Non-Additive Ah Receptor Ligand Interactions

非加性 Ah 受体配体相互作用

• 批准号: 7064099
• 负责人: Timothy R. Zacharewski
• 金额: $ 22.13万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7064099
• 关键词: aromatic hydrocarbon receptor; benzofurans; carbopolycyclic compound; clinical chemistry; dioxins; environmental toxicology; fatty liver; gene expression; halobiphenyl /halotriphenyl compound; hepatotoxin; histopathology; immunocytochemistry; laboratory mouse; lipid metabolism; lipid transport; method development; microarray technology; molecular biology; morphometry; pollutant interaction; polymerase chain reaction; statistics /biometry; toxicant interaction; western blottings

Although human exposure to toxicants occurs as a complex mixture, risk assessments are typically based on single chemical studies conducted in rodent models. Limitations associated with current approaches are increasingly being questioned due to the potential for significant health, societal and economic consequences. In order to improve the quantitative risk assessment of chronic and subchronic exposure to synthetic and natural chemicals and their complex mixtures, uncertainties within the source-to-outcome continuum must be minimized in the context of the whole organisms, and its genome. In this proposal, 2,3,7,8-tetrachlrodibenzo-p-dioxin (TCDD), 3,3',4,4',5-pentachlorobiphenyl (PCB126), and 2,2',4,4',5,5'- hexachlorobiphenyl (PCB153) as well as a reconstituted mixture that reflects environmental levels of these contaminants will be systematically examined to elucidate the mechanisms of action of additive, antagonistic and synergistic interactions that occur at molecular and physiological levels. Ray designs and modeling approaches will be used to minimize full factorial studies in order to investigate the hypothesis that a mixture of TCDD, PCB126 and PCB153 at environmentally relevant levels elicit non-additive hepatotoxic effects. Dose- and time-dependent hepatic gene expression and fatty liver effects will be assessed using a mouse cDNA array enriched with dioxin responsive genes and complementary histopathology approaches. Microarray data will be computationally integrated with histopathology and clinical chemistry to identify associations between changes in gene expression and physiological/toxic outcomes that facilitates the elucidation the mechanisms of action of dioxin-mediated fatty liver toxicity. The mixture will then be examined to detect and characterize the additive, synergistic and antagonistic interactions that affect the fatty liver response using response surface models for genes associated with fatty liver. This proposal will not only develop innovative and credible statistical strategies to rigorously assess interactions induced by mixtures containing chemicals that use a common mechanism of action, but will also further elucidate mechanisms of toxicity associated with TCDD-induced fatty.

尽管人类接触毒物是一种复杂的混合物，但风险评估通常基于 在啮齿动物模型中进行的单一化学研究。与当前方法相关的局限性是 由于对健康、社会和经济产生重大影响的潜力，越来越受到质疑 结果。为了改进慢性和亚慢性暴露的定量风险评估 合成和天然化学品及其复杂混合物，从来源到结果的不确定性 在整个生物体及其基因组的背景下，连续体必须被最小化。在这个提案中， 2,3,7,8-四氯二苯并-对二恶英 (TCDD)、3,3',4,4',5-五氯联苯 (PCB126) 和 2,2',4,4',5,5'- 六氯联苯 (PCB153) 以及反映这些物质环境水平的重构混合物 将系统地检查污染物，以阐明添加剂、拮抗剂的作用机制 以及在分子和生理水平上发生的协同相互作用。射线设计和建模 将使用方法来最大限度地减少全面析因研究，以研究混合物的假设 TCDD、PCB126 和 PCB153 在环境相关水平下会引起非累加性肝毒性效应。 将使用小鼠评估剂量和时间依赖性的肝脏基因表达和脂肪肝效应 富含二恶英响应基因和补充组织病理学方法的 cDNA 阵列。 微阵列数据将与组织病理学和临床化学进行计算整合，以识别 基因表达变化与生理/毒性结果之间的关联，促进 阐明二恶英介导的脂肪肝毒性的作用机制。然后混合物将是 进行检查以检测和表征影响影响的加性、协同性和拮抗性相互作用 使用脂肪肝相关基因的响应面模型进行脂肪肝反应。该提案将 不仅开发创新和可靠的统计策略来严格评估由 含有使用共同作用机制的化学物质的混合物，但也将进一步阐明 与 TCDD 诱导的脂肪相关的毒性机制。