; Helper-Inducer T-Lymphocyte; Histology; Histopathology; Homeostasis; Hormones; Human; Hypothyroidism; Immune; Immune response; Immune system; Immunity; Infection; Life; Liver; Long-Term Effects; Lymphocyte; Lymphocyte Count; Mammals; Measures; Methods; Modeling; Mycobacterium marinum; Oils; Pathway interactions; Perchlorates; Perinatal; Peripheral; Phenotype; Population; Poxviridae; Rana; Ranavirus; Research Proposals; Signal Transduction; Site; Skin; Sodium; Sonic Hedgehog Pathway; Spleen; Surface; T cell differentiation; T cell response; T-Cell Development; T-Lymphocyte; T-Lymphocyte Subsets; Tadpoles; Testing; Thymus Gland; Thyroid Function Tests; Thyroid Gland; Thyroid Hormones; Tissues; Triiodothyronine; Vaccinia; Virus; Water; Water Pollutants; Xenopus; antimicrobial; biomarker-driven; burden of illness; cost effective; cost effectiveness; early life exposure; exposed human population; ground water; hormonal signals; human model; immune function; immune system function; immunoregulation; in vitro activity; innovation; insight; microbial; migration; mouse model; novel; pathogen; public health relevance; response; tetrabromobisphenol A; thyroid disruption; toxicant; transcriptomics; waterborne

This exploratory research proposal addresses growing concerns about the threats of endocrine disruptor (EDC) water pollutants released during unconventional oil and gas extraction (UOG) to human health. Specifically, these studies focus on how a mixture of 4 UOG chemicals with thyroid hormone (TH) disrupting activity affect the immune system, for which there is no systematic assessment to date. We have developed a reliable, sensitive and cost-effective model system in the amphibian Xenopus that is uniquely suited to investigate the effects of early life exposure to waterborne mixtures of UOG toxicants on immunity later in life. We propose a comparative biology approach in Xenopus to define how postembryonic exposure to a representative mixture of UOG water contaminants with TH activity impacts T cell development and weaken antimicrobial immune response later in life. Our rationale is that (1) a mixture of several EDCs acting toward one hormone axis will allow us to address cellular mechanism leading to acute and persistent effects of this mixture of chemicals on T cell development and function; (2) Although TH axis affects the immune system, little is still known about the long-term biological impacts of TH disruptors on immunity; and (3) Xenopus is a reliable, extensively characterized and widely recognized model of human perinatal endocrinology and biomedical research on the TH axis, including dependence of TH signaling for the differentiation of adult-type T cell immunity during metamorphosis. Other features advantageous for achieving our goal are the external development of tadpoles, which are free of maternal influence and easily accessible to exposure during postembryonic development, and the cost effectiveness of exposing tadpoles in large numbers to EDCs. To test the hypothesis that developmental exposure to a mixture of TH-disruptors associated with UOG alters T cell development, resulting in long-term perturbation of immune homeostasis and poorer antimicrobial immunity, we will determine: (1) acute effects of UOG-EDCs on tadpole T cell differentiation and immune homeostasis , by defining the impact of tadpole exposure on homeostatic lymphocyte populations using flow cytometry, histology and transcriptomics; (2) long-term effects on immune homeostasis and anti-microbial immunity of developmental exposure to a mixture of TH-disruptors persisting after metamorphosis , by measuring changes at steady state and in response to the ranavirus FV3 (similar to poxviruses such as vaccinia, a strong CD8 T cell inducer) and Mycobacterium marinum (a pathogen of frogs and humans, a strong CD4 T cell inducer); and (3) TH-disruptor activity of each of the 4 UOG-EDC alone and their potential additive and synergistic actions. Innovative convergent findings from infection with two different types of pathogens (pox-like FV3 and Mycobacteria) in Xenopus whose TH axis and immune system are remarkably conserved with those of mammals will provide novel and compelling evidence regarding effects of UOG-EDCs on the immune system function relevant to human health.

这项探索性研究建议解决了对内分泌破坏者威胁的日益担忧 （EDC）在非常规石油和天然气提取（UOG）中释放的水污染物对人类健康。 具体而言，这些研究集中于4种UOG化学物质与甲状腺激素（Th）的混合物如何破坏 活动会影响免疫系统，迄今为止尚无系统评估。我们已经开发了 在两栖动物中可靠，敏感和成本效益的模型系统，非常适合 研究早期生命早期毒物毒物的水生成混合物对生命后期免疫的影响。 我们提出了Xenopus中的比较生物学方法，以定义后胚后如何暴露于 UOG水污染物具有TH活性的代表性混合物会影响T细胞的发展和 弱化抗菌免疫反应后期。我们的理由是（1）几种EDC的混合物 对一个激素轴作用将使我们能够解决导致急性和持续的细胞机制 这种化学物质混合物对T细胞发育和功能的影响； （2）尽管轴轴影响 免疫系统，对于TH破坏者对免疫的长期生物学影响仍然知之甚少。和 （3）爪蟾是一种可靠的，广泛的特征和广泛认可的人围产期模型 对TH轴的内分泌学和生物医学研究，包括TH信号的依赖性 成人型T细胞免疫的分化。其他功能有利的功能 我们的目标是t的外部发展，t没有产妇影响，很容易获得 在胚胎后发展期间暴露，以及在大型中暴露t的成本效益 EDCS的数字。测试发育暴露于TH-DISPREPTORS的混合物的假设 与UOG相关的改变T细胞的发展，导致免疫的长期扰动 稳态和较差的抗菌免疫，我们将确定：（1） UOG-EDC对急性影响 t细胞分化和免疫稳态 ，通过定义t的影响对 使用流式细胞仪，组织学和转录组学使用稳态淋巴细胞群体； （2） 长期影响 关于免疫稳态和抗微生物免疫的发育暴露于Th-Disprespor的混合物 变态后持续存在 ，通过测量稳定状态的变化并响应Ranavirus FV3 （类似于疫苗，强烈的CD8 T细胞诱导剂等痘病毒）和分枝杆菌（一种病原体 青蛙和人类，强大的CD4 T细胞诱导剂）； （3） 4个UOG-EDC中每一个的th-distruptor活性 独自一人及其潜在的加性和协同作用。 来自两个感染的创新收敛发现 在Xenopus中的不同类型的病原体（类似痘痘的FV3和分枝杆菌），其TH轴和免疫系统 与哺乳动物的那些相当保守，将提供有关影响的新颖而令人信服的证据 关于免疫系统功能与人类健康有关的UOG-EDC的。