silicon and Lymphoma

Humans are exposed to charged particles in different scenarios. The use of protons and high-linear energy transfer (LET) in cancer treatment is steadily growing. In outer space, astronauts will be exposed to a mixed radiation field composed of both protons and heavy ions, in particularly the long-term space missions outside of earth's magnetosphere. Thus, understanding the radiobiology and transforming potential of these types of ionizing radiation are of paramount importance.. We examined the effect of 10 or 100 cGy of whole-body doses of protons or. We found that Mlh1 deficient animals are highly prone to develop lymphomas when exposed to either low doses of protons or. Although the incidence of malignancy is related to radiation quality, and increased due to loss of Mlh1, the phenotype of the tumors is independent of LET.

Topics: Aging; Animals; Disease Models, Animal; DNA Mismatch Repair; Female; Gene Expression Profiling; Hematopoietic System; Humans; Linear Energy Transfer; Lymphoma; Male; Mice; MutL Protein Homolog 1; Neoplasms, Radiation-Induced; Penetrance; Protons; Radiation Exposure; Sequence Analysis, RNA; Silicon; Space Flight; Whole-Body Irradiation

The hypothesis that mitochondrial dysfunction and increased superoxide levels in thymocytes over expressing Bax (Lck-Bax1 and Lck-Bax38&1) contributes to lymphomagenesis after low-dose radiation was tested. Lck-Bax1 single-transgenic and Lck-Bax38&1 double-transgenic mice were exposed to single whole-body doses of 10 or 100 cGy of (137)Cs or iron ions (1,000 MeV/n, 150 keV/μm) or silicon ions (300 MeV/n, 67 keV/μm). A 10 cGy dose of (137)Cs significantly increased the incidence and onset of thymic lymphomas in female Lck-Bax1 mice. In Lck-Bax38&1 mice, a 100 cGy dose of high-LET iron ions caused a significant dose dependent acceleration of lymphomagenesis in both males and females that was not seen with silicon ions. To determine the contribution of mitochondrial oxidative metabolism, Lck-Bax38&1 over expressing mice were crossed with knockouts of the mitochondrial protein deacetylase, Sirtuin 3 (Sirt3), which regulates superoxide metabolism. Sirt3(-/-)/Lck-Bax38&1 mice demonstrated significant increases in thymocyte superoxide levels and acceleration of lymphomagenesis (P < 0.001). These results show that lymphomagenesis in Bax over expressing animals is enhanced by radiation exposure in both an LET and gender dependent fashion. These findings support the hypothesis that mitochondrial dysfunction leads to increased superoxide levels and accelerates lymphomagenesis in Lck-Bax transgenic mice.

Topics: Animals; bcl-2-Associated X Protein; Cesium Radioisotopes; Dose-Response Relationship, Radiation; Female; Gene Dosage; Heavy Ions; Iron; Linear Energy Transfer; Lymphocyte Specific Protein Tyrosine Kinase p56(lck); Lymphoma; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Mitochondria; Neoplasms, Radiation-Induced; Neoplastic Syndromes, Hereditary; Oxidative Phosphorylation; Oxidative Stress; Radiation Dosage; Radiation Tolerance; Recombinant Fusion Proteins; Sex Characteristics; Silicon; Sirtuin 3; Superoxides; Thymocytes; Thymus Neoplasms; Whole-Body Irradiation