MOLECULAR MECHANISMS OF DIOXIN ACTION

这项研究建议的长期目标是阐明 四氯二苯并对二恶英(TCDD；二恶英)的生物反应。 具体地说，这项提议解决了TCDD修改 干扰正常对照的基因表达模式 调节组织特异性蛋白稳态水平的机制 转录因子。TCDD的多种生物学表现 暴露，无论多么无关，总是以剧烈的变化为特征。 在基因表达上。因此，根据特定的组织，TCDD可以 导致计划外细胞增殖(促进肿瘤)、高表达 角蛋白基因(氯痤疮)抑制软骨源性间充质 分化和非计划性角化(腭裂)，或 未成熟胸腺细胞程序性死亡(胸腺萎缩)。 TCDD是卤代烃的原型同系物，是一组 有毒的环境污染物被认为是有效的免疫抑制剂， 致畸物质和肿瘤促进剂。TCDD是一种异源生物的配体 受体，芳香烃(Ah)受体及其被认为 这种受体在TCDD的毒性效应中起着至关重要的作用。 其他的AH受体配体，如苯并[a]芘，是由一种 配体诱导的细胞色素P450酶转化为活性中间体 具有突变性和基因毒性。TCDD诱导相同的细胞色素P450 酶，但它不是可代谢的底物，也不会直接引起 DNA的改变，因此它不是一种遗传毒性的肿瘤启动物。 然而，TCDD是有史以来测试过的最有效的肿瘤促进剂之一 啮齿动物，这种活动的分子基础仍不清楚。 TCDD的其他生物学效应，包括诱导颅面 氯化痤疮、胸腺萎缩和门静脉症等异常症状甚至更少。 在分子水平上得到了很好的表征。拟议的研究是 根据我们实验室的观察，TCDD诱导表达 一种转录因子AP-1，它在 分化、细胞增殖和肿瘤促进。的目标是 建议的实验是为了研究TCDD暴露对小鼠的影响。 影响AP-1和TO表达的氧化应激途径 分析受该因子控制的基因的表达。主修 这项工作的目标是：(1)确定 TCDD诱导AP-1和，(2)确定是否有生物学效应 TCDD依赖于AP-1的诱导。对这一概念的理解 TCDD影响模型基因表达调控的机制 系统将提供重要信息来阐明不仅是 二恶英致病的分子基础，也是二恶英的作用 其他非遗传毒性环境污染物。这一理解可能 帮助制定适当的理由来处理出现的健康问题 由于不断增加的环境因素的影响。

The long-term objective of this research proposal is to elucidate the biological responses to tetrachlorodibenzo-p-dioxin (TCDD; dioxin). Specifically, this proposal address the hypothesis that TCDD modifies gene expression patterns by interfering with the normal control mechanisms that regulate the steady state levels of tissue-specific transcription factors. The diverse biological manifestations of TCDD exposure, however unrelated, are always characterized by drastic changes in gene expression. Thus, depending on the particular tissue, TCDD may cause unscheduled cell proliferation (tumor promotion), hyperexpression of keratin genes (chloracne), inhibition of chondrogenic mesenchyme differentiation and unscheduled keratinization (cleft palate), or programmed death of immature thymocytes (thymic atrophy). TCDD is the prototype congener of the halogenated hydrocarbons, a group of toxic environmental pollutants known to be potent immunosuppresssors, teratogens, and tumor promoters. TCDD is a ligand for a xenobiotic receptor, the aromatic hydrocarbon (Ah) receptor, and its is believed that this receptor plays an essential role in the toxic effects of TCDD. Other Ah receptor ligands, such as benzo[a]pyrene, are metabolized by a ligand-inducible cytochrome P450 enzyme into reactive intermediates that are mutagenic and genotoxic. TCDD induced the same cytochrome P450 enzyme, but it is not a metabolizable substrate nor does it cause direct alterations in DNA, and therefore it is not a genotoxic tumor initiator. TCDD, however, is one of the most potent tumor promoters ever tested in rodents, and the molecular basis of this activity is still unknown. Other biological effects of TCDD, including induction of craniofacial abnormalities, chloracne, thymic atrophy, and porphyria, are even less well characterized at the molecular level. The proposed research is based on the observation from our laboratory that TCDD induces expression of a transcription factor, AP-1, that has an essential role in differentiation, cell proliferation, and tumor promotion. The goal of the proposed experiments is to study the effect of TCDD exposure on the oxidative stress pathways operative on the expression of AP-1 and to analyze the expression of genes controlled by the factor. Major objectives of this work are, (1) to determine the mechanisms by which TCDD induces AP-1 and, (2) to ascertain whether the biological effects of TCDD are dependent on AP-1 induction. An understanding of the mechanisms by which TCDD affects the control of gene expression in model systems will provide important information to elucidate not only the molecular basis of dioxin-induced disease, but also of the effects of other non-genotoxic environmental pollutants. This understanding may help formulate an adequate rationale to deal with health problems arising from an ever-increasing exposure to environmental agents.