Environmental Arsenic Exposure and Hematotoxicity

环境砷暴露和血液毒性

• 批准号: 10675053
• 负责人: Sebastian Medina
• 金额: $ 18.56万
• 依托单位: NEW MEXICO HIGHLANDS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10675053
• 关键词: Address; Affect; Anemia; Area; Arsenic; Arsenicals; Arsenites; Biochemical; Bone Marrow; Bone Marrow Cells; Cell Culture Techniques; Cell Separation; Cells; Chronic; Co-Immunoprecipitations; Country; Deposition; Development; Drug or chemical Tissue Distribution; Environmental Pollutants; Enzyme-Linked Immunosorbent Assay; Erythrocytes; Erythroid; Erythroid Progenitor Cells; Erythropoiesis; Exposure to; Flow Cytometry; Future; GATA1 gene; Health; Hematological Disease; Hematopoietic stem cells; Human; Impairment; In Vitro; Inductively Coupled Plasma Mass Spectrometry; Intervention; Investigation; Knockout Mice; Knowledge; Mediating; Mediator; Metabolism; Methylation; Methyltransferase; Modeling; Molecular; Mus; Outcome; Outcome Study; Pathway interactions; Persons; Population; Prevention strategy; Primary Cell Cultures; Production; Proteins; Public Health; Reporting; Research; Research Project Grants; Risk; Risk Assessment; Role; Site; Small Interfering RNA; Stem Cell Development; Testing; Therapeutic; Toxic effect; Western Blotting; Work; Zinc Fingers; base; chromatin immunoprecipitation; comparative; drinking water; epidemiology study; in vivo; insight; knock-down; monomethylarsonous acid; mouse model; novel; oxidation; progenitor; small hairpin RNA; transcription factor

Project Summary Anemia adversely impacts the health of more than a billion people worldwide. A strong association between anemia and arsenic (As) exposure has been reported in epidemiological studies from multiple countries. However, the mechanistic bases for the association between As exposure and anemia is not fully understood. Previous research by our group provides evidence of arsenic hematotoxicity spanning from humans to mouse models. Our previous work focused on establishing the role of inorganic arsenite (As3+) as a hematotoxicant, particularly by determining the effects of As3+ on the zinc finger transcription factor GATA-1, which is essential for normal red blood cell (RBC) development (i.e. erythropoiesis). Based on this work, we found that As exposure causes anemia via the suppression of early erythroid progenitor cell development. We provide further evidence that this inhibition of RBC development occurs as a result of disruptions to GATA-1 function. These findings provide essential information regarding a molecular mechanism of As-induced inhibition of erythropoiesis, but also highlight an area requiring further investigation. Many studies suggest that the As3+ metabolite, monomethylarsonous acid (MMA3+) may be the major form of As responsible for toxicity observed in vivo; however, few studies have been performed to directly evaluate the role of As metabolism in the tissue distribution of arsenicals and subsequent toxicity at these sites. The proposed Focus Research Project will provide novel information regarding the role of As metabolism as a potential mediator of the observed hematotoxicity. The studies proposed in Aim 1 will address this important knowledge gap by examining the role of As metabolites in the hematotoxicity observed following As3+ and MMA3+ exposures, in vivo and in vitro. Aim 2 will investigate mechanisms of As metabolism-mediated inhibition of erythropoiesis by comparing the effects of As3+ to MMA3+ on important protein regulators of erythropoiesis. Outcomes from the proposed research will provide critical information essential for understanding the role of As metabolism in As-associated anemias and other hematological disorders.

项目摘要 贫血对全球超过十亿人口的健康不利影响。强壮 贫血与砷之间的关联已在流行病学中报道 来自多个国家的研究。但是，AS之间关联的机械基础 暴露和贫血尚未完全理解。我们小组的先前研究提供了证据 从人到小鼠模型的砷血毒性。我们以前的工作重点 在确定无机砷（AS3+）作为血毒剂的作用时，特别是通过 确定AS3+对锌指转录因子GATA-1的影响，这是必不可少的 对于正常的红细胞（RBC）发育（即红细胞生成）。基于这项工作，我们发现 由于暴露会导致贫血通过抑制早期红细胞祖细胞 发展。我们提供进一步的证据，表明这种对RBC发展的抑制是作为一个 GATA-1功能中断的结果。这些发现提供了有关的基本信息 AS诱导的红细胞生成抑制的分子机制，但也突出显示了一个区域 需要进一步调查。许多研究表明AS3+代谢产物， 单甲基酸（MMA3+）可能是负责毒性的主要形式 在体内观察到；但是，很少有研究直接评估AS的作用 在这些部位的组织分布中的代谢和随后的毒性。这 拟议的重点研究项目将提供有关AS的作用的新颖信息 代谢是观察到的血毒性的潜在介体。提出的研究 AIM 1将通过研究AS代谢中的作用来解决这一重要知识差距 在体内和体外观察到AS3+和MMA3+暴露后观察到的血毒素。 AIM 2意志 通过比较AS代谢介导的促红细胞生成的抑制的机制 AS3+对MMA3+对促红细胞生成的重要蛋白质调节剂的影响。结果 拟议的研究将为了解AS的作用提供至关重要的关键信息 AS相关性贫血和其他血液学疾病中的代谢。