Mechanism(s) Of Leukemogenesis In Disease Models

疾病模型中白血病发生的机制

• 批准号: 7006469
• 负责人: JOHN EDGAR FRENCH
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7006469
• 关键词: animal genetic material tag; benzene; chemical carcinogen; chemical carcinogenesis; environment related neoplasm /cancer; environmental exposure; gene environment interaction; gene expression; genetic regulation; genetically modified animals; hematopoietic stem cells; laboratory mouse; leukemia; microarray technology; molecular oncology; neoplasm /cancer genetics; p53 gene /protein; toxin metabolism

Public health concern over ionizing radiation and benzene, a radiomimetic, because of their potential to induce cancer. Exposure to radiation and benzene is associated with depression of blood forming elements leading to anaplastic anemia, followed by myelodysplastic syndrome (MDS) and, ultimately, to leukemia or lymphoma. Inhalation or dermal exposure to benzene results in a slower rate of delivery and a greater internal dose than other routes of exposure. At equivalent oral dose (mg/kg), more benzene is expired unmetabolized after administration by the oral route (60%) than by inhalation (14%). Mice may also produce a greater variety of benzene metabolites by inhalation. Most critical to selection of dose for experimental studies is to know the exposure level that becomes saturating to pathways of detoxification. For inhalation exposure this is 200 ppm (6 h TWA. Between 5 and 50 ppm benzene (6 h TWA, there is no significant difference between urinary metabolites. Available data also suggests that the ratio of hydroquinone or muconic acid to phenol ratio after inhalation exposure to 50 ppm (6 h TWA) is closer between mice and humans than either rats or Cynomolgus monkeys. This is critical because these may be the most toxic benzene intermediates. Thus, an exposure model must take into account saturation of benzene metabolism pathways, available data on exposures and high-affinity, low capacity pathways of metabolism that result in the most hematotoxic intermediates. We have been able to show that p53 deficient mice exposed to low levels (100 ppm, 6 h TWA) develop thymic lymphomas rapidly whereas mice exposed to higher levels (200 ppm, 6 h TWA) less rapidly and a significantly decreased incidence. In these studies, benzene induced lymphomas in the p53 deficient mice were: 1) clonal (T-cell receptor rearrangements were common), 2) showed a pattern of loss or deletions in chromosome 11 carrying the p53 wildtype allele different from sporadic lymphomas, and 3) showed a pattern of dysregulation of critical genes in both the p53 and Rb pathways that affected cell cycle control and population growth and apoptosis. We are continuing to investigate the effect of benzene dose and dose rate exposure by inhalation or drinking water. Using low doses and reduced frequency of exposure, metabolic pathways in the hematopoietic stem cell compartment that show high affinity for oxidation of benzene to mutagenic metabolites are targeted. At high doses and rates, these data suggest that conjugated metabolites are efficiently excreted. More research is required to investigate these phenomena.

公众健康对电离辐射和苯（一种拟辐射物质）的担忧，因为它们有可能诱发癌症。接触辐射和苯与造血元素抑制有关，导致再生障碍性贫血，随后出现骨髓增生异常综合征 (MDS)，最终导致白血病或淋巴瘤。与其他接触途径相比，吸入或皮肤接触苯会导致输送速度较慢和内部剂量更大。在同等口服剂量（mg/kg）下，口服给药后未代谢的苯（60%）比吸入给药（14%）多。小鼠也可能通过吸入产生更多种类的苯代谢物。选择实验研究剂量最关键的是了解解毒途径饱和的暴露水平。对于吸入暴露，该浓度为 200 ppm（6 小时 TWA）。在 5 和 50 ppm 苯（6 小时 TWA）之间，尿液代谢物之间没有显着差异。现有数据还表明，吸入暴露于 50 ppm（6 小时 TWA）后，小鼠和人类之间的对苯二酚或粘康酸与苯酚的比率比大鼠或食蟹猴更接近。这是 至关重要，因为这些可能是毒性最强的苯中间体。因此，暴露模型必须考虑苯代谢途径的饱和度、暴露的可用数据以及产生最具血液毒性中间体的高亲和力、低容量的代谢途径。我们已经能够证明，暴露于低水平（100 ppm，6 小时 TWA）的 p53 缺陷小鼠会迅速发展为胸腺淋巴瘤 而暴露于较高浓度（200 ppm，6 小时 TWA）的小鼠则速度较慢且发病率显着降低。在这些研究中，p53 缺陷小鼠中苯诱导的淋巴瘤为：1) 克隆性（T 细胞受体重排很常见），2) 携带 p53 野生型等位基因的 11 号染色体显示出与散发性淋巴瘤不同的丢失或缺失模式， 3) 显示 p53 和 Rb 通路中关键基因的失调模式，影响细胞周期控制以及群体生长和凋亡。我们正在继续研究吸入或饮用水苯剂量和剂量率暴露的影响。使用低剂量和减少暴露频率，针对造血干细胞区室中对苯氧化成诱变代谢物表现出高亲和力的代谢途径。在高剂量和高速率下，这些数据表明缀合代谢物可以有效地排出体外。需要更多的研究来调查这些现象。