Cellular distribution of cell cycle-related molecules in the renal tubules of rats treated with renal carcinogens for 28 days-Relationship between cell cycle aberration and carcinogenesis
Cellular distribution of cell cycle-related molecules in the renal tubules of rats treated with renal carcinogens for 28 days-Relationship between cell cycle aberration and carcinogenesis
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肾癌药物治疗28天大鼠肾小管细胞周期相关分子的细胞分布-细胞周期畸变与癌变的关系
DOI：
10.1007/s00204-012-0829-z
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发表时间：
2012
影响因子：
6.1
通讯作者：
Shibutani M
中科院分区：
文献类型：
--
作者：
Taniai E;Hayashi H;Yafune A;Watanabe M;Akane H;Suzuki K;Mitsumori K;Shibutani M
一些肾致癌物质从接触的早期阶段就可以诱发核肿大，这反映了肾小管中细胞分裂的异常。为了阐明肾癌发生早期阶段与细胞周期相关的变化，我们对接受致癌剂量的代表性肾癌物质治疗 28 天的雄性 F344 大鼠的肾小管细胞进行了免疫组织化学分析。为此，对诱发核肿大的致癌物质赭曲霉毒素A (OTA)、次氮基三乙酸铁和莫努隆，以及非核肿大诱发的致癌物质磷酸三(2-氯乙基)酯和溴酸钾进行了检查。为了进行比较，还检查了一种引起核肿大的非致癌物质对硝基苯甲酸和一种非致癌的非引起核肿大的肾毒物对乙酰氨基酚。对外髓质 (OSOM) 和皮质 + OSOM 的外条纹进行免疫反应性近端肾小管细胞的形态测定分析。肾致癌物，无论其诱导核肿大的潜力如何，都会增加近端肾小管细胞增殖，并伴有拓扑异构酶 IIα-免疫反应性细胞的增加，表明细胞增殖的反映。核肥大诱导致癌物增加了这两个区域的核 Cdc2-、γH2AX- 和磷酸化 Chk2 免疫反应性细胞，前两者对 DNA 损伤做出反应，而后一个则暗示持续的 G2。 OTA 是一种针对 OSOM 的致癌物，通过评估 OSOM 中 DNA 损伤和 G2/M 转变的分子响应，可以轻松地将 OTA 与未经处理的对照和非致癌物区分开来。因此，所有检查的肾致癌物都通过重复短期治疗促进近端肾小管增殖。其中，引起核肿大的致癌物质可能会导致目标肾小管细胞中的 DNA 损伤和 G2 阻滞。
Some renal carcinogens can induce karyomegaly, which reflects aberrant cell division in the renal tubules, from the early stages of exposure. To clarify the cell cycle-related changes during the early stages of renal carcinogenesis, we performed immunohistochemical analysis of tubular cells in male F344 rats treated with carcinogenic doses of representative renal carcinogens for 28 days. For this purpose, the karyomegaly-inducing carcinogens ochratoxin A (OTA), ferric nitrilotriacetic acid, and monuron, and the non-karyomegaly-inducing carcinogens tris(2-chloroethyl) phosphate and potassium bromate were examined. For comparison, a karyomegaly-inducing non-carcinogen,p-nitrobenzoic acid, and a non-carcinogenic non-karyomegaly-inducing renal toxicant, acetaminophen, were also examined. The outer stripe of the outer medulla (OSOM) and the cortex + OSOM were subjected to morphometric analysis of immunoreactive proximal tubular cells. Renal carcinogens, irrespective of their karyomegaly-inducing potential, increased proximal tubular cell proliferation accompanied by an increase in topoisomerase IIα−immunoreactive cells, suggesting a reflection of cell proliferation. Karyomegaly-inducing carcinogens increased nuclear Cdc2-, γH2AX-, and phosphorylated Chk2-immunoreactive cells in both areas, the former two acting in response to DNA damage and the latter one suggestive of sustained G2. OTA, an OSOM-targeting carcinogen, could easily be distinguished from untreated controls and non-carcinogens by evaluation of molecules responding to DNA damage and G2/M transition in the OSOM. Thus, all renal carcinogens examined facilitated proximal tubular proliferation by repeated short-term treatment. Among these, karyomegaly-inducing carcinogens may cause DNA damage and G2arrest in the target tubular cells.