Global gene expression in response to X rays in mouse models of DNA repair deficiency

There is a perceived need to develop tools for high-throughput radiation biodosimetry. In the case of an improvised nuclear device or a dirty bomb in a major city, potentially hundreds of thousands of people would have to be screened to assign exposed individuals to appropriate treatment. Gene expression represents an emerging approach to biodosimetry and could potentially provide an estimate of both absorbed dose and individual radiation-induced injury. Mice have been used as an in vivo model to elucidate the radiation response and to construct biodosimetric gene expression profiles. However, while most studies have used mouse strains with “average” radiation sensitivity, 2-4% of humans are thought to be radiosensitive. Such individuals would suffer greater radiological injury at a given dose than members of the general population, so it is of interest to determine how such sensitivity may impact the biodosimetric gene expression signatures being developed. Here, we use wild-type mice and genetically engineered mouse models deficient in two DNA repair pathways that can contribute to radiation sensitivity. Humans with ataxia telangiectasia or Atm-/- mice are deficient in double-strand break repair and show increased radiosensitivity. Atm-/- mice have a LD50/30 of 4 Gy compared with 8 Gy in the parental wild-type (WT) C57BL/6 mice. Humans with SCID, or Prkdcscid mice are deficient in non-homologous end joining, and are also radiosensitive. SCID mice have a LD50/30 of 3 Gy. These animal models represent a “worse-case” scenario, and should be viewed as an extreme of radiation sensitivity. Most radiosensitive members of the population will not have full-blown DNA repair deficiency syndromes, but these extreme models should help to define the maximum impact of DNA repair deficiency on gene expression following radiation exposure. Three genotypes (wild-type, ATM-/-, and Scid) were either exposed to a LD50/30 dose of x rays, or were sham-irradiated as controls, and then sacrificed 24h later. 5 replicates, representing individual mice, were used for each condition, with the exception of un-exposed (0 Gy) wild types and irradiated Atm-/- (4 Gy), for which six replicate mice were used.