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Title: Low Dose Gamma Irradiation Potentiates Secondary Exposure to Gamma Rays or Protons in Thyroid Tissue Analogs

Abstract

We have utilized our unique bioreactor model to produce three-dimensional thyroid tissue analogs that we believe better represent the effects of radiation in vivo than two-dimensional cultures. Our thyroid model has been characterized at multiple levels, including: cell-cell exchanges (bystander), signal transduction, functional changes and modulation of gene expression. We have significant preliminary data on structural, functional, signal transduction and gene expression responses from acute exposures at high doses (50-1000 rads) of gamma, protons and iron (Green et al., 2001a; 2001b; 2002a; 2002b; 2005). More recently, we used our DOE funding (ending Feb 06) to characterize the pattern of radiation modulated gene expression in rat thyroid tissue analogs using low-dose/low-dose rate radiation, plus/minus acute challenge exposures. Findings from these studies show that the low-dose/low-dose rate “priming” exposures to radiation invoked changes in gene expression profiles that varied with dose and time. The thyrocytes transitioned to a “primed” state, so that when the tissue analogs were challenged with an acute exposure to radiation they had a muted response (or an increased resistance) to cytopathological changes relative to “un-primed” cells. We measured dramatic differences in the primed tissue analogs, showing that our original hypothesis was correct: that low dose gamma irradiation willmore » potentiate the repair/adaptation response to a secondary exposure. Implications from these findings are that risk assessments based on classical in vitro tissue culture assays will overestimate risk, and that low dose rate priming results in a reduced response in gene expression to a secondary challenge exposure, which implies that a priming dose provides enhanced protection to thyroid cells grown as tissue analogs. If we can determine that the effects of radiation on our tissue analogs more closely resemble the effects of radiation in vivo, then we can better estimate the risks and modify assign limits to radiation worker and astronauts. Additionally, confirmation that tissue analogs represent a realistic in vivo response to radiation will allow scientists to perform tissue relevant experiments without the expense of using animals. Confirmation of the in vivo approximation of our model will strengthen our findings from the recent completion of our DOE funding which is the subject of the current proposal.« less

Authors:
Publication Date:
Research Org.:
Loma Linda University
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
882942
Report Number(s):
DOE/ER63448-1
3423; TRN: US200716%%285
DOE Contract Number:
FG02-02ER63448
Resource Type:
Technical Report
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; ACUTE EXPOSURE; BIOREACTORS; DOSE RATES; FUNCTIONALS; GENES; IN VITRO; IN VIVO; IRON; IRRADIATION; MODULATION; PROTONS; RADIATIONS; RISK ASSESSMENT; THYROID; THYROID CELLS; TISSUE CULTURES; Bioreactor-Tissue Analogs; microarray analysis; gamma-rays; protons

Citation Formats

Green, Lora M. Low Dose Gamma Irradiation Potentiates Secondary Exposure to Gamma Rays or Protons in Thyroid Tissue Analogs. United States: N. p., 2006. Web. doi:10.2172/882942.
Green, Lora M. Low Dose Gamma Irradiation Potentiates Secondary Exposure to Gamma Rays or Protons in Thyroid Tissue Analogs. United States. doi:10.2172/882942.
Green, Lora M. 2006. "Low Dose Gamma Irradiation Potentiates Secondary Exposure to Gamma Rays or Protons in Thyroid Tissue Analogs". United States. doi:10.2172/882942. https://www.osti.gov/servlets/purl/882942.
@article{osti_882942,
title = {Low Dose Gamma Irradiation Potentiates Secondary Exposure to Gamma Rays or Protons in Thyroid Tissue Analogs},
author = {Green, Lora M},
abstractNote = {We have utilized our unique bioreactor model to produce three-dimensional thyroid tissue analogs that we believe better represent the effects of radiation in vivo than two-dimensional cultures. Our thyroid model has been characterized at multiple levels, including: cell-cell exchanges (bystander), signal transduction, functional changes and modulation of gene expression. We have significant preliminary data on structural, functional, signal transduction and gene expression responses from acute exposures at high doses (50-1000 rads) of gamma, protons and iron (Green et al., 2001a; 2001b; 2002a; 2002b; 2005). More recently, we used our DOE funding (ending Feb 06) to characterize the pattern of radiation modulated gene expression in rat thyroid tissue analogs using low-dose/low-dose rate radiation, plus/minus acute challenge exposures. Findings from these studies show that the low-dose/low-dose rate “priming” exposures to radiation invoked changes in gene expression profiles that varied with dose and time. The thyrocytes transitioned to a “primed” state, so that when the tissue analogs were challenged with an acute exposure to radiation they had a muted response (or an increased resistance) to cytopathological changes relative to “un-primed” cells. We measured dramatic differences in the primed tissue analogs, showing that our original hypothesis was correct: that low dose gamma irradiation will potentiate the repair/adaptation response to a secondary exposure. Implications from these findings are that risk assessments based on classical in vitro tissue culture assays will overestimate risk, and that low dose rate priming results in a reduced response in gene expression to a secondary challenge exposure, which implies that a priming dose provides enhanced protection to thyroid cells grown as tissue analogs. If we can determine that the effects of radiation on our tissue analogs more closely resemble the effects of radiation in vivo, then we can better estimate the risks and modify assign limits to radiation worker and astronauts. Additionally, confirmation that tissue analogs represent a realistic in vivo response to radiation will allow scientists to perform tissue relevant experiments without the expense of using animals. Confirmation of the in vivo approximation of our model will strengthen our findings from the recent completion of our DOE funding which is the subject of the current proposal.},
doi = {10.2172/882942},
journal = {},
number = ,
volume = ,
place = {United States},
year = 2006,
month = 5
}

