Mechanism(s) Of Leukemogenesis In Genetically-altered Mo

苯是人类和啮齿动物的致癌物。对苯的公共卫生关注是有道理的，因为它在空气、水、土壤中无处不在，因此也存在于食品和饮料中。接触苯会导致血液形成元素的抑制，导致间变性贫血，随后是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，吸入苯会导致输送速率较慢，体内剂量较大。在同等口服剂量（mg/kg）下，经口给药后未代谢的苯（60%）多于吸入给药后未代谢的苯（14%）。小鼠也可通过吸入产生更多种类的苯代谢物。选择实验研究剂量的最关键是了解解毒途径饱和的接触水平。对于吸入暴露，这是200 ppm（6 h TWA。在5和50 ppm苯之间（6 h TWA），尿代谢物之间无显著差异。现有数据还表明，吸入暴露于50 ppm（6 h TWA）后，小鼠和人类之间的对苯二酚或粘康酸与苯酚的比值比大鼠或食蟹猴更接近。这是至关重要的，因为这些可能是最有毒的苯中间体。因此，暴露模型必须考虑到苯代谢途径的饱和度、关于暴露的现有数据以及导致最具血液毒性的中间体的高亲和力、低能力代谢途径。我们已经能够表明，p53缺陷小鼠暴露于低水平（100 ppm，6小时TWA）迅速发展胸腺淋巴瘤，而小鼠暴露于较高水平（200 ppm，6小时TWA）不太迅速，发病率显着降低。在这些研究中，苯诱导的p53缺陷小鼠淋巴瘤为：1）克隆（T细胞受体重排是常见的），2）显示携带与散发性淋巴瘤不同的p53野生型等位基因的11号染色体丢失或缺失的模式，和3）显示了p53和Rb通路中关键基因的失调模式，其影响细胞周期控制和群体生长和凋亡。我们正在继续调查苯剂量和剂量率的影响，通过吸入或饮用水。使用低剂量和降低的暴露频率，靶向造血干细胞隔室中对苯氧化为致突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，这些数据表明结合代谢物被有效排泄。需要更多的研究来调查这些现象。

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.