Physical, heritable and age-related factors as modifiers of radiation cancer risk in patched heterozygous mice.
OBJECTIVE
To address the tumorigenic potential of exposure to low/intermediate doses of ionizing radiation and to identify biological factors influencing tumor response in a mouse model highly susceptible to radiogenic cancer.


METHODS
Newborn Ptc1 heterozygous mice were exposed to X-ray doses of 100, 250, and 500 mGy, and tumor development was monitored for their lifetime. Additional groups were irradiated with the same doses and sacrificed at fixed times for determination of short-term endpoints, such as apoptosis and early preneoplastic lesions in cerebellum. Finally, groups of Ptc1 heterozygous mice were bred on the C57BL/6 background to study the influence of common variant genes on radiation response.


RESULTS
We have identified a significant effect of low-intermediate doses of radiation (250 and 500 mGy) in shortening mean survival and inducing early and more progressed stages of tumor development in the cerebellum of Ptc1(+/-) mice. In addition, we show that age at exposure and heritable factors are potent modifiers of radiation-related cancer risk.


CONCLUSIONS
The Ptc1 knockout mouse model offers a highly sensitive system that may potentially help to improve understanding and quantification of risk at low doses, such as doses experienced in occupational and medical exposures, and clarify the complex interactions between genetic and environmental factors underlying cancer susceptibility.
Pazzaglia
Simonetta
S
Section of Toxicology and Biomedical Sciences, Biotechnologies, Agro-Industry and Health Protection Department, ENEA CR Casaccia, 00123 Rome, Italy. pazzaglia@casaccia.enea.it
Pasquali
Emanuela
E
Tanori
Mirella
M
Mancuso
Mariateresa
M
Leonardi
Simona
S
di Majo
Vincenzo
V
Rebessi
Simonetta
S
Saran
Anna
A
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D002528:Cerebellar Neoplasms / Q000235:genetics* / Q000401:mortality; D004307:Dose-Response Relationship, Radiation; D006579:Heterozygote; D019656:Loss of Heterozygosity; D008527:Medulloblastoma / Q000235:genetics* / Q000401:mortality; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D009381:Neoplasms, Radiation-Induced / Q000235:genetics* / Q000401:mortality; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011230:Precancerous Conditions / Q000235:genetics / Q000473:pathology; D011956:Receptors, Cell Surface / Q000235:genetics*; D013234:Stem Cells / Q000502:physiology / Q000528:radiation effects; D014916:Whole-Body Irradiation
D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface