Environmental Arsenic Exposure and Hematotoxicity

项目摘要 贫血对全世界10亿多人的健康产生不利影响。一个强大 贫血与砷（As）暴露之间的关联在流行病学中已有报道， 来自多个国家的研究。然而，As之间缔合的机制基础 暴露和贫血还不完全清楚。我们小组先前的研究提供了证据 从人类到小鼠模型的砷血液毒性研究。我们之前的工作主要集中在 关于确定无机亚砷酸盐（As 3+）作为血液毒物的作用，特别是通过 确定As 3+对锌指转录因子加塔-1的影响，这是必不可少的 用于正常红细胞（RBC）发育（即红细胞生成）。基于这项工作，我们发现 砷暴露通过抑制早期红系祖细胞而引起贫血， 发展我们提供了进一步的证据，表明这种抑制红细胞发育的发生是因为 加塔-1功能中断的结果。这些发现提供了有关以下方面的重要信息： 一个分子机制的砷诱导抑制红细胞生成，而且还突出了一个领域 需要进一步调查许多研究表明，As 3+代谢产物， 一甲基亚胂酸（MMA 3+）可能是砷的主要毒性形式 在体内观察到;然而，很少有研究直接评估As的作用 砷化合物组织分布中的代谢以及这些部位随后的毒性。的 拟议中的重点研究项目将提供有关作为作用的新信息 代谢作为观察到的血液毒性的潜在介质。建议的研究 目标1将通过检查As代谢物在细胞中的作用来解决这一重要的知识缺口。 在体内和体外As 3+和MMA 3+暴露后观察到血液毒性。目标2将 通过比较研究砷代谢介导红细胞生成抑制机制 As ~（3+）对MMA ~（3+）对红细胞生成重要蛋白调节因子的影响。的成果 拟议中的研究将为理解As的作用提供关键信息 砷相关贫血和其他血液疾病的代谢。

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.