BENZENE TOXICITY AND THE HEMOPOIETIC MICROENVIRONMENT

苯毒性与造血微环境

• 批准号: 3251316
• 负责人: GEORGE F KALF
• 金额: $ 16.68万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-05-01 至 1989-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3251316
• 关键词: aplastic anemia; benzene; blood disorder; bone marrow; centrifugation; chemical carcinogenesis; covalent bond; drug adverse effect; electrochemistry; environment related neoplasm /cancer; environmental toxicology; hematopoiesis; hemotoxin; high performance liquid chromatography; hydroquinones; macrophage; molecular site; quinones; scintillation counter; tissue /cell culture; toxicant interaction; ultraviolet spectrometry

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导致再生障碍性贫血， 血液中完全缺乏有形成分，在人类中也会导致 几种类型的急性白血病 有形成分的形成 血液，造血，是造血干细胞相互作用的结果， 细胞与骨髓基质，这提供了一个微环境， 调节血细胞前体的增殖和分化。 苯可能对基质微环境有毒，但对靶细胞和 有毒代谢物的身份尚不清楚。 方法现在 可用于在液体培养中研究造血，该系统 需要形成骨髓粘附层， 在组成和功能上，体内基质狭窄。 这意味着 研究苯及其代谢产物对生物活性影响的理想体系 基质细胞支持造血的能力。 一个这样的细胞， 巨噬细胞是粒细胞/巨噬细胞主要生物合成来源 集落刺激活性（CSF-GM），我们以前已经表明， 巨噬细胞中的大分子合成被苯抑制。 因此，目的是确定： 苯中毒部位为骨髓粘附层。 〇粘附层中的靶细胞是巨噬细胞。 o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。 o苯、氢醌和对苯醌的醌代谢物 代表有毒物种。 这些实验应提供有关苯目标的信息 毒性和有毒物种，从而为进一步研究 苯引起再生障碍性贫血的机制，并可能提供一个 关于苯如何成为白血病原的见解