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All sourcesNASA NTRSDOE OSTI
NASA NTRS2007

Distribution of Micronuclei in Human Fibroblasts across the Bragg Curve of Light and Heavy Ions

The space environment consists of energetic particles of varying mass and energy, and understanding the :biological Bragg curve" is essential in optimizing shielding effectiveness against space radiation induced biological impacts. The "biological Bragg curve" is dependent on the energy and the type of the primary particle, and may vary for different biological endpoints. Previously, we studied the induction of micronuclei (MN) across the Bragg curve of energetic Fe and Si ions, and observed no increased yield of MN at the location of the Bragg peak. However, the ratio of mono- to bi-nucleated cells, which indicates inhibition of cell progression, was found higher at the Bragg peak location in comparison to the plateau region of the Bragg curve. Here, we report the induction of MN in normal human fibroblast cells across the Bragg curve of incident protons generated at Loma Linda University. Similar to Si and Fe ions, the ratio of mono- to bi-nucleated cells showed a clear spike as the protons reached the Bragg peak. Unlike the two heavy ions, however, the MN yield also increased at the Bragg peak location. These results confirm the hypothesis that severely damaged cells at the Bragg peak of heavy, but not light ions are more likely to go through reproductive death and not be evaluated for micronuclei.

Hada, M.↗
NASA NTRS2009

Induction of Micronuclei in Human Fibroblasts from the Los Alamos High Energy Neutron Beam

The space radiation field includes a broad spectrum of high energy neutrons. Interactions between these neutrons and a spacecraft, or other material, significantly contribute to the dose equivalent for astronauts. The 15 degree beam line in the Weapons Neutron Research beam at Los Alamos Nuclear Science Center generates a neutron spectrum relatively similar to that seen in space. Human foreskin fibroblast (AG1522) samples were irradiated behind 0 to 20 cm of water equivalent shielding. The cells were exposed to either a 0.05 or 0.2 Gy entrance dose. Following irradiation, micronuclei were counted to see how the water shield affects the beam and its damage to cell nuclei. Micronuclei induction was then compared with dose equivalent data provided from a tissue equivalent proportional counter.

Cox, Bradley↗
NASA NTRS2000

Impact of p53 status on heavy-ion radiation-induced micronuclei in circulating erythrocytes

Transgenic mice that differed in their p53 genetic status were exposed to an acute dose of highly charged and energetic (HZE) iron particle radiation. Micronuclei (MN) in two distinct populations of circulating peripheral blood erythrocytes, the immature reticulocytes (RETs) and the mature normochromatic erythrocytes (NCEs), were measured using a simple and efficient flow cytometric procedure. Our results show significant elevation in the frequency of micronucleated RETs (%MN-RETs) at 2 and 3 days post-radiation. At 3 days post-irradiation, the magnitude of the radiation-induced MN-RET was 2.3-fold higher in the irradiated p53 wild-type animals compared to the unirradiated controls, 2.5-fold higher in the p53 hemizygotes and 4.3-fold higher in the p53 nullizygotes. The persistence of this radiation-induced elevation of MN-RETs is dependent on the p53 genetic background of the animal. In the p53 wild-type and p53 hemizygotes, %MN-RETs returned to control levels by 9 days post-radiation. However, elevated levels of %MN-RETs in p53 nullizygous mice persisted beyond 56 days post-radiation. We also observed elevated MN-NCEs in the peripheral circulation after radiation, but the changes in radiation-induced levels of MN-NCEs appear dampened compared to those of the MN-RETs for all three strains of animals. These results suggest that the lack of p53 gene function may play a role in the iron particle radiation-induced genomic instability in stem cell populations in the hematopoietic system.

NASA Discipline Radiation Health↗
NASA NTRS2006

Induction of micronuclei in human fibroblasts across the Bragg curve of energetic heavy ions

The space environment consists of a varying field of radiation particles including high energy ions, with spacecraft shielding material providing the major protection to astronauts from harmful exposure. Unlike low-L or X-rays, the presence of shielding does not always reduce the radiation risks for energetic charged particle exposure. Although the dose delivered by the charged particle increases sharply as the particle approaches the Bragg peak, the Bragg curve does not necessarily represent the biological damage along the particle traversal. The "biological Bragg curve" is dependent on the energy and the type of the primary particle, and may vary for different biological endpoints. To investigate "biological Bragg curves", we analyzed micronuclei (MN) induction along the particle traversal of Si and Fe ions at incident energies of 300 MeV/nucleon and 1 GeV/nucleon. A quantitative biological response curve did not reveal an increased yield of MN at the location of the Bragg peak. However, the ratio of mono-to bi-nucleated cells, which indicates inhibition in cell progression, increased at the Bragg peak location. These results confirm the hypothesis that "over kill" at the Bragg peak will affect the outcome of other biological endpoints.

