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BENZENE TOXICITY AND THE HEMOPOIETIC MICROENVIRONMENT

苯毒性与造血微环境

基本信息

批准号：
3251317
负责人：
GEORGE F KALF
金额：
$ 17.01万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1986
资助国家：
美国
起止时间：
1986-05-01 至 1990-04-30
项目状态：
已结题

项目摘要

Chronic exposure of animals and humans to benzene causes aplastic anemia, a complete absence of the formed elements in blood, and in humans also causes several forms of acute leukemia. The formation of the formed elements of the blood, hemopoiesis, results from an interaction of hemopoietic stem cells with the bone marrow stroma which provides a microenvironment for regulated proliferation and differentiation of the blood cell precursors. Benzene may be toxic to the stromal microenviroment but the target cell and the identity of the toxic metabolite are unknown. Methods are now available for studying hemopoiesis in liquid culture, a system which requires the development of a marrow adherent layer which closely resembles in composition and function, the narrow stroma in vivo. This represents an ideal system for studing the effects of benzene and its metabolites on the ability of the cells of thestroma to support hemopoiesis. One such cell, the macrophage, is a major biosynthetic source of granulacyte/macrophage colony-stimulating activity (CSF-GM) and we have previously shown that macromolecular synthesis in the macrophage is inhibited by benzene. Therefore, the aims are to determine whether: o The site of benzene toxicity is the marrow adherent layer. o The target cell in the adherent layer is the macrophage. o Toxicity results from an inability of the benzene-poisoned macrophage to produce growth factors such as GM-CSF required for granulopoiesis. o The quinone metabolites of benzene, hydroquinone and p-benzoquinone represent the toxic species. These experiments should provide information on the target of benzene toxicity and the toxic species and thus pave the way for futher studies on the mechanisms whereby benzene causes aplastic anemia and may provide an insight as to how benzene acts as a leukemogen.

动物和人类长期接触苯会引起再生障碍性贫血在血液和人类中完全没有形成的元素，也会导致几种形式的急性白血病。的形成要素的形成血液，即造血，是造血干细胞相互作用的结果具有骨髓基质的细胞，为调节血细胞前体细胞的增殖和分化。苯可能对基质微环境有毒性，但靶细胞和有毒代谢物的身份尚不清楚。方法现在是可用于液体培养中的造血学研究，该系统需要骨髓粘附层的形成，它与在组成和功能上，体内狭窄的间质。这表示一个研究苯及其代谢物对人体健康影响的理想体系间质细胞支持造血的能力。一间这样的牢房，巨噬细胞是粒细胞/巨噬细胞的主要生物合成来源。集落刺激活性(CSF-GM)，我们之前已经证明苯抑制巨噬细胞的大分子合成。因此，目标是确定是否： O苯中毒的部位是骨髓粘附层。 O粘附层中的靶细胞是巨噬细胞。毒性是由于苯中毒的巨噬细胞不能产生粒细胞生成所需的生长因子，如GM-CSF。苯、对苯二酚和对苯二酚的苯醌代谢物代表有毒物种。这些实验应该提供有关苯的目标的信息毒性和有毒物种，从而为进一步研究奠定了基础苯引起再生障碍性贫血的机制可能提供关于苯是如何作为白血病原的洞察力。