ORGAN CULTURE IN INTERACTIVE TOXICOLOGY

交互式毒理学中的器官培养

• 批准号: 3755178
• 负责人: KLAUS BRENDEL
• 金额: --
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3755178
• 关键词: alternatives to animals in research; arsenic; biomarker; biotransformation; cadmium; carbon tetrachloride; chlorobenzenes; chloroform; chlorohydrocarbon; covalent bond; detoxification; environmental contamination; environmental toxicology; free radical oxygen; heavy metals; hepatotoxin; high performance liquid chromatography; histology; human tissue; laboratory rat; lead; liver; mercury; metal metabolism; method development; organ culture; selenium; toxicant interaction; toxicant screening; toxin metabolism; trichloroethylene; waste disposal

The goal of this proposal is to develop precision cut liver slice culture into a tool for the study of interactive hepatotoxicology. Our studies will concentrate on specific pairs chosen from a group of metal(oids) [As, Cd, Hg, Pb, Se] and a group of halogenated hydrocarbons [carbon tetrachloride, chloroform, trichloroethylene, chlorobenzene, dichlorobenzenes] known to be present at chemical waste sites and with past evidence of indications of interactive toxicity. Three exposure modes will be utilized: one in which both toxicans are administered in vivo, secondly a mode in which one of the toxicants is administered to the intact animal and consecutively the other to liver slices produced from the preexposed animal and finally a mode in which both toxicants are either simultaneously or consecutively added to cultured liver slices. This latter mode is also applied to human tissue with the hope to correlate in vitro with in vivo data in the rat and to predict from in vitro human data interactive hepatotoxicology in exposed human populations. Toxic endpoints are determined with general viability assays applicable to all three exposure modes. Mechanisms of interactive toxicity will be investigated by probing a number of cellular biochemical parameters indicative of: cellular energy status, covalent binding of reactive intermediates generated from the organic toxicant, cell membrane integrity, cellular macromolecule synthesis membrane transport phenomena, deleterious effects of active oxygen species, biotransformation pathways, cellular glutathione status and abnormal cellular architecture.

该提案的目标是开发精密切割肝切片培养物 成为交互式肝毒理学研究的工具。 我们的研究 将专注于从一组金属（类）中选择的特定对[如， Cd、Hg、Pb、Se]和一组卤代烃[碳 四氯化物、氯仿、三氯乙烯、氯苯、 二氯苯]已知存在于化学废物场并且过去 相互作用毒性迹象的证据。 三种曝光模式将 使用：其中两种毒物均在体内施用的一种，其次 将其中一种毒物施用于完整动物的模式 并连续另一个从预曝光产生的肝脏切片 动物，最后是两种毒物同时作用的模式 或连续添加至培养的肝切片中。 后一种模式也是 应用于人体组织，希望将体外与体内关联起来 大鼠数据并根据体外人体数据进行预测交互 暴露人群的肝毒理学。 有毒终点是 通过适用于所有三种暴露的一般活力测定来确定 模式。 将通过探测研究相互作用毒性的机制 一些细胞生化参数表明：细胞能量 状态，从产生的反应中间体的共价结合 有机毒物、细胞膜完整性、细胞大分子合成 膜传输现象、活性氧的有害影响、 生物转化途径、细胞谷胱甘肽状态和异常 细胞结构。