MECHANISMS OF DIOXIN TOXICITY

TCDD具有广泛的毒性作用，包括物种和组织 特异性的，可能涉及干扰细胞生长的正常调节 和差异化。TCDD可以调节受体的水平 糖皮质激素、雌激素和表皮生长因子。在.期间 发展，TCDD导致内侧和内侧EGF受体增加 上颌骨上皮和输尿管上皮，并引起内侧 上皮细胞分化为口腔上皮而不是转化 进入间充质和输尿管上皮进行增殖。这些 在活体内导致腭裂和肾积水的影响可能是 在发育中的腭突和尿液中实现器官培养 大片区域，允许物种比较。缺乏裂隙诱导的先天性心脏病 TCDD暴露后发育的大鼠胚胎是由于对 将靶胎儿与小鼠进行比较，因为在培养中，大鼠的腭部 货架可能会受到高浓度TCDD的影响。在活体内，这些 对母体来说是有毒的。人类胚胎的相对敏感性 组织也可以用这种方法来探测。TCDD诱导细胞增殖 人鳞状细胞癌细胞显然是由于 细胞经历高密度生长停滞，而不是直接有丝分裂 刺激。在这些细胞系中看到的一些TCDD效应，例如诱导 EROD活性，可以通过添加转化生长因子β来阻断，这是一种强有力的生长 调整器。然而，TCDD不影响TGFβ与细胞的结合， 这些细胞分泌转化生长因子β或这些细胞对 外源添加了TGFbeta。TCDD的诱导机制 已对肾积水进行了调查。上皮衬里增生症 输尿管狭窄导致管腔闭塞并限制输尿管血流 尿液，导致输尿管积水和肾积水。这一效应与 输尿管上皮细胞EGF受体和DNA表达增加 合成，以氚胸苷掺入增加为指示。

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.