Hada, Megumi↗
NASA NTRS2006

Micronuclei Induction in Human Fibroblasts Exposed In Vitro to Los Alamos High-Energy Neutrons

High-energy secondary neutrons, produced by the interaction of galactic cosmic rays with the atmosphere, spacecraft structure and planetary surfaces, contribute to a significant fraction to the dose equivalent in crew members and passengers during commercial aviation travel, and astronauts in space missions. The Los Alamos Nuclear Science Center (LANSCE) neutron facility#s ICE House 30L beamline is known to generate neutrons that simulate the secondary neutron spectra of earth#s atmosphere. The neutron spectrum is also similar to that measured onboard spacecraft like the MIR and International Space Station (ISS). To evaluate the biological damage, we exposed human fibroblasts in vitro to the LANSCE neutron beams without degrader at an entrance dose rate of 25 mGy/hr and analyzed the micronuclei (MN) induction. The cells were also placed behind a 9.9 cm water column to study effect of shielding in the protection of neutron induced damages. It was found that the dose response in the MN frequency was linear for the samples with and without shielding and the slope of the MN yield behind the shielding was reduced by a factor of 3.5. Compared to the MN induction in human fibroblasts exposed to a gamma source at a low dose rate, the RBE was found to be 16.7 and 10.0 for the neutrons without and with 9.9 cm water shielding, respectively.

Gersey, Brad↗
NASA NTRS2006

Induction of Micronuclei in Human Fibroblasts across the Bragg Curve of Energetic Si and Fe Ions

The space environment consists of a varying field of radiation particles including high-energy ions, with spacecraft shielding material providing the major protection to astronauts from harmful exposure. Unlike low-LET gamma or X-rays, the presence of shielding does not always reduce the radiation risks for energetic charged particle exposure. Since the dose delivered by the charged particle increases sharply as the particle approaches the end of its range, a position known as the Bragg peak, the Bragg curve does not necessarily represent the biological damage along the particle traversal since biological effects are influenced by the track structure of both primary and secondary particles. Therefore, the biological Bragg curve is dependent on the energy and the type of the primary particle, and may vary for different biological endpoints. We studied micronuclei (MN) induction across the Bragg curve of Si and Fe ions at incident energies of 300 MeV/nucleon and 1 GeV/nucleon. A quantitative biological response curve did not reveal an increased yield of MN at the location of the Bragg peak. However, the ratio of mono- to bi-nucleated cells, which indicates inhibition in cell progression, increased at the Bragg peak location. These results confirm the hypothesis that severely damaged cells at the Bragg peak are likely to go through reproduction death.

Wu, H.↗
NASA NTRS2007

A Start Toward Micronucleus-Based Decompression Models; Altitude Decompression

Do gaseous micronuclei trigger the formation of bubbles in decompression sickness (DCS)? Most previous instructions for DCS prevention have been oriented toward supersaturated gas in tissue. We are developing a mathematical model that is oriented toward the expected behavior of micronuclei. The issue is simplified in altitude decompressions because the aviator or astronaut is exposed only to decompression, whereas in diving there is a compression before the decompression. The model deals with four variables: duration of breathing of 100% oxygen before going to altitude (O2 prebreathing), altitude of the exposure, exposure duration, and rate of ascent. Assumptions: a) there is a population of micronuclei of various sizes having a range of characteristics, b) micronuclei are stable until they grow to a certain critical nucleation radius, c) it takes time for gas to diffuse in or out of micronuclei, and d) all other variables being equal, growth of micronuclei upon decompression is more rapid at high altitude because of the rarified gas in the micronuclei. To estimate parameters, we use a dataset of 4,756 men in altitude chambers exposed to various combinations of the model s variables. The model predicts occurrence of DCS symptoms quite well. It is notable that both the altitude chamber data and the model show little effect of O2 prebreathing until it lasts more than 60 minutes; this is in contrast to a conventional idea that the benefit of prebreathing is directly due to exponential washout of tissue nitrogen. The delay in response to O2 prebreathing can be interpreted as time required for outward diffusion of nitrogen; when the micronuclei become small enough, they are disabled, either by crushing or because they cannot expand to a critical nucleation size when the subject ascends to altitude.

