MICROTUBULES IN TESTICULAR TOXICITY OF CARBENDAZIM

描述(改编自《调查者摘要》)：苯菌灵及其 代谢产物多菌灵是引起睾丸的苯并咪唑类杀菌剂。 在不影响其他器官系统的情况下，剂量水平对大鼠的毒性。一个 最近的研究提供了强有力的证据表明卡苯那津(CBZ)，而不是 Benomyl是睾丸损伤的罪魁祸首。从组织病理学角度来看， CBZ给药后的睾丸毒性具有阶段性特征 生精上皮的特殊松弛。已知卡马西平可抑制 微管组装及其与细胞事件的关系 坍塌背后的原因尚不清楚。这一假设的核心是 目前的建议是，睾丸对卡马西平的单一敏感性 毒性是相关的特定微管破坏的结果。 蛋白质(MAP)/微管蛋白相互作用仅在睾丸中发现 微管组装丢失和MAP或微管蛋白磷酸化降低 蛋白质(S)。提出了一个模型，它解决了睾丸的作用。 阶段特异性微管与中间丝结构的比较 卡马西平引起的塌陷。第一个具体目标是确定 卡马西平对微管组装的影响是睾丸微管特有的 组装，涉及破坏睾丸特异的MAP-微管蛋白 互动。第二个特定目标是识别MAP/微管蛋白 受卡马西平影响的睾丸特异蛋白质，并解决 卡马西平诱导蛋白质磷酸化改变的可能性 细胞骨架崩溃。最终的具体目标将决定 卡马西平引起的早期细胞骨架改变的衰弱关系 给药剂量高于或低于人体衰弱阈值 正常大鼠和VIM基因敲除小鼠。初步的免疫细胞化学数据显示 表明，伴随着微管结构的丧失，中间体 细丝向基底膜塌陷。提出了一种新的模型，该模型 根据CBZ的功能解释CBZ的阶段特定效应 生殖细胞不同发育阶段的微管和中间丝 发展。Vimentin基因敲除小鼠提供了一个很好的实验 测试中间细丝在坍塌事件中的作用的模型 这是在CBZ政府之后发布的。

DESCRIPTION (Adapted from the Investigator's Abstract): Benomyl and its metabolite carbendazim are benzimidazole fungicides which cause testicular toxicity in rats at dose levels where no other organ system is affected. A recent study has supplied strong evidence that carbenazim (CBZ), and not benomyl, is responsible for testicular damage. Histopathologically, testicular toxicity after CBZ administration is characterized by a stage specific sloughing of the seminiferous epithelium. CBZ is known to inhibit microtubule assembly but the relationship of this to the cellular events which underlie sloughing is not known. The hypothesis central to the present proposal is that the singular sensitivity of the testis to CBZ toxicity is the result of disruption of a specific microtubule associated protein (MAP)/tubulin interaction only found in the testis with resultant loss of microtubule assembly and decreased phosphorylation of MAP or tubulin protein(s). A model is presented which addresses the role of testis microtubule vs. intermediate filament structures in the stage specific sloughing induced by CBZ. The first specific aim is to establish that the effect of CBZ on microtubule assembly is specific for testis microtubule assembly and involves disruption of a testis specific MAP-tubulin interaction. The second specific aim is to identify the MAP/tubulin testis-specific proteins which are affected by CBZ and address the possibility that CBZ induced changes in protein phosphorylation play a role in cytoskeletal collapse. The final specific aim will determine the relationship to sloughing of early cytoskeletal changes induced by CBZ administered at dose levels both above and below the sloughing threshold in normal rats and vim-knockout mice. Preliminary immunocytochemical data has indicated that, concomitant with loss of microtubule structure, intermediate filaments collapse towards the basal membrane. A model is proposed which explains the stage specific effects of CBZ in terms of the function of microtubules and intermediate filaments at different stages of germ cell development. The vimentin-knockout mouse provides an excellent experimental model for testing the role of intermediate filaments in the sloughing events which follow CBZ administration.