Mechanism(s) Of Leukemogenesis In Genetically-altered Mo

基因改变的 Mo 中白血病发生的机制

• 批准号: 6837354
• 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/6837354
• 关键词: benzene; carcinogen testing; chemical carcinogen; chemical carcinogenesis; dosage; environment related neoplasm /cancer; environmental contamination; environmental exposure; gene environment interaction; gene expression; genetically modified animals; hematopoietic stem cells; inhalation drug administration; laboratory mouse; leukemia; loss of heterozygosity; microarray technology; mixed tissue /cell culture; neoplasm /cancer genetics; oral administration; p53 gene /protein; protooncogene; toxin metabolism; tumor suppressor genes

Benzene is a human and rodent carcinogen. Public health concern over benzene is warranted because it is ubiquitous in air, water, soil, and, thus, in food and beverages. Exposure to 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 of 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.

苯是人类和啮齿动物的致癌物。公众对苯的关注是合理的，因为它在空气、水、土壤中普遍存在，因此在食品和饮料中也普遍存在。接触苯会导致再生障碍性贫血，随后是骨髓增生异常综合征(MDS)，最终会导致白血病或淋巴瘤。与其他暴露途径相比，吸入苯会导致较慢的分娩速度和较大的内部剂量。在相同的口服剂量(mg/kg)下，口服给药后过期未代谢的苯(60%)比吸入给药(14%)多。老鼠也可能通过吸入产生更多种类的苯代谢物。对于实验研究的剂量选择，最关键的是知道达到脱毒途径饱和的暴露水平。对于吸入暴露，这是200ppm(6小时TWA。在5ppm和50ppm苯(6h TWA)之间，尿代谢物之间没有显著差异。现有数据还表明，吸入50ppm(6h TWA)后对苯二酚或肉豆蔻酸/苯酚的比率比大鼠或食蟹猴更接近于人和小鼠。这一点至关重要，因为这些可能是毒性最大的苯中间体。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高亲和力、低容量的代谢途径，从而导致最具血液毒性的中间体。我们已经能够证明，暴露于低水平(100ppm，6h TWA)的p53缺陷小鼠迅速发展为胸腺淋巴瘤，而暴露于高水平(200ppm，6h TWA)的小鼠则较慢，发病率显著下降。在这些研究中，P53基因缺陷小鼠的苯致淋巴瘤有：1)克隆性(常见的T细胞受体重排)，2)11号染色体上携带P53野生型等位基因的丢失或缺失模式，不同于散发性淋巴瘤，3)P53和Rb通路中关键基因的异常调节模式，影响细胞周期控制和种群生长和凋亡。我们正在继续调查吸入或饮用水中苯的剂量和剂量率暴露的影响。利用低剂量和减少暴露频率，针对造血干细胞舱中显示出高亲和力的代谢途径，将苯氧化为致突变代谢物。在高剂量和高速率下，这些数据表明结合的代谢物可以有效地排出。需要更多的研究来调查这些现象。