REGULATION OF PROSTATE GENE EXPRESSION BY 1,3 BUTADIENE

1,3丁二烯对前列腺基因表达的调节

• 批准号: 8168125
• 负责人: WESLEY GRAY
• 金额: $ 10.37万
• 依托单位: LOUISIANA STATE UNIV A&M COL BATON ROUGE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-15 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8168125
• 关键词: Air; Androgens; Apoptosis; Apoptotic; Biochemical; Breathing; Butadiene; Carcinogens; Caspase; Cell physiology; Cells; Computer Retrieval of Information on Scientific Projects Database; Cytochromes; Dose; Environment; Funding; Gasoline; Gene Expression; Grant; Human; Institution; LNCaP; Messenger RNA; Ovary; Petroleum; Prostate; Prostatic Neoplasms; Proteins; Regulation; Research; Research Personnel; Resources; Route; Skin; Smoking; Source; Testis; Time; Tissues; Toxic effect; Transfection; Tumor Markers; United States National Institutes of Health; absorption; cytotoxicity; protein expression; reproductive; tumor

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. BDO2, the most active metabolite of 1,3-BD a potential human carcinogen is released into the environment as a result of petroleum byproduct, smoking or combustion of gasoline products. Once in ambient air its readily enters the body by several routs such as inhalation or absorption through the skin where it is metabolized to a BDO2 by cytochrome P450s. In the body, BDO2 may induce reproductive toxicity in target tissue such as ovaries, testis, and prostate. However, the biochemical mechanism of BDO2 toxicity in prostate and BDO2's effects on prostate cell function is undefined. Therefore, the objective of this study was to define some of the cellular changes that are associated with BDO2 toxicity in prostate cells under androgen sensitive (LNCaP(AR+)) and androgen insensitive DU-145 (DU145(AR-)) status. We observed that micro-doses of BDO2 resulted in a dose- and time-dependent decreases in PSA secretion by LNCaP cells and increases expression of prostate tumor marker in LNCaP(AR+) and DU145(AR-) cells. BDO2 induces a higher decrees of cytotoxicity in DU145(AR-) cells as compared to LNCaP(AR+) at the micro-doses examined. The increases sensitive of DU145(AR-) cells to BDO2 toxicity is likely due to the absence of AR since transient transfection of AR into theses cell reverses the BDO2 sensitivity. Exposure of prostate cells to micro-doses of BDO2 increases apoptosis, which correlates with increases caspases and Bcl2 protein and mRNA levels. In cell DU145(AR-) cell transient transfection with AR, the levels of cytotoxicity and caspases activity was decreased in the presence of BDO2 but BDO2 induce apoptotic proteins expression was unaltered. This study provides evident that micro-doses of BDO2 modulates prostate cell toxicity by promoting apoptosis and tumor gene expression.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 BDO2 是 1,3-BD 最活跃的代谢物，是一种潜在的人类致癌物，由于石油副产品、吸烟或汽油产品燃烧而释放到环境中。一旦进入环境空气，它很容易通过多种途径进入人体，例如吸入或通过皮肤吸收，并在细胞色素 P450 的作用下代谢为 BDO2。在体内，BDO2 可能会引起卵巢、睾丸和前列腺等靶组织的生殖毒性。然而，BDO2 对前列腺的毒性以及 BDO2 对前列腺细胞功能的影响的生化机制尚不清楚。因此，本研究的目的是确定雄激素敏感 (LNCaP(AR+)) 和雄激素不敏感 DU-145 (DU145(AR-)) 状态下前列腺细胞中与 BDO2 毒性相关的一些细胞变化。我们观察到微剂量的 BDO2 导致 LNCaP 细胞 PSA 分泌呈剂量和时间依赖性减少，并增加 LNCaP(AR+) 和 DU145(AR-) 细胞中前列腺肿瘤标志物的表达。在所检测的微剂量下，与 LNCaP(AR+) 相比，BDO2 在 DU145(AR-) 细胞中诱导更高的细胞毒性。 DU145(AR-)细胞对BDO2毒性的敏感性增加可能是由于AR的缺失，因为将AR瞬时转染到这些细胞中会逆转BDO2敏感性。前列腺细胞暴露于微剂量的 BDO2 会增加细胞凋亡，这与半胱天冬酶、Bcl2 蛋白和 mRNA 水平的增加相关。在用AR瞬时转染的DU145(AR-)细胞中，在BDO2存在下，细胞毒性和半胱天冬酶活性水平降低，但BDO2诱导凋亡蛋白的表达没有改变。这项研究证明微剂量的 BDO2 通过促进细胞凋亡和肿瘤基因表达来调节前列腺细胞毒性。