MOLECULAR MECHANISMS OF DIOXIN ACTION

这项研究的长期目标是阐明 对四氯二苯并对二恶英（TCDD;二恶英）的生物反应。 具体来说，这项建议解决了TCDD修改的假设， 通过干扰正常对照的基因表达模式 调节组织特异性稳态水平的机制 转录因子 TCDD的多种生物学表现 暴露，无论多么无关，总是以剧烈变化为特征， in gene基因expression表达. 因此，根据特定组织，TCDD可以 引起非程序性细胞增殖（肿瘤促进），过度表达 角蛋白基因（氯痤疮），抑制软骨形成间充质 分化和不定期角化（腭裂），或 未成熟胸腺细胞的程序性死亡（胸腺萎缩）。 TCDD是卤代烃的原型同系物， 有毒的环境污染物是有效的免疫抑制剂， 致畸剂和肿瘤促进剂。 TCDD是一种异生物质的配体 受体，芳香烃（Ah）受体，据信 这种受体在TCDD的毒性作用中起着重要作用。 其他Ah受体配体，如苯并[a]芘，通过一种代谢途径代谢。 配体诱导的细胞色素P450酶转化为活性中间体， 具有诱变性和遗传毒性。 TCDD诱导相同的细胞色素P450 酶，但它不是代谢底物，也不会直接导致 因此，它不是一种遗传毒性肿瘤引发剂。 然而，TCDD是有史以来测试过的最有效的肿瘤促进剂之一， 啮齿类动物，这种活动的分子基础仍然未知。 TCDD的其他生物学效应，包括诱导颅面 异常，氯痤疮，胸腺萎缩和卟啉症，甚至更少 在分子水平上得到很好的表征。 拟议的研究是 基于我们实验室的观察，TCDD诱导表达 转录因子AP-1，在 分化、细胞增殖和肿瘤促进。 的目标 本实验旨在研究TCDD暴露对大鼠脑组织的影响， 氧化应激途径对AP-1的表达起作用， 分析该因子控制的基因表达。 主要 这项工作的目标是，（1）确定机制， TCDD诱导AP-1和，（2）以确定是否生物效应 TCDD的表达依赖于AP-1的诱导。 的理解 TCDD影响模型中基因表达控制的机制 系统将提供重要的信息，以阐明不仅 二恶英引起的疾病的分子基础，但也影响 其他非遗传毒性环境污染物。 这种理解可能 协助制订充分理据，以处理因健康问题而引致的 环境因子的不断增加。

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.