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Office
of Biological and Environmental Research
DOE
Lowdose Radiation Program Workshop IV
Abstract
_____________________________________________________________________
Title:
Cellular responses to Low Dose/Very Low Dose Rate Ionizing Radiation:
The Role of Endogenous Oxidative Metabolism
Authors: Sonia M. de Toledo*, Perumal Venkatachalam*,
Jeffrey P. Gardner*, Ling Li†, Roger W. Howell*, Douglas
R. Spitz† and Edouard Azzam*
Institutions: * Department of Radiology, New
Jersey Medical School, Newark, NJ 07103† Free Radical
and Radiation Biology Program, University of Iowa, Iowa City,
IA 52242
We are testing the hypothesis that “endogenous oxidative
metabolism modulates the
signaling pathways induced in mammalian cells by low dose, low
dose rate ?-radiation and affects the level of residual DNA
damage, proliferation potential and the frequency of neoplastic
transformation of irradiated cells”. This hypothesis is
being tested in vitro using normal human diploid fibroblasts
adapted to grow in a three-dimensional tissuelike architecture
that mimics the way cells grow in vivo. In preliminary experiments,
cells were exposed to a dose of 10 cGy (from a 137Cs source)
delivered at variable dose rates extending from 0.0035 to 0.24
cGy/min. Data, describing modulation of gene expression and
induction of DNA damage in AG1522 cells, indicate that protraction
of the dose rate reduces the level of residual DNA damage in
irradiated cells and results in altered patterns of gene expression.
Of relevance to radiation protection, cellular exposure to a
10 cGy dose delivered over 48 h reduced the micronucleus frequency
below the spontaneous frequency. Data on the rate of telomere
attrition (a surrogate measure of proliferation potential) in
sham-manipulated and irradiated cells will be described.
In preliminary studies to investigate the role of endogenous
oxidative metabolism
in the cellular response to low dose ionizing radiation exposure,
we have established the criteria for over-expression of various
antioxidant enzymes in AG1522 fibroblasts.
Interestingly, ectopic overexpression of glutathione peroxidase
resulted in significant
increase (3-fold) in the level of glutathione. Experiments are
in progress to measure the effects of ectopically overexpressed
Mn-SOD on residual DNA damage in cells exposed to 10 cGy delivered
at variable dose rates.
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