The Role of Biotransformation in Arsenic-Induced Hematotoxicity

生物转化在砷引起的血液毒性中的作用

• 批准号: 10009795
• 负责人: Ke Jian Liu
• 金额: $ 9.72万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10009795
• 关键词: Acute; Address; Adverse effects; Affect; Anemia; Arsenic; Bangladesh; Biochemical; Biological Models; Blood; Bone Marrow; Cells; Cellular biology; Chronic; Country; Defect; Development; Environment; Environmental Exposure; Epidemiology; Erythrocytes; Erythropoiesis; Exposure to; Foundations; Functional disorder; GATA1 gene; Health; Hematology; Hematopoiesis; Hemoglobin; Hemoglobin concentration result; Human; Impairment; Incidence; Interruption; Intervention; Investigation; K562 Cells; Knowledge; Lead; Link; Measures; Mediating; Medical; Metabolic Biotransformation; Methods; Molecular Conformation; Molecular Target; Mus; Mutation; Outcome; Pathway interactions; Physiological; Population; Prevention strategy; Preventive Intervention; Process; Production; Protein Inhibition; Proteins; Public Health; Red Blood Cell Count; Regulator Genes; Research; Research Design; Role; Rural; Safety; Solid; Testing; Thymus Gland; Work; World Health Organization; Zinc; Zinc Fingers; Zinc supplementation; adaptive immunity; base; cost; design; drinking water; effective therapy; epidemiology study; experimental study; in vivo evaluation; insight; mouse model; novel; polypeptide; prevent; protein function; sodium arsenite; stem cells; transcription factor

Project Summary Arsenic exposure is associated with various acute and chronic health effects. The World Health Organization (WHO) estimates that over 200 million people worldwide are chronically exposed to arsenic in drinking water at concentrations above the WHO safety standard. Emerging evidence from epidemiological studies in multiple countries indicate a strong link between environmental arsenic exposure and increased incidence of anemia, suggesting that arsenic is a human hematotoxicant. However, little is known about how arsenic causes hematotoxicity and how this adverse effect of arsenic can be prevented. Research from our labs demonstrates that: i) Analysis of blood collected from a group of people in Bangladesh exposed to a wide range of arsenic in their drinking water revealed positive effects of arsenic exposure on hematological indicators of anemia; ii) Hematology analysis of blood from mice treated 60 days via drinking water with environmentally relevant concentrations of sodium arsenite (As+3) showed significant alterations in measures of hemoglobin as well as impaired bone marrow erythropoiesis; iii) More intriguingly, our preliminary study revealed that GATA-1, a key transcription factor that mediates both the development and function of red blood cells, is a sensitive molecular target for arsenic interaction. We found that As+3 could replace zinc in the zinc finger moiety of GATA-1 at low non-cytotoxic concentrations, resulting in loss of zinc and protein function. Based on our compelling experimental evidence, we hypothesize that exposure to environmentally relevant concentrations of arsenic causes anemia through inhibiting GATA-1 function by disrupting its zinc finger domain. In Aim 1, we will utilize a variety of cell biology and biochemical methods to definitively examine the impact of As+3 exposure on the process of red blood cell production. These findings will establish what specific steps in the lineage of RBC production that arsenic exposure affects, and how arsenic interrupts these steps. Aim 2 will investigate As+3 interaction with GATA-1 and the functional consequences of this interaction. The experiments are designed to reveal the specific mechanisms by which As+3 interacts with GATA-1 to disrupt its function in cells. In Aim 3, we will validate GATA-1 as a sensitive target in vivo, and test the hypothesis that zinc supplement can prevent arsenic-induced hematotoxicity. The outcomes from our vigorously designed studies are expected to provide novel insights in our understanding of mechanisms underlying increased incidents of anemia in populations exposed to arsenic, thus filling a critical gap in our knowledge of arsenic-induced anemia. Importantly, our study will provide a solid foundation for a clear mechanistic understanding of how supplemental zinc reduces arsenic-induced anemia, and provide the proof of principle for the potential of zinc supplements to prevent arsenic-induced anemia. If validated, supplemental zinc could represent a low cost and easily implemented strategy to prevent anima in arsenic exposed populations.

项目概要 砷暴露与各种急性和慢性健康影响有关。世界卫生组织 （世界卫生组织）估计，全世界有超过 2 亿人长期接触饮用水中的砷。 浓度高于世界卫生组织安全标准。来自多个国家流行病学研究的新证据 各国表明环境砷暴露与贫血发病率增加之间存在密切联系， 表明砷是一种人类血液毒物。然而，人们对砷是如何引起的知之甚少。 血液毒性以及如何预防砷的这种不利影响。我们实验室的研究表明 i) 对从孟加拉国暴露于多种砷的一群人采集的血液进行分析 他们的饮用水显示砷暴露对贫血的血液学指标有积极影响；二） 对通过饮用水处理 60 天的小鼠血液进行与环境相关的血液学分析 亚砷酸钠 (As+3) 的浓度显示血红蛋白测量值以及 骨髓红细胞生成受损； iii) 更有趣的是，我们的初步研究表明，GATA-1 是一个关键的 介导红细胞发育和功能的转录因子是一种敏感的分子 砷相互作用的目标。我们发现As+3可以在低浓度下取代GATA-1锌指部分中的锌。 非细胞毒性浓度，导致锌和蛋白质功能丧失。基于我们引人注目的实验 有证据表明，我们假设接触环境相关浓度的砷会导致贫血 通过破坏 GATA-1 的锌指结构域来抑制其功能。在目标 1 中，我们将利用各种细胞 采用生物学和生化方法明确检查 As+3 暴露对红血过程的影响 细胞生产。这些发现将确定砷在红细胞生产谱系中的哪些具体步骤 暴露会产生影响，以及砷如何中断这些步骤。目标 2 将研究 As+3 与 GATA-1 的相互作用以及 这种相互作用的功能后果。实验旨在揭示具体机制 As+3 与 GATA-1 相互作用，破坏其在细胞中的功能。在目标 3 中，我们将验证 GATA-1 是一个敏感的 体内目标，并检验补充锌可以预防砷引起的血液毒性的假设。这 我们精心设计的研究结果预计将为我们的理解提供新颖的见解 暴露于砷的人群中贫血事件增加的机制，从而填补了一个关键的空白 我们对砷引起的贫血的认识存在差距。重要的是，我们的研究将为明确的目标提供坚实的基础。 了解补充锌如何减少砷引起的贫血的机制，并提供证据 锌补充剂预防砷引起的贫血的潜力原理。如果有效，补充锌 可以代表一种低成本且易于实施的策略来预防砷暴露人群中的阿尼玛。