IN VIVO GENTOXICITY TO HEMOPOIETIC STEM CELLS

描述：（改编自研究者摘要）。 长期 暴露于环境污染物的健康影响是主要的公众 性问题 职业或环境暴露于辐射、燃料 碳氢化合物和多氯联苯与 恶性肿瘤的风险，特别是白血病。 然而，评估 环境污染物的遗传毒性和致癌潜力是 难 在物理暴露和生理变化方面无差异 个人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外推是有问题的。 幸运的是，最近在分子和细胞方法学以及 体内模型有望减轻这些限制中的一些。 分子 细胞遗传学有助于使用荧光检测易位， 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，从而提供机会，以评估分子和 体内暴露于遗传毒素的人造血细胞的功能变化。 HU-小鼠应允许评估遗传毒素对人类造血系统的影响。 干细胞（HSC）在体内。 我们提出了一种新的方法来评估基因组和 暴露于体内环境污染物的人HSC的细胞变化。 具体地说，我们将确定暴露于 单次和间歇性低剂量辐射或化学品提供了一个 用于估计暴露的读出分析。 具体而言，我们将1） 确定是否遗传损伤的人HSC在一个细胞中的频率 优化的HU-小鼠模型反映了体外暴露于辐射或苯。 2)建立体内辐射与苯暴露之间的关系 和遗传损伤的人HSC的频率。 3)测试的假设 人类间歇性低剂量体内暴露于遗传毒素， 伴随的血液毒性将导致比 剂量当量单次照射。 这些研究将建立 使用HU-小鼠模型来增加对 遗传毒素剂量与人肝星状细胞遗传损伤的关系 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.