SPLENIC TOXICITY OF ANILINE

苯胺是一种有毒的芳香胺，是一种广泛使用的工业化学品， 特别是在染料、颜料和药物的制造中。的 造血系统是苯胺损伤早期靶点。除了造成 高铁血红蛋白血症和溶血性贫血，苯胺暴露也导致 选择性脾毒性导致脾肿大、出血、包膜 增生、纤维化和最终的各种肉瘤。 之甚少 已知苯胺和苯胺相关的 化合物诱导脾的选择性损伤，这是本发明的焦点。 项目我们对大鼠的初步亚慢性研究表明 铁的依赖性沉积，血管充血和血栓是 脾脏由于苯胺暴露。我们的数据还表明共价键 大鼠脾脏中放射性的结合和蓄积 至14 C-苯胺HCl。我的总体目标是确定 苯胺对脾脏造成选择性损伤。在这些研究中， 重点将给予评估的作用，铁超载及其 与苯胺代谢物的关系，导致共价结合 大分子 目的1将阐明选择性作用的可能机制， 苯胺对脾脏的自由基形成，脂质过氧化， 蛋白质氧化，共价结合和形态变化， 从老鼠体内暴露。目标2将阐明铁的作用 苯胺诱导的脾毒性过载，通过研究（i） 通过增加铁负荷增强毒性（ii）减少铁负荷， 通过减少铁负荷来降低毒性。 目标3将确定脾毒性 苯胺的代谢物（N-和环羟基化）。 完成这项工作的方法是 通过在大鼠中进行已知苯胺代谢物的毒性研究。 如果未发现已知代谢物具有脾毒性，则新的 将对特定目标1下确定的代谢物进行毒性试验。 这些研究将提供苯胺诱导的 脾毒性，也将确定铁和苯胺的作用 代谢物的毒性。 从这些信息中获得的信息 研究可进一步用于制定预防战略。

Aniline, a toxic aromatic amine, is a widely used industrial chemical, particularly in the manufacture of dyes, pigments and drugs. The hemopoietic system is an early target of aniline insult. Besides causing methemoglobinemia and hemolytic anemia, aniline exposure also results in selective splenic toxicity leading to splenomegaly, hemorrhage, capsular hyperplasia, fibrosis and eventually a variety of sarcomas. Little is known about the mechanism(s) by which aniline and aniline-related compounds induce selective damage to spleen which is the focus of this project. Our preliminary subchronic studies in rats indicate time dependent deposition of iron, vascular congestion and fibro is of the spleen as a result of aniline exposure. Our data also indicates covalent binding and accumulation of radioactivity in the spleens of rats exposed to 14C-aniline HCl. My overall objective is to determine how and why aniline causes selective damage to spleen. In these studies a special emphasis will be given to assess the role of iron overload and its relationship to aniline metabolites which result in covalent binding to macromolecules. Aim 1 will elucidate the possible mechanisms of the selective effects of aniline on spleen in terms of free radical formation, lipid peroxidation, protein oxidation, covalent binding and morphological changes resulting from in vivo exposure in rats. Aim 2 will elucidate the role of iron overload in the aniline-induced splenic toxicity, by studying (i) potentiation of toxicity by increasing iron load (ii) diminution of the toxicity by reducing the iron load. Aim 3 will identify the splenotoxic metabolites (N- and ring-hydroxylated) of aniline. This will be achieved by conducting toxicity studies in rats with known metabolites of aniline. If known metabolite(s) are not found to be splenotoxic, then new metabolite(s) identified under Specific Aim 1 will be tested for toxicity. These studies will provide the mechanism(s) of aniline-induced splenotoxicity and will also define the role of iron and aniline metabolites in the observed toxicity. The information obtained from these studies can be further used to develop preventive strategies.