Van Liew, H. D.↗
NASA NTRS2001

Relative effectiveness of HZE iron-56 particles for the induction of cytogenetic damage in vivo

One of the risks of prolonged manned space flight is the exposure of astronauts to radiation from galactic cosmic rays, which contain heavy ions such as (56)Fe. To study the effects of such exposures, experiments were conducted at the Brookhaven National Laboratory by exposing Wistar rats to high-mass, high-Z, high-energy (HZE) particles using the Alternating Gradient Synchrotron (AGS). The biological effectiveness of (56)Fe ions (1000 MeV/nucleon) relative to low-LET gamma rays and high-LET alpha particles for the induction of chromosome damage and micronuclei was determined. The mitotic index and the frequency of chromosome aberrations were evaluated in bone marrow cells, and the frequency of micronuclei was measured in cells isolated from the trachea and the deep lung. A marked delay in the entry of cells into mitosis was induced in the bone marrow cells that decreased as a function of time after the exposure. The frequencies of chromatid aberrations and micronuclei increased as linear functions of dose. The frequency of chromosome aberrations induced by HZE particles was about 3.2 times higher than that observed after exposure to (60)Co gamma rays. The frequency of micronuclei in rat lung fibroblasts, lung epithelial cells, and tracheal epithelial cells increased linearly, with slopes of 7 x 10(-4), 12 x 10(-4), and 11 x 10(-4) micronuclei/binucleated cell cGy(-1), respectively. When genetic damage induced by radiation from (56)Fe ions was compared to that from exposure to (60)Co gamma rays, (56)Fe-ion radiation was between 0.9 and 3.3 times more effective than (60)Co gamma rays. However, the HZE-particle exposures were only 10-20% as effective as radon in producing micronuclei in either deep lung or tracheal epithelial cells. Using microdosimetric techniques, we estimated that 32 cells were hit by delta rays for each cell that was traversed by the primary HZE (56)Fe particle. These calculations and the observed low relative effectiveness of the exposure to HZE particles suggest that at least part of the cytogenetic damage measured was caused by the delta rays. Much of the energy deposited by the primary HZE particles may result in cell killing and may therefore be "wasted" as far as production of detectable micronuclei is concerned. The role of wasted energy in studies of cancer induction may be important in risk estimates for exposure to HZE particles.

Non-NASA Center↗
NASA NTRS2001

Induction and repair of HZE induced cytogenetic damage

Wistar rats were exposed to high-mass, high energy (HZE) 56Fe particles (1000 GeV/AMU) using the Alternating Gradient Synchrotron (AGS). The animals were sacrificed at 1-5 hours or after a 30-day recovery period. The frequency of micronuclei in the tracheal and the deep lung epithelial cells were evaluated. The relative effectiveness of 56Fe, for the induction of initial chromosome damage in the form of micronuclei, was compared to damage produced in the same biological system exposed to other types of high and low-LET radiation. It was demonstrated that for animals sacrificed at short times after exposure, the tracheal and lung epithelial cells, the 56Fe particles were 3.3 and 1.3 times as effective as 60Co in production of micronuclei, respectively. The effectiveness was also compared to that for exposure to inhaled radon. With this comparison, the 56Fe exposure of the tracheal epithelial cells and the lung epithelial cells were only 0.18 and 0.20 times as effective as radon in the production of the initial cytogenetic damage. It was suggested that the low relative effectiveness was related to potential for 'wasted energy' from the core of the 56Fe particles. When the animals were sacrificed after 30 days, the slopes of the dose-response relationships, which reflect the remaining level of damage, decreased by a factor of 10 for both the tracheal and lung epithelial cells. In both cases, the slope of the dose-response lines were no longer significantly different from zero, and the r2 values were very high. Lung epithelial cells, isolated from the animals sacrificed hours after exposure, were maintained in culture, and the micronuclei frequency evaluated after 4 and 6 subcultures. These cells were harvested at 24 and 36 days after the exposure. There was no dose-response detected in these cultures and no signs of genomic instability at either sample time.

