Mouse genetic approaches applied to the normal tissue radiation response

Abstract

The varying responses of inbred mouse models to radiation exposure present a unique opportunity to dissect the genetic basis of radiation sensitivity and tissue injury. Such studies are complementary to human association studies as they permit both the analysis of clinical features of disease, and of specific variants associated with its presentation, in a controlled environment. Herein I review how animal models are studied to identify specific genetic variants influencing predisposition to radiation-induced traits. Among these radiation-induced responses are documented strain differences in repair of DNA damage and in extent of tissue injury (in the lung, skin, and intestine) which form the base for genetic investigations. For example, radiation-induced DNA damage is consistently greater in tissues from BALB/cJ mice, than the levels in C57BL/6J mice, suggesting there may be an inherent DNA damage level per strain. Regarding tissue injury, strain specific inflammatory and fibrotic phenotypes have been documented for principally, C57BL/6 C3H and A/J mice but a correlation among responses such that knowledge of the radiation injury in one tissue informs of the response in another is not evident. Strategies to identify genetic differences contributing to a trait based on inbred strain differences, which include linkage analysis and the evaluation of recombinant congenic (RC) strains, are presented, with a focus on the lung response to irradiation which is the only radiation-induced tissue injury mapped to date. Such approaches are needed to reveal genetic differences in susceptibility to radiation injury, and also to provide a context for the effects of specific genetic variation uncovered in anticipated clinical association studies. In summary, mouse models can be studied to uncover heritable variation predisposing to specific radiation responses, and such variations may point to pathways of importance to phenotype development in the clinic.

The Effects of CX3CR1 Deficiency and Irradiation on the Homing of Monocyte-Derived Cell Populations in the Mouse Eye

“…Variations in the response to radiation exposure between inbred mouse strains has been well established. Differences in susceptibility to DNA damage and cell death, as well as differences in tissue responses and repair mechanisms, have been previously reported as the underlying mechanisms [50–52]. For example, greater radiation-induced DNA damage occurs in BALB/c mice, a radiation-sensitive strain, when compared to DNA damage in C57BL/6J mice, a radiation resistant strain in this context [53].…”

Do Variations in Mast Cell Hyperplasia Account for Differences in Radiation-Induced Lung Injury among Different Mouse Strains, Rats and Nonhuman Primates?

“…This approach has been employed extensively in associating distinct radiobiological phenotypes with certain candidate genes aimed at allowing the recognition of sensitive patients undergoing radiation therapy and identifying targets for therapeutic intervention (26–28). However, some mouse models produce a response that are not reflected in the human phenotype and may therefore render the applicability of genetic analyses invalid.…”

EGLN Inhibition Reduces Gastrointestinal Radiation Toxicity and Improves Survival in a Murine Model of Locally Advanced Pancreatic Cancer

“…These animals were chosen because previous reports had demonstrated that this model presented with locally advanced disease (19) instead of widespread metastases, which common in models that use the Trp53 R172H mutant knock-in construct (20). Moreover, our KPC animals were backcrossed to C57BL/6 genetic background over 10 generations to reduce potential variability in normal tissue radiation responses that often occurs in mixed backgrounds (21). The experimental schema is shown in Fig 3A. KPC mice with the appropriate genotype were screened for tumors by weekly ultrasounds beginning at 16 weeks of age.…”

“…The administration of high-dose radiation therapy of >65Gy (high-dose) with or without radioprotection improved survival compared to all animals that received ≤65Gy (low-dose) of treatment or no RT ( Fig 3B; 37 days [95% CI [33][34][35][36][37][38][39][40][41] vs. 15 days [10][11][12][13][14][15][16][17][18][19][20][21] vs. 15 days [10-20], respectively; p=0.005). The median overall survival was compared amongst the treatment groups and was highest ( Fig 3C;…”