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.

这一探索性的研究提案解决了人们对内分泌干扰物威胁的日益关注。 (EDC)非常规石油和天然气开采过程中释放的水污染物对人类健康的影响。 具体来说，这些研究集中在如何与甲状腺激素（TH）干扰4 UOG化学品的混合物， 活动影响免疫系统，迄今没有系统的评估。我们已经开发出一种 可靠，灵敏和具有成本效益的模型系统在两栖动物爪蟾，是唯一适合于 研究生命早期暴露于水性UOG毒物混合物对生命后期免疫力的影响。 我们提出了一个比较生物学的方法，在非洲爪蟾，以确定如何胚后暴露于 具有TH活性的UOG水污染物的代表性混合物影响T细胞发育， 在以后的生活中削弱抗菌免疫反应。我们的理由是：（1）几种内分泌干扰物的混合物 作用于一个激素轴将使我们能够解决导致急性和持续性 这种化学物质的混合物对T细胞发育和功能的影响;（2）虽然TH轴影响T细胞的发育和功能， 免疫系统，关于TH干扰物对免疫力的长期生物学影响仍然知之甚少; (3)非洲爪蟾是一种可靠的，广泛表征和广泛认可的人类围产期模型。 TH轴的内分泌学和生物医学研究，包括TH信号传导对 变态期间成体型T细胞免疫的分化。有利于实现的其他特征 我们的目标是蝌蚪的外部发展，这是免费的母亲的影响，并容易获得 暴露在胚胎后发育，以及暴露蝌蚪在大的成本效益 数字为EDCs。为了验证这一假设，发育暴露于TH-干扰物的混合物 与UOG相关的改变T细胞发育，导致免疫系统的长期扰动， 体内平衡和较差的抗微生物免疫力，我们将确定：（1） UOG-EDCs的急性效应 蝌蚪T细胞分化与免疫稳态 ，通过定义蝌蚪暴露对 使用流式细胞术、组织学和转录组学的稳态淋巴细胞群体;（2） 长期影响 TH-干扰物混合物对发育期免疫稳态和抗微生物免疫的影响 变态后持续存在的 通过测量稳态和响应于Ranavirus FV 3的变化， （类似于痘病毒，如牛痘，一种强的CD 8 T细胞诱导剂）和海洋分枝杆菌（一种病原体） 青蛙和人类，强CD 4 T细胞诱导剂）;和（3） 4个UOG-EDC中每一个的TH-破坏剂活性 以及它们潜在的相加和协同作用。 从两种感染中获得的创新性聚合发现 不同类型的病原体（痘样FV 3和分枝杆菌）在非洲爪蟾，其TH轴和免疫系统 与哺乳动物的基因非常保守，这将提供有关影响的新的和令人信服的证据。 UOG-EDCs对人体免疫系统功能的影响。