Non-NASA Center↗
NASA NTRS2002

The effect of exercise and rest duration on the generation of venous gas bubbles at altitude

BACKGROUND: Decompression, as occurs with aviators and astronauts undergoing high altitude operations or with deep-sea divers returning to surface, can cause gas bubbles to form within the organism. Pressure changes to evoke bubble formation in vivo during depressurization are several orders of magnitude less than those required for gas phase formation in vitro in quiescent liquids. Preformed micronuclei acting as "seeds" have been proposed, dating back to the 1940's. These tissue gas micronuclei have been attributed to a minute gas phase located in hydrophobic cavities, surfactant-stabilized microbubbles, or arising from musculoskeletal activity. The lifetimes of these micronuclei have been presumed to be from a few minutes to several weeks. HYPOTHESIS: The greatest incidence of venous gas emboli (VGE) will be detected by precordial Doppler ultrasound with depressurization immediately following lower extremity exercise, with progressively reduced levels of VGE observed as the interval from exercise to depressurization lengthens. METHODS: In a blinded cross-over design, 20 individuals (15 men, 5 women) at sea level exercised by performing knee-bend squats (150 knee flexes over 10 min, 235-kcal x h(-1)) either at the beginning, middle, or end of a 2-h chair-rest period without an oxygen prebreathe. Seated subjects were then depressurized to 6.2 psia (6,706 m or 22,000 ft altitude equivalent) for 120 min with no exercise performed at altitude. RESULTS: Of the 20 subjects with VGE in the pulmonary artery, 10 demonstrated a greater incidence of bubbles with exercise performed just prior to depressurization, compared with decreasing bubble grades and incidence as the interval of rest increased prior to depressurization. No decompression illness was reported. CONCLUSIONS: There is a significant increase in decompression-induced bubble formation at 6.2 psia when lower extremity exercise is performed just prior to depressurization as compared with longer rest intervals. Analysis indicated that micronuclei half-life is on the order of an hour under these hypobaric conditions.

Controlled Clinical Trial↗
NASA NTRS2001

Response of thyroid follicular cells to gamma irradiation compared to proton irradiation. I. Initial characterization of DNA damage, micronucleus formation, apoptosis, cell survival, and cell cycle phase redistribution

The RBE of protons has been assumed to be equivalent to that of photons. The objective of this study was to determine whether radiation-induced DNA and chromosome damage, apoptosis, cell killing and cell cycling in organized epithelial cells was influenced by radiation quality. Thyroid-stimulating hormone-dependent Fischer rat thyroid cells, established as follicles, were exposed to gamma rays or proton beams delivered acutely over a range of physical doses. Gamma-irradiated cells were able to repair DNA damage relatively rapidly so that by 1 h postirradiation they had approximately 20% fewer exposed 3' ends than their counterparts that had been irradiated with proton beams. The persistence of free ends of DNA in the samples irradiated with the proton beam implies that either more initial breaks or a quantitatively different type of damage had occurred. These results were further supported by an increased frequency of chromosomal damage as measured by the presence of micronuclei. Proton-beam irradiation induced micronuclei at a rate of 2.4% per gray, which at 12 Gy translated to 40% more micronuclei than in comparable gamma-irradiated cultures. The higher rate of micronucleus formation and the presence of larger micronuclei in proton-irradiated cells was further evidence that a qualitatively more severe class of damage had been induced than was induced by gamma rays. Differences in the type of damage produced were detected in the apoptosis assay, wherein a significant lag in the induction of apoptosis occurred after gamma irradiation that did not occur with protons. The more immediate expression of apoptotic cells in the cultures irradiated with the proton beam suggests that the damage inflicted was more severe. Alternatively, the cell cycle checkpoint mechanisms required for recovery from such damage might not have been invoked. Differences based on radiation quality were also evident in the alpha components of cell survival curves (0.05 Gy(-1) for gamma rays, 0.12 Gy(-1) for protons), which suggests that the higher level of survival of gamma-irradiated cells could be attributed to the persistence of nonlethally irradiated thyrocytes and/or the capacity to repair damage more effectively than cells exposed to equal physical doses of protons. The final assessment in this study was radiation-induced cell cycle phase redistribution. Gamma rays and protons produced a similar dose-dependent redistribution toward a predominantly G(2)-phase population. From our cumulative results, it seems likely that a majority of the proton-irradiated cells would not continue to divide. In conclusion, these findings suggest that there are quantitative and qualitative differences in the biological effects of proton beams and gamma rays. These differences could be due to structured energy deposition from the tracks of primary protons and the associated high-LET secondary particles produced in the targets. The results suggest that a simple dose-equivalent approach to dosimetry may be inadequate to compare the biological responses of cells to photons and protons.

