BENZENE--MECHANISMS OF TOXICITY AND CHEMOPROTECTION

描述：(改编自《调查者摘要》)令人担忧 关于人类接触各种来源的苯的情况，包括 某些职业环境、危险废物场地、汽车和 抽烟。人类暴露在苯中与 再生障碍性贫血和白血病的发展。虽然有一种欣赏 由于骨髓是苯中毒的靶器官， 毒性的潜在机制和决定因素尚不完全清楚。 调查人员正在调查的假设是， 骨髓细胞群体的易感性在一定程度上取决于 铜锌超氧化物歧化酶对苯代谢物的活化作用 由苯醌还原酶和谷胱甘肽提供的相对保护。 此外，他们假设，对苯二酚还原酶的诱导和 1，2-二硫醇-3-硫酮对谷胱甘肽的保护作用 苯在体外和体内引起的血液中毒。相应地， 这项提案的具体目的是：1)调查因素 它调节生物有效浓度和早期生物 苯代谢物对相关骨髓细胞的影响 种群和其他细胞模型；2)评估人类外周血 细胞可以用来筛选人类对苯的可能易感性； 和3)进行基于机械的化学保护研究 苯对DBA/2小鼠的骨髓毒性。这些研究将 利用一系列生化、细胞和分子生物学方法 分析技术，以解决在具体的 目标。作为这个项目的结果，调查人员应该更好地 了解苯致毒性的机制，以便 信息可用于人类风险评估、生物标记物和 易感人群和暴露人群的化学保护研究。

DESCRIPTION: (Adapted from the Investigator's Abstract) There is concern about human exposure to benzene arising from a variety of sources, including certain occupational settings, hazardous waste sites, automobiles and cigarette smoking. Exposure of humans to benzene is associated with the development of aplastic anemia and leukemia. While there is an appreciation of the bone marrow being a target organ of benzene-induced toxicity, the underlying mechanisms and determinants of toxicity are not fully understood. The hypothesis the investigators are investigating is that the susceptibility of bone marrow cell populations is determined in part by the activation of benzene-derived metabolites by CuZn superoxide dismutase and the relative protection provided by quinone reductase and glutathione. Moreover, they hypothesize that the induction of quinone reductase and glutathione by 1,2-dithiole-3-thione affords protections against benzene-induced hematoxicities both in vitro and in vivo. Accordingly the specific aims of this proposal are designed to: 1) investigate factors which regulate the biologically effective concentration and early biological effects of benzene-derived metabolites in relevant bone marrow cell populations and other cellular models; 2) assess if human peripheral blood cells can be used to screen for possible human susceptibility to benzene; and 3) conduct a mechanistically-based chemoprotection study for benzene-induced bone marrow toxicity in DBA/2 mice. These studies will utilize a spectrum of biochemical, cell and molecular biology approaches and analytical techniques, to address the hypotheses put forth in the specific aims. As a result of this project the investigators should better understand the mechanisms of benzene-induced toxicity so that this information can be applied to human risk assessment, biomarker and chemoprotection studies in susceptible individuals and exposed populations.