MICROTUBULES IN TESTICULAR TOXICITY OF CARBENDAZIM

多菌灵睾丸毒性中的微管

• 批准号: 2018589
• 负责人: MARION G MILLER
• 金额: $ 23.21万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-01 至 2000-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2018589
• 关键词: antifungal agents; benzimidazoles; environmental toxicology; intermediate filaments; laboratory mouse; laboratory rat; male; microtubules; pesticide biological effect; pesticide residues; testis disorder; toxin metabolism; vimentin

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.

描述（改编自研究者摘要）：苯菌灵及其 代谢物多菌灵是苯并咪唑杀真菌剂， 在不影响其他器官系统的剂量水平下对大鼠的毒性。 一 最近的研究提供了强有力的证据表明，多菌灵（CBZ），而不是 苯菌灵是造成睾丸损伤的罪魁祸首 组织病理学上， CBZ给药后的睾丸毒性的特征在于 生精上皮的特殊脱落。 已知CBZ抑制 微管组装，但这与细胞事件的关系 其作为脱落的基础是未知的。 这一假设的核心是 目前的建议是，睾丸对CBZ的单一敏感性 毒性是特定微管相关的破坏的结果， 蛋白质（MAP）/微管蛋白相互作用仅见于睾丸， 微管组装的丧失和MAP或微管蛋白磷酸化的降低 蛋白质。 提出了一个解决睾丸作用的模型 阶段特异性微管与中间丝结构 CBZ引起的坍塌。 第一个具体目标是， CBZ对微管组装影响是睾丸微管特异性的 组装并涉及睾丸特异性微管蛋白的破坏 互动 第二个具体目标是鉴定MAP/微管蛋白 睾丸特异性蛋白，受CBZ影响，并解决 CBZ诱导的蛋白质磷酸化变化可能在 在细胞骨架崩溃。 最终的具体目标将决定 CBZ诱导的早期细胞骨架变化与脱落的关系 以高于和低于脱落阈值的剂量水平给药， 正常大鼠和病毒敲除小鼠。 初步的免疫细胞化学数据 表明，伴随着微管结构的丧失， 纤维向基底膜收缩。 提出了一种模型， 解释了CBZ在功能方面的阶段特异性效应， 生殖细胞不同时期的微管和中间丝 发展 波形蛋白敲除小鼠提供了一个极好的实验 用于测试中间丝在坍塌事件中的作用的模型 CBZ给药后。