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QUALITATIVE DISTINCTIONS OF DOSE-EFFECT RELATIONSHIPS
BETWEEN DIFFERENT STRESS RESPONSES TO IONIZING RADIATION IN
NORMAL HUMAN FIBROBLASTS
I.O. Velegzhaninov1, A.V. Ermakova1, D.M. Shadrin1, Y.I. Pylina1, O.A. Shostal1,
E.S. Belykh1, A.V. Kaneva1, O.V. Ermakova1, D.Y. Klokov2
1
Institute of Biology, Komi Science Center of RAS, Syktyvkar, Russia.
2
Canadian Nuclear Laboratories, Chalk River, Ontario, Canada
Understanding the mechanisms producing low dose ionizing radiation specific
biological effects represents one of the major challenges of radiation biology. Although
experimental evidence does suggest that various molecular stress response pathways
may be involved in the production of low dose effects, much of the detail of those
mechanisms remains elusive. We hypothesized that the regulation of various stress
response pathways upon irradiation may differ from one another in complex doseresponse manners, causing the specific and subtle low dose radiation effects. To verify
this hypothesis in the present study, the DNA damage induction, DNA repair, caspase-3
induction, and the transcription level of 22 genes involved in stress responses were
analyzed in normal human fibroblasts (HELF-104) exposed to a range of gamma-doses
from 1 to 200 cGy. Furthermore, the senescence dynamic of irradiated cell were
analyzed using histochemical staining for β-galactosidase until a complete stop of
culture growth.
We found non-linear dose responses for the repair of DNA damage after exposure
to gamma-radiation. Alterations in gene expression were also not linear with dose for
several of the genes examined and did not follow a single pattern. Rather, several
patterns could be seen. In addition, qualitatively different changes in dynamic of βgalactosidase accumulation in cells irradiated by different doses were shown. Low dose
irradiation may delay the onset of senescence in normal human fibroblasts. The latter
result confirms our earlier data, that shows for the first time the effect of radioinduced
delay of senescense in HFL-1 cell line. Our results suggest a complex interplay of
various stress response pathways triggered by low radiation doses, with various low
dose thresholds for reactions of different systems. Funding for this study was provided
by the Russian Fund for Fundamental Research Grant 13-04-01750.