Due to risks from potential exposures to ionizing radiation (IR), improved radiological countermeasures are required, as well as rapid high-throughput biodosimetry. Genotypic variation in the general population contributes to differences in radiosensitivity that may affect biodosimetry accuracy. Previous studies utilized radiosensitive mutant mouse models (Parp1^−/− and Atm^−/−) to determine the effects of genotypic deficiency on radiation signatures. Here, we extend this approach by examining changes in the urinary metabolome in a hematopoietic (HP) resistant mouse model (p53^−/−) after IR exposure. As p53 is a primary regulator in radiation response and apoptosis, limited hematopoietic stem cell apoptosis leads to reduced mortality at doses of ~8–10 Gy but increased mortality at higher doses (> 15 Gy) due to mitotic catastrophe in gastrointestinal (GI) crypt cells. Urine was collected from mice (wild-type (WT), p53^+/−, and p53^−/−) pre-irradiation and at 4 and 24 h after total body irradiation (TBI) (WT: 8 and 10 Gy; p53^−/−: 10 Gy) for metabolic phenotyping using an ultra-performance liquid chromatography mass spectrometry (UPLC-MS) platform. Minimal differences were detected between unirradiated WT, p53^+/−, and p53^−/− mice. While similar perturbations were observed for metabolites involved in tryptophan, vitamin B6, and histamine pathways, glycine conjugation, and redox metabolism for WT and p53^−/− mice after TBI, an overall dampened response was observed in p53-deficient mice. Despite comparable metabolite patterns between genotypes, differentiation was achieved through receiver operating characteristic curve analysis with high specificity and sensitivity for carnitine, N1-acetylspermidine, and creatine. These studies highlight that both attenuated and dampened metabolic responses due to genetic variability in the general population need to be addressed in biodosimetry frameworks.

中文翻译：

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遗传变异对电离辐射暴露后小鼠尿小分子特征的影响：p53缺乏症的研究。

由于潜在暴露于电离辐射（IR）中的风险，因此需要改进的放射对策以及快速的高通量生物剂量测定法。一般人群中的基因型变异导致放射敏感性的差异，这可能会影响生物剂量测定的准确性。先前的研究利用放射敏感性突变小鼠模型（Parp1 ^-/-和Atm ^-/-）来确定基因型缺陷对辐射信号的影响。在这里，我们通过检查造血（HP）耐药小鼠模型中尿液代谢组的变化来扩展这种方法（p53 ^-/-）。由于p53是放射反应和细胞凋亡的主要调节剂，有限的造血干细胞凋亡导致胃肠道（GI）隐窝中的有丝分裂灾难导致〜8-10 Gy剂量下死亡率降低，但更高剂量（> 15 Gy）下死亡率增加。细胞。尿从小鼠（野生型（WT），p53的收集^+/-和p53 ^{- / -} ）的预照射，并在全身照射后4和24小时（TBI）（WT：8和10戈瑞; p53蛋白^{- /}：：10 Gy）用于使用超高效液相色谱质谱（UPLC-MS）平台进行代谢表型分析。在未照射的WT，p53 ^+/-和p53 ^-/-之间检测到最小差异老鼠。尽管在TBI后，WT和p53 ^-/-小鼠的色氨酸，维生素B6和组胺途径，甘氨酸结合和氧化还原代谢涉及的代谢物发生了类似的扰动，但在p53缺陷型小鼠中却观察到总体的反应减弱。尽管基因型之间具有可比的代谢物模式，但通过对肉碱，N1-乙酰基亚精胺和肌酸具有高特异性和敏感性的接收器操作特征曲线分析仍可实现区分。这些研究强调，在生物剂量测定框架中需要解决由于一般人群中的遗传变异引起的衰减和衰减的代谢反应。