Development of a Model of the Acute and Delayed Effects of High Dose Radiation Exposure in Jackson Diversity Outbred Mice; Comparison to Inbred C57BL/6 Mice

Abstract

Development of medical countermeasures against radiation relies on robust animal models for efficacy testing. Mouse models have advantages over larger species due to economics, ease of conducting aging studies, existence of historical databases, and research tools allowing for sophisticated mechanistic studies. However, the radiation Dose Response Relationship of inbred strains is inherently steep and sensitive to experimental variables, and inbred models have been criticized for lacking genetic diversity. Jackson Diversity Outbred (JDO) mice are the most genetically diverse strain available, developed by the Collaborative Cross Consortium using eight founder strains, and may represent a more accurate model of humans than inbred strains. Herein, models of the Hematopoietic-Acute Radiation Syndrome and the Delayed Effects of Acute Radiation Exposure were developed in JDO mice and compared to inbred C57BL/6. The Dose Response Relationship curve in JDO mice mirrored the more shallow curves of primates and humans, characteristic of genetic diversity. JDO mice were more radioresistant than C57BL/6, and differed in sensitivity to antibiotic countermeasures. The model was validated with pegylated-G-CSF, which provided significantly enhanced 30-day survival and accelerated blood recovery.Long-term JDO survivors exhibited increased recovery of blood cells and functional bone marrow hematopoietic progenitors compared to C57BL/6. While JDO hematopoietic stem cells declined more in number, they maintained a greater degree of quiescence compared to C57BL/6, which is essential for maintaining function. These JDO radiation models offer many of the advantages of small animals with the genetic diversity of large animals, providing an attractive alternative to currently available radiation animal models.

An Automated, Home-Cage, Video Monitoring-based Mouse Frailty Index Detects Age-associated Morbidity in C57BL/6 and Diversity Outbred Mice

“…Also, the stresses of single housing must be balanced against the stresses and dangers of group housing, especially for male mice, due to aggressive behavior: the effects of social stresses and best practices can be strain-specific ( 43 , 49 ). For the male J:DO mice used in our experiment, best practice is single housing in the home cage (eg, ( 50 , 51 )) due to documented aggressive behavior ( 52 ). Group housing may still be practiced if littermates are co-housed from an early age ( 53 ), but animals with such a history are not always available.…”

Fate of Hematopoiesis During Aging. What Do We Really Know, and What are its Implications?

“…Hematopoietic DEARE, also known as residual bone marrow damage (RBMD), is characterized by diminished immunity and decreased production of blood cells persisting for years after radiation exposure [173][174][175][176][177][178][179]. Survivors of H-ARS exhibit severe lifelong damage to HSC, characterized by significantly decreased complete blood count, loss of HSC repopulating potential, loss of HSC quiescence, decreased numbers of HPC, and dramatic myeloid skewing, all most evident under stress [173][174][175][176][177][178][179][180][181][182][183].…”

“…Hematopoietic DEARE, also known as residual bone marrow damage (RBMD), is characterized by diminished immunity and decreased production of blood cells persisting for years after radiation exposure [173][174][175][176][177][178][179]. Survivors of H-ARS exhibit severe lifelong damage to HSC, characterized by significantly decreased complete blood count, loss of HSC repopulating potential, loss of HSC quiescence, decreased numbers of HPC, and dramatic myeloid skewing, all most evident under stress [173][174][175][176][177][178][179][180][181][182][183]. An increased incidence of lymphoid malignancies, shortened life span, decreased mesenchymal stem/progenitor cell (MSC) number, and aberrant levels of endothelial cell-derived HSC niche proteins in aged H-ARS survivors have also been documented (Orschell, unpublished data).…”

Effects of Simulated 5-Ion Galactic Cosmic Radiation on Function and Structure of the Mouse Heart

“…Mouse models allow us to determine the risks of high linear energy transfer (LET) radiation, but there is debate on which models best represent the human health effects of space radiation, and data from mice do not always translate to humans [ 13 ]. One approach to increase the translatability of mouse model data is to include both inbred and outbred mouse strains to include more diversity in the genetic background [ 14 , 15 ].…”