NASA Discipline Radiation Health↗
NASA NTRS1993

A mechanism for the reduction in risk of decompression sickness in microgravity environment

There is an apparent reduction in the incidence of decompression sickness reported by astronauts (from both the USA and the USSR) during extravehicular activity (EVA). The expected incidence, based on studies conducted under unit gravity conditions in Earth-based laboratories, is greater than that encountered during EVA. A biophysical explanation has been proposed for this difference based upon the mechanism of stress-assisted nucleation. Since the partial pressure ratio at which this gas phase forms is considerably smaller in living systems that in quiescent in vitro models, it was proposed that mechanical forces are involved. In that the lower extremities of astronautics are not gravitationally loaded in microgravity, it is possible that tissue gas micronuclei are but minimally regenerated. Most likely, gas micronuclei formed on Earth (by ambulation under 1 g conditions) would be eventually depleted. In a crossover study, 20 individuals were decompressed--from 1 ATA to 0.43 ATA for 3 hours--following either being fully ambulatory at unit gravity or following being hypokinetic and adynamic (simulated microgravity of 3-day bed rest). The subjects were monitored for gas phase formation by means of precordial Doppler monitoring. The results indicate a reduction in whole body gas phase formation in individuals who were bed rested as compared with themselves when fully ambulatory (p = 0.02). In hypokinetic individuals, the protection conferred was equivalent to an extra 175 minutes of oxygen prebreathe. These results are compatible with a hypothesis relating stress-assisted nucleation to the continual formation of tissue gas micronuclei and their gradual depletion with hypokinesia.

Powell, Michael R.↗
NASA NTRS2007

Utility of DF-1 for Radioprotection in Lymphocytes

The development of degenerative changes in the vasculature, such as atherosclerosis, is a known consequence of exposure to ionizing radiation, and is thus a concern for astronaut health following long duration space flight. Cellular damage caused by radiation is due to free radical generation and DNA damage. The goal of this project was to assess the ability of a C60-derivative, DF-1, to mitigate cellular damage resulting from radiation exposure in primary human lymphocytes. DF-1 is a water-soluble C60 fullerene encapsulated in dendrimeric functional groups that is proposed to exhibit antioxidant properties. Human lymphocytes are radiosensitive and travel throughout the body potentially causing bystander effects in any tissues they contact. These cells were subjected to varying doses of gamma radiation in the presence or absence of DF-1. Cells were collected at 48 hours post-irradiation for chromosomal aberration studies and at 72 hours post-irradiation for micronuclei studies. These studies showed that the irradiated cells contained more chromosomal aberrations and micronuclei than the control cells. Addition of the DF-1 reduced the amount of observed DNA damage in the irradiated cells. Growth curves were measured for the lymphocytes exposed to 0 and 4 Gray gamma irradiations, and we observed less growth in the cells irradiated at 4 Gy. 2,7-dichlorofluorescein diacetate was used to detect reactive oxygen species production, and increased production of ROS was observed in the irradiated lymphocytes. Human lymphocytes were subjected to varying doses of gamma or photon radiation in the presence and absence of DF-1 and a known radioprotectant, amifostine. After irradiation, the production of reactive oxygen species, growth curves and cell viability were measured. These cells were also collected to quantify chromosomal aberrations and micronuclei formation. We predict that irradiated cells will show the most damage and that DF-1 will provide protective effects similar to those of amifostine, an established radioprotectant.

