MECHANISM OF DIOXIN TOXICITY

二恶英的毒性机制

• 批准号: 3918635
• 负责人: L S BIRNBAUM
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3918635
• 关键词: chemical carcinogenesis; cleft palate; dioxins; enzyme induction /repression; epidermal growth factor; glucocorticoids; growth factor; hairless mouse; halobiphenyl /halotriphenyl compound; hormone receptor; hydronephrosis; laboratory mouse; squamous cell carcinoma; toxin metabolism; transforming growth factors; tumor promoters

TCDD has a broad range of effects which are species and tissue specific. The relative dermal toxicity and promoting ability of two polychlorinated dibenzofurans (PCDFs), 2,3,4,7,8-pentaCDF (PeCDF) and 1,2,3,4,7,8-hexaCDF (HCDF) was examined using the hairless mouse. TCDD is approximately 2.5X and 6X as dermally toxic as PeCDF and HCDF which is less of a difference than would have been predicted based upon studies of acute toxicity. Both PCDFs were also potent skin tumor promoters. The effects of TCDD on enzyme induction and glucocorticoid receptors were compared in the liver and skin of haired and hairless mice. The TCDD effects were tissue specific. No effect of TCDD was detected on the epidermal growth factor receptor in the skin. Whether these effects are under the control of the Ah receptor is currently being examined using congenic mice. The role of growth factors in TCDD toxicity is currently being studied using human squamous carcinoma cell (SCC) lines which have been reported to differentiate and/or proliferate in response to TCDD. The effect of transforming growth factor (TGF beta) is also under investigation. TCDD causes cleft palate (CP)and hydronephrosis (HN) prenatally in mice. HN is due to hyperplasia of the ureteric epithelium as well as a decrease in density of the extracellular matrix proteins surrounding the developing glomeruli. The reversibility and functional implications of HN are under investigation. TCDD-and retinoic acid (RA)-induced CP is due to failure of fusion of the palatal shelves. However, the events at a cellular level are distinct, with TCDD causing the medial edge cells to become oral-like and RA inducing a nasal-like epithelium. Organ culture techniques are being used to further dissect out the events involved in palatal fusion and kidney development.

TCDD具有广泛的物种和组织效应