Compact portable sources of high-LET radiation: Validation and potential application for galactic cosmic radiation countermeasure discovery
Year: 2022
Type: article
Abstract: • This article explores issues relating to the use of compact portable neutron sources, including DD and DT neutron generators and an AmBe radionuclide source, as ground-based space radiation analogs for countermeasure discovery. • Modeling shows that neutron-induced charged particles have a linear energy transfer (LET) distribution that, within a 10 to 200 keV/..m range of biological interest, resembles the LET distribution of GCR fields experienced in a spacecraft or on the lunar surface. • Experimental validation shows that DD neutrons induce large, persistent 53BP1 DNA repair foci in human bronchial epithelial cells, consistent with the presence of complex, high-LET radiation damage. • Compact portable neutron sources could be integrated with a multiplex microfluidic cell culture system for protracted, low dose-rate exposures. Implementation of a systematic program for galactic cosmic radiation (GCR) countermeasure discovery will require convenient access to ground-based space radiation analogs. The current gold standard approach for GCR simulation is to use a particle accelerator for sequential irradiation with ion beams representing different GCR components. This has limitations, particularly for studies of non-acute responses, strategies that require robotic instrumentation, or implementation of complex in vitro models that are emerging as alternatives to animal experimentation. Here we explore theoretical and practical issues relating to a different approach to provide a high-LET radiation field for space radiation countermeasure discovery, based on use of compact portable sources to generate neutron-induced charged particles. We present modeling studies showing that DD and DT neutron generators, as well as an AmBe radionuclide-based source, generate charged particles with a linear energy transfer (LET) distribution that, within a range of biological interest extending from about 10 to 200 keV/μm, resembles the LET distribution of reference GCR radiation fields experienced in a spacecraft or on the lunar surface. We also demonstrate the feasibility of using DD neutrons to induce 53BP1 DNA double-strand break repair foci in the HBEC3-KT line of human bronchial epithelial cells, which are widely used for studies of lung carcinogenesis. The neutron-induced foci are larger and more persistent than X ray-induced foci, consistent with the induction of complex, difficult-to-repair DNA damage characteristic of exposure to high-LET (>10 keV/μm) radiation. We discuss limitations of the neutron approach, including low fluence in the low LET range (<10 keV/μm) and the absence of certain long-range features of high charge and energy particle tracks. We present a concept for integration of a compact portable source with a multiplex microfluidic in vitro culture system, and we discuss a pathway for further validation of the use of compact portable sources for countermeasure discovery.
Source: Life Sciences in Space Research
