MECHANISMS OF DIOXIN TOXICITY

TCDD对物种和组织都有广泛的毒性作用

TCDD has a broad range of toxic effects which are both species and tissue specific and may involve interference with normal regulation of cell growth and differentiation. TCDD can modulate the levels of receptors glucocorticoids, estrogens, and epidermal growth factor. During development, TCDD causes increases in the EGF receptor in both the medial epithelium of the palate and the ureteric epithelium, and causes the medial epithelium to differentiate into an oral epithelium rather than transform into mesenchyme and the ureteric epithelium to undergo hyperplasia. These effects, which result in cleft palate and hydronephrosis in vivo, can be achieved in organ culture of the developing palatal shelves and the urinary tract, allowing for species comparison. The lack of cleft induction in the developing rat fetus following TCDD exposure is due to lower sensitivity of the target fetus as compared to the mouse since in culture, rat palatal shelves can be affected by high concentrations of TCDD. In vivo, these does are maternally toxic. The relative sensitivity of human embryonic tissue can also be explored by this method. TCDD induces proliferation of human squamous carcinoma cells apparently as a result of a failure of the cells to undergo high density growth arrest rather than a direct mitogenic stimulus. Some TCDD effects seen in thee cell lines, such as induction of EROD activity, can be blocked by the addition of TGFbeta, a potent growth regulator. TCDD, however, does not effect binding of TGFbeta to cells, secretion of TGFbeta by these cells or responsiveness of these cells to exogenously added TGFbeta. The mechanism by which TCDD induces hydronephrosis has been investigated. Hyperplasia of the epithelial lining of the ureter results in occlusion of the lumen and restricts flow of urine, resulting in hydroureter and hydronephrosis. This effect correlates with increased ureteric epithelial expression of EGF receptors and DNA synthesis as indicated by increased tritiated thymidine incorporation.