Low-dose radiation-induced enhancement of thymic lymphomagenesis in lck-bax mice is dependent on LET and gender

James A. Jacobus, Chester G. Duda, Mitchell C. Coleman, Sean M. Martin, Kranti Mapuskar, Gaowei Mao, Brian J. Smith, Nukhet Aykin-Burns, Peter Guida, David Gius, Frederick E. Domann, C. Michael Knudson, Douglas R. Spitz*

*Corresponding author for this work

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

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 137Cs or iron ions (1,000 MeV/n, 150 keV/μm) or silicon ions (300 MeV/n, 67 keV/μm). A 10 cGy dose of 137Cs significantly increased the incidence and onset of thymic lymphomas in female Lck-Bax1 mice. In Lck-Bax38 and 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 and 1 over expressing mice were crossed with knockouts of the mitochondrial protein deacetylase, Sirtuin 3 (Sirt3), which regulates superoxide metabolism. Sirt3-/-/Lck-Bax38 and 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.

Original languageEnglish (US)
Pages (from-to)156-165
Number of pages10
JournalRadiation Research
Volume180
Issue number2
DOIs
StatePublished - Aug 1 2013

ASJC Scopus subject areas

  • Biophysics
  • Radiation
  • Radiology Nuclear Medicine and imaging

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    Jacobus, J. A., Duda, C. G., Coleman, M. C., Martin, S. M., Mapuskar, K., Mao, G., Smith, B. J., Aykin-Burns, N., Guida, P., Gius, D., Domann, F. E., Knudson, C. M., & Spitz, D. R. (2013). Low-dose radiation-induced enhancement of thymic lymphomagenesis in lck-bax mice is dependent on LET and gender. Radiation Research, 180(2), 156-165. https://doi.org/10.1667/RR3293.1