Reynolds, Julia↗
DOE OSTI2020

Green synthesis and characterization of nontoxic L-methionine capped silver and gold nanoparticles

The simple green method for synthesis of stable L-Methionine (L-Met) capped silver (Ag@LM NPs) and gold (Au@LM NPs) nanoparticles (NPs) without adding any additional reduction agent or stabilizer was developed. Colloidal dispersions were characterized by UV–Vis spectrophotometry. The size and spherical shape of NPs were evaluated by transmission electron microscopy. Their surface covering was confirmed by atomic force microscopy, Fourier transform infrared spectroscopy, dynamic light scattering, and zeta potential measurements. Density functional theory calculations pointed that the preferential adsorption mode of L-Met on both Ag and Au surfaces was a vertical binding geometry via –NH2 group, while horizontal binding mode via [sbnd]S[sbnd] and –NH2 groups is also possible. The genotoxicity (evaluated by the micronucleus assay) of NPs, as well as their effects on some oxidative stress parameters (catalase activity, malondialdehyde level), were assessed in vitro using human peripheral blood cells as a model system. The influence of NPs on the morphology of lymphocyte cells studied using atomic force microscopy revealed that the membrane of cells remained unaffected after the treatment with NPs. When considering the effects of NPs on catalase activity and malondialdehyde level, neither particle type promoted oxidative stress. However, the treatment of lymphocytes with Ag@LM NPs induced a concentration-dependent enhancement of the micronuclei incidence and suppression of the cell proliferation while Au@LM NPs promoted cell proliferation, with no significant effects on micronuclei formation. The Ag@LM NPs were more prone to induce DNA damage than Au@LM NPs, which makes the latter type more suitable for further studies in nano-medicine. © 2019.

60 APPLIED LIFE SCIENCES↗
NASA NTRS1988

Micronucleation in the lens epithelium following in vivo exposure to physical and chemical mutagens

Rats were exposed to cataractogenic doses of known physical and chemical genotoxic agents in order to study the efficacy of using micronuclei to monitor mutagenicity in the lens epithelium. The total numbers of micronuclei were counted in lens epithelia from rats exposed to graded doses of either 250 kVp X-rays or the anti-leukemic drug, 1,4 dimethanesulfonoxybutane (Myleran (R)). The results indicate a dose-dependent incidence of micronucleation in the lens epithelium following exposure. The findings are consistent with the hypothesis that the cataractogenicity of certain agents may be related to their effect on the genome of lens epithelial cells.

NASA Discipline Number 22-70↗
NASA NTRS2005

In Vitro Experimental Model to Investigate the Biological Effects across the Bragg Curve of High-LET Radiation

The space environment consists of a varying field of radiation particles including high energy ions, with a spacecrafts shielding material providing the only major protection to astronauts from harmful exposure. Unlike lowLET gamma or Xrays, the presence of shielding does not always reduce the radiation risks for energetic charged particle exposure since the dose delivered by the charged particle increases sharply as the particle approaches the end of its range, a position known as the Bragg peak and the correlating spatial dose distribution identified as the Bragg curve. The Bragg curve does not necessarily represent the biological damage along the particle traversal since biological effects are influenced by the track structure of both primary and secondary particles. Therefore, the biological Bragg curve is dependent of the energy and the type of the primary particle, and may vary for different biological endpoints. Here we describe a unique irradiation geometry and experimental system to measure the biological response across the Bragg curve in one consistent biological sample. Polyethylene shielding was used to achieve a Bragg curve distribution with the beam geometry parallel to a monolayer of fibroblast cells. We present data that highlights the differential formation of DNA double strand breaks (DSBs) and chromosomal deletions across the Bragg curve in human fibroblasts irradiated with 600 MeV/nucleon iron ion beams. Qualitative analyses of gammaH2AX fluorescence, a known marker of DSBs, indicated potentially increased clustering of DNA damage before the Bragg peak, enhanced homogenous distribution at the peak, and provided visual evidence of high linear energy transfer (LET) particle traversal of cells beyond the Bragg peak in agreement with one-dimensional transport approximations. A biological response curve generated for micronuclei induction across the Bragg curve for 600 MeV/n Fe ions did not reveal an increase in the yield of micronuclei at the Bragg peak location. Assessment of such biological parameters employing the described in vitro experimental system may provide improved platforms to measure a number of biological consequences of shielding materials across the Bragg curve for high charge and energy (HZE) ions.

