Non-Additive Ah Receptor Ligand Interactions

虽然人类接触有毒物质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、社会和经济的潜在影响， 后果为了改进对慢性和亚慢性接触的定量风险评估， 合成和天然化学品及其复杂的混合物，来源到结果的不确定性 必须在整个生物体及其基因组的背景下将连续体最小化。在这一提议中， 2，3，7，8-四氯二苯并对二恶英（TCDD）、3，3 '，4，4'，5-五氯联苯（PCB 126）和2，2 '，4，4'，5，5 '- 六氯联苯（PCB 153）以及反映这些物质环境水平的重组混合物 将系统地检查污染物，以阐明添加剂、拮抗剂 以及在分子和生理水平上发生的协同相互作用。Ray设计和建模 方法将用于最小化全因子研究，以研究混合物 四氯二苯并对二恶英、多氯联苯126和多氯联苯153在环境相关水平上的浓度可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肝脏基因表达和脂肪肝效应。 富含二恶英反应基因的cDNA阵列和互补的组织病理学方法。 微阵列数据将与组织病理学和临床化学进行计算整合，以确定 基因表达的变化与生理/毒性结果之间的关联， 阐明二恶英介导的脂肪肝毒性的作用机制。然后，混合物将 检查以检测和表征影响生物活性的加和、协同和拮抗相互作用。 脂肪肝反应使用与脂肪肝相关的基因的响应面模型。这项建议会 不仅要制定创新和可信的统计战略，严格评估 含有化学品的混合物，使用共同的作用机制，但也将进一步阐明 与TCDD诱导的脂肪相关的毒性机制。

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.