Discordant gene responses to radiation in humans and mice and the role of hematopoietically humanized mice in the search for radiation biomarkers

• Published in: Scientific reports 2019-12, Vol.9 (1), p.19434-13, Article 19434
• Main Authors: Ghandhi, Shanaz A., Smilenov, Lubomir, Shuryak, Igor, Pujol-Canadell, Monica, Amundson, Sally A.
• Format: Article
• Language: English
• Subjects: 38/39; 38/61; 38/90; 45/61; 45/77; 45/90; 631/337/572; 631/80/86; Animals; Biomarkers; Biomarkers - analysis; Blood cells; Dose-Response Relationship, Radiation; Down-Regulation - physiology; Down-Regulation - radiation effects; Gadd45A protein; Gene expression; Gene Expression Regulation - radiation effects; Hematopoietic Stem Cell Transplantation; Humanities and Social Sciences; Humans; Ionizing radiation; Irradiation; Male; MDM2 protein; Mice; Models, Animal; multidisciplinary; Myc protein; Potassium channels (calcium-gated); Proliferating cell nuclear antigen; Science; Science (multidisciplinary); Species Specificity; Transplantation Chimera - physiology; Up-Regulation - physiology; Up-Regulation - radiation effects; Whole-Body Irradiation - adverse effects
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-55982-2

The mouse ( Mus musculus ) is an extensively used model of human disease and responses to stresses such as ionizing radiation. As part of our work developing gene expression biomarkers of radiation exposure, dose, and injury, we have found many genes are either up-regulated (e.g. CDKN1A, MDM2, BBC3 , and CCNG1 ) or down-regulated (e.g. TCF4 and MYC ) in both species after irradiation at ~4 and 8 Gy. However, we have also found genes that are consistently up-regulated in humans and down-regulated in mice (e.g. DDB2, PCNA, GADD45A, SESN1, RRM2B, KCNN4, IFI30 , and PTPRO ). Here we test a hematopoietically humanized mouse as a potential in vivo model for biodosimetry studies, measuring the response of these 14 genes one day after irradiation at 2 and 4 Gy, and comparing it with that of human blood irradiated ex vivo , and blood from whole body irradiated mice. We found that human blood cells in the hematopoietically humanized mouse in vivo environment recapitulated the gene expression pattern expected from human cells, not the pattern seen from in vivo irradiated normal mice. The results of this study support the use of hematopoietically humanized mice as an in vivo model for screening of radiation response genes relevant to humans.