Molloy C J, Gallo M A, Laskin J D
Carcinogenesis. 1987 Sep;8(9):1193-9. doi: 10.1093/carcin/8.9.1193.
The potent toxin 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) causes chloracne and acts as a tumor promoter in the hairless HRS/J mouse model. In the present study we characterized changes in mouse epidermal keratin expression following a single topical application of TCDD to the skin of hairless (hr/hr) and haired (hr/+) HRS/J mice. Morphologic changes and alterations in keratin biosynthesis following TCDD treatment were compared with those induced by the phorbol ester tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). Both TPA and TCDD induced dose-dependent epidermal hyperplasia in hr/hr and hr/+ mice and this was associated with altered keratin subunit expression. In hr/hr mice TCDD caused a pattern of keratin expression that was similar to TPA, characterized by a marked decrease in the synthesis of the Mr 67,000 (basic) and 59,000 (acidic) keratins that are specific markers for suprabasal differentiation in the epidermis. In addition, the synthesis of an acidic keratin of Mr 48,000 and a basic keratin of Mr 62,000 was also decreased. Concomitantly, TCDD caused an increase in the synthesis of a basic keratin of Mr 60,000 and acidic keratins of Mr 54,000, 52,000 and 49,000 that are normally observed in proliferating basal cells and primary epidermal cell cultures. In contrast, while TPA induced similar changes in keratinization in both the hr/+ and hr/hr mice, TCDD-induced hyperplasia in hr/+ mice was only associated with changes in keratin synthesis reflecting increased basal cell proliferation. These results demonstrate that a single application of TCDD to the skin alters the normal pattern of epidermal differentiation in the hr/hr mouse. Molecular events influencing the expression of the keratin genes associated with this process may be linked to the strain- and/or species-specific toxicity of TCDD.
强效毒素2,3,7,8-四氯二苯并-对-二恶英（TCDD）可引发氯痤疮，并在无毛HRS/J小鼠模型中充当肿瘤促进剂。在本研究中，我们对TCDD单次局部应用于无毛（hr/hr）和有毛（hr/+）HRS/J小鼠皮肤后小鼠表皮角蛋白表达的变化进行了表征。将TCDD处理后的形态学变化和角蛋白生物合成改变与佛波酯肿瘤促进剂12-O-十四酰佛波醇-13-乙酸酯（TPA）诱导的变化进行了比较。TPA和TCDD均可在hr/hr和hr/+小鼠中诱导剂量依赖性的表皮增生，这与角蛋白亚基表达改变有关。在hr/hr小鼠中，TCDD导致的角蛋白表达模式与TPA相似，其特征是分子量为67,000（碱性）和59,000（酸性）的角蛋白合成显著减少，这两种角蛋白是表皮基底层以上分化的特异性标志物。此外，分子量为48,000的酸性角蛋白和分子量为62,000的碱性角蛋白的合成也减少。同时，TCDD导致分子量为60,000的碱性角蛋白以及分子量为54,000、52,000和49,000的酸性角蛋白合成增加，这些角蛋白通常在增殖的基底细胞和原代表皮细胞培养物中可见。相比之下，虽然TPA在hr/+和hr/hr小鼠中均诱导了类似的角质化变化，但TCDD在hr/+小鼠中诱导的增生仅与反映基底细胞增殖增加的角蛋白合成变化有关。这些结果表明，TCDD单次应用于皮肤会改变hr/hr小鼠表皮分化的正常模式。影响与该过程相关的角蛋白基因表达的分子事件可能与TCDD的品系和/或物种特异性毒性有关。