Authors: Nolan E. Hertel, Steven R. Biegalski, Victoria I. Nelson, William A. Nelson, Sharmistha Mukhopadhyay, Zitong Su, Alexis M. Chan, Aparna H. Kesarwala, William S. Dynan
Language: English
Subfield: Radiation
Field: Physics and Astronomy
Domain: Physical Sciences
Open Access status: hybrid
Estimated APC paid: $2,200
Awards: CURRENT PREDICTIONS OF THE RISK OF RADIATION EXPOSURE INDUCED DEATH HAVE LARGE UNCERTAINTIES IN PART THIS IS BECAUSE OF POOR UNDERSTANDING OF FACTORS THAT INFLUENCE RISK IN THE LOW DOSE RANGE CORRESPONDING TO ANTICIPATED HUMAN EXPOSURE. MODELING SUGGESTS THAT THE DOSE RESPONSE MAY BE STRONGLY NONLINEAR WITH AN INCREASE IN RISK AT LOW DOSES ATTRIBUTABLE TO NON-TARGETED EFFECTS (NTES) IN CELLS NOT DIRECTLY TRAVERSED BY A RADIATION TRACK. A MODEL INCORPORATING NTES FITTED TO MOUSE HARDERIAN GLAND CARCINOGENESIS DATA PREDICTS THAT MARS MISSION CANCER RISK MAY BE TWO-FOLD GREATER THAN THAT ATTRIBUTABLE TO TARGETED EFFECTS ALONE . THESE FINDINGS HIGHLIGHT THE NEED FOR A BETTER UNDERSTANDING OF THE MECHANISMS UNDERLYING THE HIGH RELATIVE BIOLOGICAL EFFECTIVENESS (RBE) OF GCR FOR CARCINOGENESIS INCLUDING ITS ABILITY TO ELICIT NTES. THE PRINCIPAL HYPOTHESIS FOR THIS PROPOSAL IS THAT EXPOSURE TO GCR AND PARTICULARLY ITS HIGH CHARGE AND ENERGY (HZE) PARTICLE COMPONENTS IS ASSOCIATED WITH CHRONIC DNA DAMAGE SIGNALING LEADING TO DECLINE IN THE FUNCTIONAL STATUS OF THE DNA REPAIR MACHINERY AND THAT THIS IS A KEY CONTRIBUTOR TO GCR CARCINOGENESIS. PRIOR STUDIES ESTABLISH THE SCIENTIFIC PREMISE FOR THIS HYPOTHESIS AND IDENTIFY POTENTIAL UNDERLYING MECHANISMS ONE OF WHICH IS DEPLETION OF CELLULAR NAD+ POOLS AS A CONSEQUENCE OF PERSISTENT DNA DAMAGE RESULTING IN REDUCED ACTIVITY OF IMPORTANT NAD+-DEPENDENT ENZYMES. THESE INCLUDE THE DNA DAMAGE SENSING AND REPAIR FACTOR PARP1 AND PROTEIN DEACYLASES KNOWN AS SIRTUINS. EXPERIMENTS WILL INVESTIGATE THE ROLE OF THE NAD+/PARP1/SIRTUIN AXIS IN EXPERIMENTS USING BOTH HUMAN BRONCHIAL EPITHELIAL CELLS AND WILD-TYPE C57BL/6 MICE. THE WORK WILL FOCUS ON LUNG CANCER RISK AS AN ENDPOINT. SPECIFIC AIMS ARE: AIM 1. TO INVESTIGATE THE SCOPE AND MECHANISTIC BASIS FOR A GCR EXPOSURE-RELATED DECLINE IN THE FUNCTIONAL STATUS OF THE REPAIR MACHINERY USING A BRONCHIAL EPITHELIAL CELL MODEL. AIM 2.TO TEST THE HYPOTHESIS THAT GCR EXPOSURE LEADS TO A CHRONIC DNA DAMAGE RESPONSE IN MOUSE LUNG AND WHETHER THIS CAN BE ABATED WITH A DIETARY COUNTERMEASURE. WE WILL INVESTIGATE GENDER DOSE AND RADIATION QUALITY EFFECTS. AIM 3. TO DETERMINE WHETHER RADIOGENIC TUMORS DISPLAY A MUTATIONAL SIGNATURE INDICATIVE OF A DECLINE IN THE FUNCTIONAL STATUS OF THE DNA REPAIR MACHINERY AS REFLECTED IN THEIR MUTATIONAL SIGNATURE THUS ESTABLISHING A FUNCTIONAL LINK TO TUMORIGENESIS. ANTICIPATED DELIVERABLES INCLUDE RESEARCH RESULTS TO IMPROVE EVALUATION OF SEX DEPENDENCE OF RADIOGENIC LUNG CANCER; TO ALLOW FOR CALCULATION OF RBES INCLUDING MIXED FIELD RBES FOR MALES AND FEMALES PARTICULARLY AT LOW DOSES AND IN WILD TYPE BACKGROUNDS WHERE DIRECT MEASUREMENTS OF RBE FOR RADIATION-INDUCED CANCERS IS INFEASIBLE OR SUBJECT TO LARGE EXPERIMENTAL UNCERTAINTIES AND TO PERFORM AN INITIAL EVALUATION OF A POTENTIAL COUNTERMEASURE., Monitoring the interactions between cancer cell metabolism and radiation response, G7958047629
OpenAlex ID: W4306770621