IN VIVO GENTOXICITY TO HEMOPOIETIC STEM CELLS

描述：(改编自调查人员的摘要)。从长远来看 暴露在环境污染物中对健康的影响是主要的公众 担忧。职业或环境中的辐射、燃料暴露 碳氢化合物和多氯联苯与增加的 有患上恶性肿瘤的风险，尤其是白血病。然而，对 环境污染物的遗传毒性和致癌潜力是 很难。物理暴露的不确定性和生理变化 个体之间的反应使风险评估复杂化。跨物种数据 从体外和体内动物模型系统进行外推是有问题的。 幸运的是，分子和细胞方法学以及 活体模型有望缓解其中一些限制。分子 细胞遗传学促进使用荧光蛋白检测易位 原位杂交。人脐带移植免疫缺陷小鼠 血细胞(HU-小鼠)维持高水平的持续多谱系 造血，从而提供了评估分子和 体内暴露于基因毒素的人造血细胞的功能变化。 HU-小鼠应允许评估基因毒素对人类造血的影响 体内干细胞(HSC)。我们提出一种新的方法来评估基因组和 活体环境污染物暴露下人肝星状细胞的细胞变化。 具体地说，我们将确定人的HSC是否暴露在HU-小鼠体内 单次和间歇性的低剂量辐射或化学品提供了 读出化验对估计暴露很有用。具体地说，我们将1) 确定基因受损的人类HSC在一种 优化的HU-小鼠模型反映了辐射或苯的体外暴露。 2)建立体内辐射与苯暴露的关系 和人类HSC基因损伤的频率。3)检验假设 人在体内间歇性、低剂量暴露于一种具有 相伴的血液毒性将导致更多的基因组损伤 剂量当量的单次曝光。这些研究将确立 HU-MICE模型的有用性对增加对 人HSC-AN基因毒素剂量与遗传损伤的关系 风险评估的重要组成部分。

DESCRIPTION: (Adapted from the investigator's abstract). The long term health effects of exposure to environmental contaminants are major public concerns. Occupational or environmental exposure to radiation, fuel hydrocarbons, and polychlorinated biphenyls is associated with increased risk of malignancy, particularly leukemia. However, assessment of the genotoxic and carcinogenic potential of environmental contaminants is difficult. Uncertainties in physical exposure and variations in physiologic response among individuals complicates risk assessment. Cross-species data extrapolation from in vitro and in vivo animal model systems is problematic. Fortunately, recent advances in molecular and cellular methodologies and in vivo models promise to alleviate some of these limitations. Molecular cytogenetics facilitates detection of translocations using fluorescence in situ hybridization. Immune -deficient mice transplanted with human cord blood cells (HU-mice) maintain high levels of persistent multi-lineage hematopoiesis, thereby providing opportunities to evaluate molecular and functional changes in human hemopoietic cells exposed to genotoxins in vivo. HU-mice should allow assessment of genotoxin effects on human hemopoietic stem cells (hsc) in vivo. We propose a novel approach to assess genomic and cellular changes in human hsc exposed to environmental contaminants in vivo. specifically, we will determine whether human hsc in HU-mice exposed to single and intermittent low doses of radiation or chemicals provide a read-out assay useful to estimate exposure. Specifically, we will 1) determine whether the frequency of genetically-damaged human hsc in an optimized HU-mouse model reflects in vitro exposure to radiation or benzene. 2) establish the relationship between in vivo radiation and benzene exposure and frequency of genetically damaged human hsc. 3) Test the hypothesis that intermittent, low dose in vivo exposure of human has to a genotoxin with concomitant hematotoxicity will result in more genomic damage than dose-equivalent single exposures. These studies will establish the usefulness of the HU-mouse model to increase understanding of the relationship between genotoxin dose and genetic damage in human hsc- an important component of risk assessment.