MECHANISMS OF DIOXIN TOXICITY

TCDD具有广泛的毒性作用，既有物种毒性，也有组织毒性 特异性，可能涉及干扰细胞生长的正常调节 和差异化。 TCDD可调节受体水平 糖皮质激素、雌激素和表皮生长因子。 期间 TCDD引起表皮生长因子受体的增加， 腭上皮和输尿管上皮，并导致中膜 上皮分化成口腔上皮，而不是转化成 进入间充质和输尿管上皮进行增生。 这些 影响，导致腭裂和肾积水在体内，可以是 在发育中的腭架和泌尿系统的器官培养中实现 #21518;，允许物种比较。 缺乏裂缝诱导， TCDD暴露后发育中的大鼠胎儿对TCDD的敏感性较低， 目标胎儿与小鼠相比，因为在培养中，大鼠腭 货架可能会受到高浓度的TCDD的影响。 在体内，这些 是对母体有害的 人胚肺组织的相对敏感性 组织也可以通过该方法进行探查。 TCDD可诱导 人类鳞状细胞癌细胞显然是由于失败的， 细胞进行高密度生长停滞，而不是直接促有丝分裂 刺激。 在这些细胞系中观察到的一些TCDD效应，例如诱导细胞凋亡， EROD活性，可以通过加入TGF β，一种有效的生长抑制剂， 调节器 然而，TCDD不影响TGF β与细胞的结合， 这些细胞分泌TGF β或这些细胞对 外源性TGF β TCDD诱导的机制 已经研究了肾积水。 上皮衬里增生 输尿管的扩张导致管腔闭塞， 尿液，导致输尿管积水和肾盂积水。 这种效应与 输尿管上皮EGF受体和DNA表达增加 氚标记胸苷掺入增加表明了合成。

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.