Desai, N.↗
NASA NTRS2009

Cytogenetic Response to Ionizing Radiation Exposure in Human Fibroblasts with Suppressed Expression of Non-DSB Repair Genes

Changes of gene expression profile are one of the most important biological responses in living cells after ionizing radiation (IR) exposure. Although some studies have shown that genes up-regulated by IR may play important roles in DNA damage repair, the relationship between the regulation of gene expression by IR, particularly genes not known for their roles in double-strand break (DSB) repair, and its impact on cytogenetic responses has not been well studied. The purpose of this study is to identify new roles of IR inducible genes in radiation-induced chromosome aberrations and micronuclei formation. In the study, the expression of 25 genes selected on the basis of their transcriptional changes in response to IR was individually knocked down by small interfering RNA in human fibroblast cells. Frequencies of micronuclei (MN) formation and chromosome aberrations were measured to determine the efficiency of cytogenetic repair, and the fraction of bi-nucleated cells in the MN analysis was used as a marker for cell cycle progression. In response to gamma radiation, the formation of MN was significantly increased by suppressed expression of five genes: Ku70 (DSB repair pathway), XPA (nucleotide excision repair pathway), RPA1 (mismatch repair pathway), RAD17 and RBBP8 (cell cycle control). Knocked-down expression of four genes (MRE11A, RAD51 in the DSB pathway, SESN1, and SUMO1) significantly inhibited cell cycle progression, possibly because of severe impairment of DNA damage repair. Moreover, decreased XPA, p21, or MLH1 expression resulted in both significantly enhanced cell cycle progression and increased yields of chromosome aberrations, indicating that these gene products modulate both cell cycle control and DNA damage repair. Nine of these eleven genes, whose knock-down expression affected cytogenetic repair, were up-regulated in cells exposed to gamma radiation, suggesting that genes transcriptionally modulated by IR were critical to regulate IR-induced biological consequences. Furthermore, eight non-DBS repair genes showed involvement in regulating DSB repair, indicating that successful DSB repair requires both DSB repair mechanisms and non-DSB repair systems.

Zhang, Ye↗
NASA NTRS2011

Summer Research Paper

Certain populations such as chemotherapy patients and atomic bomb survivors have been exposed to ionizing radiation and experience tissue damage and cancer initiation and progression. One cancer that can be initiated from radiation is esophageal squamous cell carcinoma (ESCC), an epithelial cancer that has a survival rate as low as 20%. Researchers have found that when protein tyrosine kinase receptors (RPTK) activate oncogenes, they can create epithelial tumors and cause deadly cancers like ESCC. The RPTK family has one group, MET, that has only two receptors, MET and RON, present in the human body. MET s ligand is the hepatocyte growth factor (HGF) and RON's ligand is the macrophage-stimulating protein (MSP-1). Both HGF and MSP-1 have been shown to activate their receptors and are implicated in certain processes. Since radiation damages cells throughout the biological system, researchers are investigating whether or not HGF and MSP-1 protects or kills certain normal and cancerous cells by being part of cell recovery processes. One research group recently reviewed that the HGF-MET pathway has an important role in the embryonic development in the liver, migration of myogenic precursor cells, regulation of epithelial morphogenesis and growth, and regeneration and protection in tissues. In addition, since the RON receptor is more commonly expressed in cells of epithelial origin, and when activated is part of epithelial cell matrix invasion, dissociation, and migration processes, scientists conclude that RON might be one of the factors causing epithelial cancer initiation in the biological system. In order to examine HGF and MSP-1 s effect on cancer initiation and progression we used two immortalized esophageal epithelial cell lines. One is a normal human cell line (EPC2-hTERT), while the other had a p53 mutation at the 175th amino acid position (EPC2-hTERT-p53(sup R175H)). For this investigation, we used 0(control), 2, and 4 Gray doses of gamma (Cs137) radiation and selected various concentrations from 0-100 ng/mL of HGF and MSP-1 in our assays. Since the HGF and MSP-1 pathways have proliferative roles in epithelial cells, we conducted the MTT proliferation assay to see if either drug enhances or inhibits cell proliferation over time. Also, a MTT cytotoxicity assay was necessary to observe whether the drugs are protecting the cells from radiation and if a trend is occurring depending upon the amount of dose added. In addition, a wound healing assay was done since both drugs have been to known to promote cell motility. Since cell damage occurs when radiation is added, apoptosis and micronuclei assays are vital to see if HGF and MSP-1 increase or decrease cell death and damage in normal and pre-cancerous cells and by how much based on the radiation dosage. Overall, we used the MTT, wound healing, apoptosis and micronuclei assays to investigate the effects ofHGF and MSP-1 on irradiated esophageal epithelial cells.

Patel, Zarana↗