Center for Radiological Research, Columbia University Irving Medical Center, 630, W 168th Street, VC11-237, New York, NY, 10032, USA.
Sci Rep. 2022 Aug 19;12(1):14124. doi: 10.1038/s41598-022-18558-1.
In the search for biological markers after a large-scale exposure of the human population to radiation, gene expression is a sensitive endpoint easily translatable to in-field high throughput applications. Primarily, the ex-vivo irradiated healthy human blood model has been used to generate available gene expression datasets. This model has limitations i.e., lack of signaling from other irradiated tissues and deterioration of blood cells cultures over time. In vivo models are needed; therefore, we present our novel approach to define a gene signature in mouse blood cells that quantitatively correlates with radiation dose (at 1 Gy/min). Starting with available microarray datasets, we selected 30 radiation-responsive genes and performed cross-validation/training-testing data splits to downselect 16 radiation-responsive genes. We then tested these genes in an independent cohort of irradiated adult C57BL/6 mice (50:50 both sexes) and measured mRNA by quantitative RT-PCR in whole blood at 24 h. Dose reconstruction using net signal (difference between geometric means of top 3 positively correlated and top 4 negatively correlated genes with dose), was highly improved over the microarrays, with a root mean square error of ± 1.1 Gy in male and female mice combined. There were no significant sex-specific differences in mRNA or cell counts after irradiation.
在大规模人群暴露于辐射后寻找生物标志物时，基因表达是一个敏感的终点，很容易转化为现场高通量应用。最初，使用体外辐照的健康人血液模型来生成可用的基因表达数据集。然而，该模型存在一些局限性，例如缺乏来自其他辐照组织的信号以及血细胞培养物随时间的恶化。因此，我们需要体内模型；因此，我们提出了一种新方法来定义小鼠血液细胞中的基因特征，该特征与剂量（1Gy/min）呈定量相关性。从现有的微阵列数据集开始，我们选择了 30 个辐射反应基因，并进行了交叉验证/训练-测试数据拆分，以进一步选择 16 个辐射反应基因。然后，我们在另一组辐照的成年 C57BL/6 小鼠（男女各半）中测试了这些基因，并在 24 小时时通过定量 RT-PCR 在全血中测量 mRNA。与微阵列相比，使用净信号（与剂量呈正相关的前 3 个基因和负相关的前 4 个基因的几何平均值之间的差异）进行剂量重建得到了极大的改善，雄性和雌性小鼠的均方根误差均为±1.1Gy。在照射后，mRNA 或细胞计数没有明显的性别特异性差异。
