MOLECULAR TOXICOLOGY OF TCDD

氯化二苯并对二恶英是毒性最大的合成化合物之一。 已知的化合物。此外，最近的证据表明，这些化合物可以 是非常有效的肿瘤促进剂。 所描述的研究的总体目标是更好地理解 2，3，7，8-四氯二苯并对二恶英的生化机理(S) (TCDD)和相关化合物对动物产生毒性。证据 提示这些化合物的毒性是通过它们的特异性 与胞浆蛋白结合、核转位和随后的 基因表达的调节。各种放射性同位素，动力学，和 将利用层析技术来研究生化 受体的性质，以及获得特异和灵敏的探针 这种分子的改变形式。这些研究的信息将是 用于设计一种纯化受体分子的方案。这个 TCDD受体复合体在无细胞条件下的核转位动力学 系统以及这些过程对结合、转化、 细胞质因子将被确定。研究利用技术 体内和体外分离的肝细胞将决定暂时性和 受体的核占有率与其受体的剂量-反应关系 TCDD的毒性。需要衡量的具体反应包括 肝酶改变和生化事件导致的卟啉症。这些 研究旨在关注导致TCDD诱导的早期事件 基因表达调控与卟啉症。利用类似的协议， 胸腺中TCDD受体在TCDD诱导的胸腺萎缩中的作用 下定决心。胸腺中受体所在的细胞类型(S) 将被确定，因此可能会计划进一步的重点生化研究。 最后，我们将检查怀孕能力，维生素B6缺乏， 细胞色素p-450耗竭与维生素A或氢化可的松治疗 改变胸腺和肝脏中TCDD受体的水平、分布 胞浆和胞核之间的受体，或转位能力 发生在体内的受体。这些研究可能会提出什么控制措施 这一受体在体内，以及这一可能的生理作用 分子。

The chlorinated dibenzo-p-dioxins are among the most toxic synthetic compounds known. In addition recent evidence suggests these compounds to be extremely potent tumor promoting agents. The overall objective of the research described is to better understand the biochemical mechanism(s) by which 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds produce toxicity in animals. Evidence suggests the toxicity of these compounds is mediated through their specific binding to a cytosolic protein, nuclear translocation and subsequent modulation of gene expression. A variety of radioisotope, kinetic, and chromatographic techniques will be utilized to investigate the biochemical nature of the receptor, as well as obtain specific and sensitive probes for altered forms of this molecule. The information from these studies will be used to devise a scheme for the purification of the receptor molecule. The kinetics of nuclear translocation of the TCDD-receptor complex in cell-free systems and the dependence of these processes on binding, transformation, and cytoplasmic factors will be determined. Studies utilizing techniques in vivo and isolated hepatocytes in vitro will determine the temporal and dose-response relationship between nuclear occupancy of the receptor and the toxicity of TCDD. The specific responses to be measured include altered hepatic enzymes and biochemical events leading to porphyria. These studies are designed to focus on early events leading to TCDD-induced modulated gene expression and porphyria. Utilizing similar protocols, the role of TCDD receptors in the thymus in TCDD-induced thymic atrophy will be determined. The cell type(s) in the thymus in which receptor is localized will be determined so further focused biochemical studies may be planned. Finally, we will examine the ability of pregnancy, vitamin B6 deficiency, cytochrome p-450 depletion and treatments with vitamin A or hydrocortisone to alter the levels of TCDD receptor in the thymus and liver, distribution of the receptor between cytosol and nucleus, or ability for translocation of the receptor to occur in vivo. These studies may suggest what controls this receptor in vivo, as well as the possible physiological role of this molecule.