Park Jin G, Paul Sunirmal, Briones Natalia, Zeng Jia, Gillis Kristin, Wallstrom Garrick, LaBaer Joshua, Amundson Sally A
a Biodesign Center for Personalized Diagnostic, Biodesign Institute, Arizona State University, Arizona.
d Center for Radiological Research, Columbia University Medical Center, New York.
Radiat Res. 2017 Jun;187(6):708-721. doi: 10.1667/RR14655.1. Epub 2017 Mar 22.
In the event of a large-scale radiation exposure, accurate and quick assessment of radiation dose received would be critical for triage and medical treatment of large numbers of potentially exposed individuals. Current methods of biodosimetry, such as the dicentric chromosome assay, are time consuming and require sophisticated equipment and highly trained personnel. Therefore, scalable biodosimetry approaches, including gene expression profiles in peripheral blood cells, are being investigated. Due to the limited availability of appropriate human samples, biodosimetry development has relied heavily on mouse models, which are not directly applicable to human response. Therefore, to explore the feasibility of using non-human primate (NHP) models to build and test a biodosimetry algorithm for use in humans, we irradiated ex vivo peripheral blood samples from both humans and rhesus macaques with doses of 0, 2, 5, 6 and 7 Gy, and compared the gene expression profiles 24 h later using Agilent human microarrays. Among the dose-responsive genes in human and using non-human primate, 52 genes showed highly correlated expression patterns between the species, and were enriched in p53/DNA damage response, apoptosis and cell cycle-related genes. When these interspecies-correlated genes were used to build biodosimetry models with using NHP data, the mean prediction accuracy on non-human primate samples was about 90% within 1 Gy of delivered dose in leave-one-out cross-validation. However, tests on human samples suggested that human gene expression values may need to be adjusted prior to application of the NHP model. A "multi-gene" approach utilizing all gene values for cross-species conversion and applying the converted values on the NHP biodosimetry models, gave a leave-one-out cross-validation prediction accuracy for human samples highly comparable (up to 94%) to that for non-human primates. Overall, this study demonstrates that a robust NHP biodosimetry model can be built using interspecies-correlated genes, and that, by using multiple regression-based cross-species conversion of expression values, absorbed dose in human samples can be accurately predicted by the NHP model.
在发生大规模辐射暴露的情况下，准确快速地评估所接受的辐射剂量对于大量潜在受照个体的分类和医疗救治至关重要。当前的生物剂量测定方法，如双着丝粒染色体分析，耗时且需要精密设备和训练有素的人员。因此，正在研究可扩展的生物剂量测定方法，包括外周血细胞中的基因表达谱。由于合适的人类样本有限，生物剂量测定的发展严重依赖小鼠模型，而小鼠模型并不直接适用于人类反应。因此，为了探索使用非人灵长类动物（NHP）模型构建和测试用于人类的生物剂量测定算法的可行性，我们用0、2、5、6和7 Gy的剂量对人类和恒河猴的离体外周血样本进行照射，并在24小时后使用安捷伦人类微阵列比较基因表达谱。在人类和非人灵长类动物的剂量反应基因中，52个基因在物种间表现出高度相关的表达模式，并在p53/DNA损伤反应、细胞凋亡和细胞周期相关基因中富集。当使用这些种间相关基因利用NHP数据构建生物剂量测定模型时，在留一法交叉验证中，在1 Gy的给药剂量范围内，对非人灵长类动物样本的平均预测准确率约为90%。然而，对人类样本的测试表明，在应用NHP模型之前，可能需要调整人类基因表达值。一种利用所有基因值进行跨物种转换并将转换后的值应用于NHP生物剂量测定模型的“多基因”方法，对人类样本的留一法交叉验证预测准确率与非人灵长类动物的高度可比（高达94%）。总体而言，本研究表明，可以使用种间相关基因构建强大的NHP生物剂量测定模型，并且通过基于多元回归的表达值跨物种转换，NHP模型可以准确预测人类样本中的吸收剂量。