Technical Report:

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  • The formation of functional tissue units is necessary in maintaining homeostasis within living systems, with individual cells contributing to these functional units through their three-dimensional organization with integrin and adhesion proteins to form a complex extra-cellular matrix (ECM). This is of particular importance in those tissues susceptible to radiation-induced tumor formation, such as epithelial glands. The assembly of epithelial cells of the thyroid is critical to their normal receipt of, and response to, incoming signals. Traditional tissue culture and live animals present significant challenges to radiation exposure and continuous sampling, however, the production of bioreactor-engineered tissues aims to bridge thismore » gap by improve capabilities in continuous sampling from the same functional tissue, thereby increasing the ability to extrapolate changes induced by radiation to animals and humans in vivo. Our study proposes that the level of tissue organization will affect the induction and persistence of low dose radiation-induced genomic instability. Rat thyroid cells, grown in vitro as 3D tissue analogs in bioreactors and as 2D flask grown cultures were exposed to acute low dose (1, 5, 10 and 200 cGy) gamma rays. To assess immediate (6 hours) and delayed (up to 30 days) responses post-irradiation, various biological endpoints were studied including cytogenetic analyses, apoptosis analysis and cell viability/cytotoxicity analyses. Data assessing caspase 3/7 activity levels show that, this activity varies with time post radiation and that, overall, 3D cultures display more genomic instability (as shown by the lower levels of apoptosis over time) when compared to the 2D cultures. Variation in cell viability levels were only observed at the intermediate and late time points post radiation. Extensive analysis of chromosomal aberrations will give further insight on the whether the level of tissue organization influences genomic instability patterns after low dose radiation exposure. Cells viability/cytotoxicity analysis data are currently being analyzed to determine how these endpoints are affected under our experimental conditions. The results from this study will be translatable to risk assessment for assigning limits to radiation workers, pre-dosing for more effective radiotherapy and the consequences of long duration space flight. The data from this study has been presented a various scientific meetings/workshops and a manuscript, containing the findings, is currently being prepared for publication. Due to unforeseen challenges in collecting the data and standardizing experimental procedures, the second and third aims have not been completed. However, attempts will be made, based on the availability of funds, to continue this project so that these aims can be satisfied.« less
  • Integral experiments were performed to measure the angular distribution of secondary gamma rays produced when various thicknesses of Fe, Pb, and H/sub 2/O samples were exposed to bare and to B/sub 4/C-filtered neutron beams from the Research Reactor of Egypt. For selected experiments, multigroup coupled neutron-gamma cross sections and a discrete ordinates transport theory code (DOT4PI-M) were used to calculate the secondary gamma rays and the transport of primary gamma rays. Integral comparisons between the calculated and measured spectra were favorable. Graphical comparisons of the measured flux for various angles of incidence of the neutron beams on the samples, formore » various angles of exit on the transmitted side of the samples, and for various sample thicknesses are shown. The comparisons show that the angular distribution of secondary gamma rays for the three materials changes slightly with a change in the angle of beam incident on the sample, but increasing the angle between the normal to the sample and the detector by 60/sup 0/ decreases the measured secondary gamma-ray flux up to a factor of two. An investigation was made to determine the consequences of using single scatter Compton theory versus using discrete ordinates transport calculations to estimate the primary gamma-ray contribution to the measured photon spectra.« less
  • Three hundred sixty female Sprague-Dawley rats, three months old, were exposed ln one hour to an acute dose of 520 rep of fast neutrons plus 110 r of gamma rays emanating from a uranium reactor. The exposure resulted in 57 percent fatalities within 30 days. Both the body and spleen weights of rats dying after the exposure were significantly less than those of the controls. However, only the spleen weight in animals dying on days 7 through 9 postexposure was significantly closer to normal range than the weight at its maximum low on day 5. Tumors began to appear inmore » the irradiated group 69 days after the exposure in contrast to 146 days in the controls. By the 200th day postexposure, 23.6 percent of the irradiated group had tumors, compared with only 7.5 percent of the controls--a difference statistically significant to the 0.05 level. (auth)« less