NITRIC OXIDE IN TETRACHLORODIBENZO-P-DIOXIN (TCDD) MEDIATED TOXICITY

四氯二苯并-对-二恶英 (TCDD) 中的一氧化氮介导的毒性

• 批准号: 6486004
• 负责人: D HECK
• 金额: $ 13.47万
• 依托单位: UNIV OF MED/DENT NJ-R W JOHNSON MED SCH
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-01 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6486004
• 关键词: dioxins; environmental toxicology; laboratory rat; nitric oxide; nitric oxide synthase; physical chemical interaction

TCCD is a ubiquitous environmental contaminant. Exposure to TCCD result in metabolic, immunologic, reproductive and neoplastic effects in animals. TCDD is a putative human carcinogen and poses a potential risk to human health. We have made the intriguing observation that TCDD up regulates expression of the cytokine inducible isoform of the enzyme nitric oxide synthase and induces nitric oxide biosynthesis by rat hepatic endothelia cells. This is the first demonstration that aryl hydrocarbons regulate an intracellular messenger in the endothelium and provides an important clue on a potential mechanism by which TCCD may alter cellular functioning and induce toxicity. It is our hypothesis that TCDD acts to induce expression of type II no synthase (N0S II) in endothelial cells and that N0 produced in response to TCDD may mediate some of the toxic effects of this contaminant. To test this hypothesis experiments are designed to analyze molecular mechanisms by which TCDD regulates N0 production, and to determine the role of N0 in TCCD-induced tissue injury in rats. These studies will provide information potentially useful for the development of clinical regimens for abrogating TCCD-induced injury in humans. These studies are important and may provide insight into one mechanism by which TCDD induces toxicity.

TCCD是一种普遍存在的环境污染物。 接触TCCD 导致代谢、免疫、生殖和肿瘤效应， 动物 TCDD是一种假定的人类致癌物， 对人类健康的风险。 我们发现了一个有趣的现象， TCDD上调细胞因子诱导型同种型的表达， 酶一氧化氮合酶，并诱导一氧化氮生物合成， 大鼠肝内皮细胞 这是第一次证明芳基 碳氢化合物调节内皮细胞内的信使 并提供了一个重要的线索， TCCD可改变细胞功能并诱导毒性。 是我们 TCDD诱导II型NO合酶表达假说 (N0S II）在内皮细胞中，以及N0响应于 TCDD可能介导该污染物的某些毒性作用。 到 为了验证这一假设，设计了一些实验， TCDD调节N0产生的机制，以及 确定N0在TCCD诱导的大鼠组织损伤中的作用。 这些 研究将提供可能对发展有用的信息， 消除TCCD诱导的人类损伤的临床方案。 这些研究是重要的，可以提供一个深入了解 TCDD诱导毒性的机制。