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

doi:10.1667/RR3293.1

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

Journal article

Peer reviewed

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, …

Radiation research, Vol.180(2), pp.156-165

08/2013

DOI: 10.1667/RR3293.1

PMCID: PMC3821998

PMID: 23819597

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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 (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.

Oxidative Stress

Iron

Cesium Radioisotopes

Lymphoma - physiopathology

Thymocytes - metabolism

Neoplasms, Radiation-Induced - etiology

Recombinant Fusion Proteins - physiology

Thymus Neoplasms - genetics

Male

Sirtuin 3 - deficiency

bcl-2-Associated X Protein - physiology

Whole-Body Irradiation - adverse effects

Neoplasms, Radiation-Induced - genetics

Oxidative Phosphorylation - radiation effects

Mice, Mutant Strains

Superoxides - metabolism

Mitochondria - radiation effects

Female

Neoplastic Syndromes, Hereditary - genetics

Silicon

Thymocytes - radiation effects

bcl-2-Associated X Protein - genetics

Thymus Neoplasms - physiopathology

Sirtuin 3 - genetics

Mice, Inbred C57BL

Lymphoma - genetics

Radiation Tolerance - genetics

Gene Dosage

Mitochondria - metabolism

Radiation Dosage

Sex Characteristics

Animals

Lymphoma - etiology

Neoplastic Syndromes, Hereditary - physiopathology

Linear Energy Transfer

Mice

Lymphocyte Specific Protein Tyrosine Kinase p56(lck) - genetics

Thymus Neoplasms - etiology

Thymocytes - pathology

Dose-Response Relationship, Radiation

Sirtuin 3 - physiology

Heavy Ions - adverse effects

Details

Title: Subtitle: Low-dose radiation-induced enhancement of thymic lymphomagenesis in Lck-Bax mice is dependent on LET and gender
Creators: James A Jacobus - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa 52242, USA
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
Resource Type: Journal article
Publication Details: Radiation research, Vol.180(2), pp.156-165
DOI: 10.1667/RR3293.1
PMID: 23819597
PMCID: PMC3821998
NLM abbreviation: Radiat Res
ISSN: 0033-7587
eISSN: 1938-5404
Publisher: Radiation Research Society; United States
Grant note: P30 ES005605 / NIEHS NIH HHS T32 CA078586 / NCI NIH HHS R01 CA168292 / NCI NIH HHS R01CA152601 / NCI NIH HHS 3 P30 CA086862 / NCI NIH HHS R01CA152799 / NCI NIH HHS R01CA168292 / NCI NIH HHS R01 CA152601 / NCI NIH HHS R01 CA152799 / NCI NIH HHS P30 CA086862 / NCI NIH HHS
Language: English
Date published: 08/2013
Academic Unit: Pathology; Biostatistics; Orthopedics and Rehabilitation; Surgery; Radiation Oncology; Holden Comprehensive Cancer Center
Record Identifier: 9983997448202771

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