Arsenic, GATA-1, and Hematotoxicity

项目摘要 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。 浓度超过世卫组织安全标准。来自多个流行病学研究的新证据 各国表示，环境砷暴露与贫血发病率增加之间存在密切联系， 这表明砷是一种人体血液毒剂。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良影响。我们实验室的研究表明 I)对孟加拉国一组暴露于#年各种砷的人的血液进行分析 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 饮用环境相关水60天小鼠血液的血液学分析 亚砷酸钠(As+3)的浓度在测量血红蛋白和 骨髓红细胞生成受损；iii)更有趣的是，我们的初步研究显示，GATA-1是一种关键的 转录因子调节红细胞的发育和功能，是一种敏感分子 砷相互作用的靶标。我们发现As+3在低浓度时可以取代GATA-1中锌指部分中的锌 无细胞毒性浓度，导致锌和蛋白质功能丧失。基于我们引人注目的实验 证据，我们假设暴露在环境相关浓度的砷会导致贫血。 通过破坏其锌指结构域来抑制GATA-1的功能。在目标1中，我们将利用各种细胞 生物学和生化方法明确检测As+3暴露对红细胞过程的影响 细胞生产。这些发现将确定在红细胞产生的谱系中有哪些具体步骤是砷 暴露会影响这些步骤，以及砷是如何中断这些步骤的。AIM 2将研究AS+3与GATA-1和 这种相互作用的功能后果。这些实验旨在揭示这种特殊的机制。 通过AS+3与GATA-1相互作用，破坏其在细胞内的功能。在目标3中，我们将验证GATA-1是一种敏感的 体内靶点，验证补锌可预防砷血毒性的假说。这个 我们精心设计的研究结果有望为我们理解 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 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 从机制上理解补充锌如何减少砷引起的贫血，并提供证据 锌补充剂预防砷所致贫血的潜力原理。如果经过验证，补充锌 可以代表一种低成本和易于实施的战略，以预防暴露于砷的人群中的动物死亡。

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.