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.

这项探索性研究提案解决了人们对内分泌干扰物威胁日益增长的担忧 （EDC）非常规石油和天然气开采（UOG）过程中释放的水污染物对人类健康的影响。 具体来说，这些研究重点关注 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，但迄今为止尚无系统评估。我们开发了一个 两栖动物爪蟾的可靠、灵敏且具有成本效益的模型系统，特别适合 研究生命早期接触 UOG 有毒物质的水性混合物对以后生命中免疫力的影响。 我们提出了一种非洲爪蟾的比较生物学方法来定义胚胎后如何暴露于 UOG 水污染物与 TH 活性的代表性混合物会影响 T 细胞的发育和 削弱晚年的抗菌免疫反应。我们的理由是 (1) 几种 EDC 的混合物 针对一个激素轴的作用将使我们能够解决导致急性和持续性的细胞机制 这种化学混合物对 T 细胞发育和功能的影响； (2) 虽然TH轴影响 免疫系统，关于 TH 干扰物对免疫的长期生物学影响仍知之甚少；和 (3) 非洲爪蟾是一种可靠的、具有广泛特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 信号对 变态过程中成体型 T 细胞免疫的分化。其他有利于实现的特征 我们的目标是蝌蚪的外部发育，不受母体影响且易于获取 胚胎后发育期间的暴露，以及大面积暴露蝌蚪的成本效益 数字 EDC。检验以下假设：发育过程中接触 TH 干扰物混合物 与 UOG 相关的 T 细胞发育发生改变，导致免疫系统的长期扰动 体内平衡和较差的抗菌免疫力，我们将确定：（1） UOG-EDCs 的急性影响 蝌蚪T细胞分化和免疫稳态 ，通过定义蝌蚪暴露对 使用流式细胞术、组织学和转录组学研究稳态淋巴细胞群； (2) 长期影响 发育暴露于 TH 干扰物混合物对免疫稳态和抗微生物免疫力的影响 变态后仍持续存在 ，通过测量稳态下的变化以及对蛙病毒 FV3 的反应 （类似于痘病毒，如牛痘，一种强 CD8 T 细胞诱导剂）和海分枝杆菌（一种病原体） 青蛙和人类的强 CD4 T 细胞诱导剂）；和（3） 4 个 UOG-EDC 中每个的 TH 干扰子活性 单独作用及其潜在的相加和协同作用。 两种感染的创新性趋同发现 非洲爪蟾的 TH 轴和免疫系统中不同类型的病原体（痘样 FV3 和分枝杆菌） 与哺乳动物的那些非常保守，将提供关于影响的新颖且令人信服的证据 UOG-EDCs 对与人类健康相关的免疫系统功能的影响。