Abstract
Purpose: :
Whether or not a subset of the human population is genetically predisposed to radiation damage is an unresolved issue with considerable currency. We have shown previously that the lenses of mice haplodeficient in ATM exhibit greater radiation sensitivity than those of wild types. The finding indicates that a genetic background which is otherwise phenotypically unremarkable but is heterozygous for a gene associated with the checkpoint pathway can still influence radiation susceptibility. This raises the question of how multiple haplodeficiencies might affect vulnerability to radiation exposure.
Methods: :
One eye of knockout mice heterozygous for the atm, mrad9 and brca1 genes was exposed to 500 mGy of 250 kVp X–rays. In addition, animals with mixed genotypes atm+/– & mrad9+/– and atm+/– & brca1+/–, as well as wild type controls, were also exposed. Each group was represented by at least 10 mice and the radiation administered at 28 days postpartum. The eyes of all the animals were followed weekly for up to 13 months (∼50% lifespan). The lenses, examined by slit–lamp biomicroscopy, were assessed using the Merriam/Focht radiation cataract scoring method.
Results: :
As was found previously, ATM haplodeficient mice developed cataracts which appeared earlier and progressed faster than in wildtypes. Mrad9 and brca1 single heterozygotes responded similarly. In the case of the dual haplodeficiency, the lenses of atm+/– & mrad9+/– animals were markedly more radiosensitive than those of mice with either mutation alone. In contrast atm+/– & brca1+/– animals were no more susceptible than the single haplodeficients.
Conclusions: :
The radiosensitivity of the lens has now been shown to be affected by three distinct genotypes. It is not clear why atm+/– and mrad9+/–, when present together, have an even greater effect whereas the atm+/– & brca1+/– genotype manifests a sensitivity equivalent to either genotype alone. It may be because ATM is an upstream regulator of BRCA1 whereas the relationship between ATM and Mrad9 appears less direct. This suggestion is supported by recent transformation, apoptosis and survival studies using atm+/– & mrad9+/– mouse embryo fibroblasts (Smilenov et al., Cancer Res. 65; 933, 2005).
Keywords: cataract • genetics • pathology: human