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 (WHO)估计全球有超过2亿人长期接触饮用水中的砷， 浓度高于WHO安全标准。流行病学研究的新证据表明， 许多国家指出，环境中的砷暴露与贫血发病率增加之间存在密切联系， 表明砷是一种人体血液毒物然而，人们对砷是如何导致 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 （一）对孟加拉国一群接触各种砷的人收集的血液进行分析， 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; ii） 来自通过饮用具有环境相关性的水处理60天的小鼠的血液的血液学分析 浓度的亚砷酸钠（As+3）显示出显着改变的措施，血红蛋白以及 更有趣的是，我们的初步研究表明，加塔-1，一个关键的 转录因子介导红细胞的发育和功能，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加塔-1锌指结构中的锌 非细胞毒性浓度，导致锌和蛋白质功能丧失。基于我们令人信服的实验 证据，我们假设暴露于环境相关浓度的砷导致贫血 通过破坏加塔-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 生物学和生物化学方法，以明确检查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生产谱系中，砷 暴露影响，以及砷如何中断这些步骤。目的2将研究As+3与加塔-1的相互作用， 这种相互作用的功能后果。实验旨在揭示其具体机制 As+3通过该途径与加塔-1相互作用以破坏其在细胞中的功能。在目标3中，我们将验证加塔-1作为敏感的 体内靶向，并验证锌补充剂可以预防砷诱导的血液毒性的假设。的 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潜在机制，从而填补了一个关键的 我们对砷致贫血的认识存在空白。重要的是，我们的研究将为一个清晰的 机制的理解如何补充锌减少砷引起的贫血，并提供证据， 锌补充剂预防砷引起的贫血的潜力的原则。如经验证，补充锌 可能是一种低成本和易于实施的策略，以防止砷暴露人群中的阿尼玛。

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.