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Project Title:  Gamma-Tocotrienol as a Countermeasure against High-Energy Charged Particle-Induced Carcinogenesis, Cardiovascular Disease, and Central Nervous System Effects Reduce
Images: icon  Fiscal Year: FY 2021 
Division: Human Research 
Research Discipline/Element:
HRP SR:Space Radiation
Start Date: 01/31/2019  
End Date: 10/31/2022  
Task Last Updated: 12/01/2020 
Download report in PDF pdf
Principal Investigator/Affiliation:   Boerma, Marjan  Ph.D. / University of Arkansas, Little Rock 
Address:  4301 W. Markham Street, Slot 522-10 
Slot 522-10 
Little Rock , AR 72205-7101 
Email: mboerma@uams.edu 
Phone: 501-686-6599  
Congressional District:
Web:  
Organization Type: UNIVERSITY 
Organization Name: University of Arkansas, Little Rock 
Joint Agency:  
Comments:  
Co-Investigator(s)
Affiliation: 
Landes, Reid  Ph.D. University of Arkansas, Little Rock 
Weil, Michael  Ph.D. Colorado State University 
Pathak, Rupak  Ph.D. University of Arkansas, Little Rock 
Key Personnel Changes / Previous PI: December 2020 report: No changes in PI or other key personnel.
Project Information: Grant/Contract No. 80NSSC19K0437 
Responsible Center: NASA JSC 
Grant Monitor: Elgart, Robin  
Center Contact: 281-244-0596 (o)/832-221-4576 (m) 
shona.elgart@nasa.gov 
Solicitation / Funding Source: 2017-2018 HERO 80JSC017N0001-BPBA Topics in Biological, Physiological, and Behavioral Adaptations to Spaceflight. Appendix C 
Grant/Contract No.: 80NSSC19K0437 
Project Type: GROUND 
Flight Program:  
TechPort: No 
No. of Post Docs:  
No. of PhD Candidates:  
No. of Master's Candidates:  
No. of Bachelor's Candidates:  
No. of PhD Degrees:  
No. of Master's Degrees:  
No. of Bachelor's Degrees:  
Human Research Program Elements: (1) SR:Space Radiation
Human Research Program Risks: (1) Bmed:Risk of Adverse Behavioral Conditions and Psychiatric Disorders
(2) Cancer:Risk of Radiation Carcinogenesis
(3) CVD:Risk of Spaceflight Induced Cardiovascular Disease (IRP Rev L)
Human Research Program Gaps: (1) BMed-103:What are the validated, efficacious treatments (individual or Team-based) and/or countermeasures to prevent adverse behavioral conditions, CNS/neurological, and/or psychiatric disorders caused by either single and/or integrated exposures to spaceflight hazards during exploration class missions? (IRP Rev L)
(2) BMed-104:Given the potentially negative spaceflight associated CNS changes and behavioral experiences of stressors during long-duration missions (e.g., isolation, confinement, reduced sensory stimulation, altered gravity, space radiation), what are validated modifications to habitat/vehicle to mitigate stressors impacting on CNS / cognition / behavioral health? (IRP Rev L)
(3) BMed-105:Given the potentially negative spaceflight associated CNS/cognitive changes and behavioral experiences of stressors during long-duration missions (e.g., isolation, confinement, reduced sensory stimulation, altered gravity, space radiation), what are validated medical or dietary countermeasures to mitigate stressors impacting on CNS / cognition / behavioral health? (IRP Rev L)
(4) Cancer-302:Identify tissue-specific surrogate end-points for space radiation induced pre-malignancy and shared biology with other degenerative diseases (IRP Rev L)
(5) Cancer-501:Identify and translate countermeasures to reduce radiation carcinogenesis and degenerative risks with shared biology (IRP Rev L)
(6) CVD-202:Develop and ground-test countermeasures against the spaceflight-induced changes in the cardiovascular system of importance for development of disease (IRP Rev L)
Flight Assignment/Project Notes: NOTE: End date changed to 10/31/2022 per NSSC information (Ed., 5/17/21)

NOTE: End date changed to 3/31/2022 per NSSC information (Ed., 11/4/20)

Task Description: Recent evidence shows that radiation encountered during deep space travel is associated with increased risks of cancer. Administration of a dietary radiation countermeasure before and/or during the mission is an attractive option to reduce the carcinogenesis risk. Gamma-tocotrienol is one of the strongest radiation protectors of all natural compounds tested so far. It is safe, non-toxic and well tolerated, exhibits no interactions with other medications and requires no special storage conditions. It has anti-oxidant and anti-inflammatory properties and protects against endothelial dysfunction. Moreover, studies with tocotrienol administration in human subjects and animal models have shown cancer prevention. In our preliminary studies, gamma-tocotrienol reduced radiation-induced genomic instability, as detected by studying chromosomal aberrations, in human endothelial cells and in bone marrow cells of gamma-ray exposed mice. Altogether, based on its safety profile, biological properties, and our preliminary results, gamma-tocotrienol has high potential as radiation countermeasure during space travel. Here, we use a mouse model to test whether gamma-tocotrienol protects against radiation-induced carcinogenesis. For this purpose, genetically modified mice will be used that show a low spontaneous cancer rate, but increased tumor incidence in response to low-dose radiation. Male and female adult mice will be exposed to mixed charged particle beams to mimic galactic cosmic rays at the NASA Space Radiation Laboratory. Twenty-four hours before each radiation exposure, mice will be administered gamma-tocotrienol. Mice will be followed for 18 months after irradiation and inspected daily for tumor formation. In addition, bone marrow cells will be collected to assess the effects of gamma-tocotrienol on genomic instability by cytogenetic analysis. These studies will advance the countermeasure readiness level of gamma-tocotrienol against carcinogenesis risks of space radiation.

Research Impact/Earth Benefits: There is concern about increased carcinogenesis risk after chronic exposures to low-dose ionizing radiation, such as from medical treatments, occupational low-dose exposures, and radiological accidents. The current project will provide evidence for gamma-tocotrienol as a safe countermeasure against radiation-induced carcinogenesis. This information will not only contribute to reducing the risk of radiation exposure during deep-space travel, but also the risks of carcinogenesis from exposure to low-dose rate radiation exposures on Earth.

Task Progress & Bibliography Information FY2021 
Task Progress: A total of 387 male and female P53deltaP mice (on an FVB/Jax genetic background) of the age of ~6 months were transported from a breeding colony at the University of Arkansas for Medical Sciences to Brookhaven National Laboratory. A total of 129 mice were assigned to the control group, 129 mice were exposed to a single dose of 0.75 Gy full-spectrum simulated galactic cosmic rays at the NASA Space Radiation Laboratory, and 129 mice were exposed to a single dose of 3 Gy gamma-rays. After irradiation, all mice were transported to Colorado State University where they are being followed for 18 months after irradiation to determine tumor formation. The mice are currently at the age of ~1 year. In all groups, about 50% of all males and 70-80% of all females have developed cancer. It is yet to soon after radiation exposure to draw conclusions on the effects of gamma or galactic cosmic rays on tumorigenesis.

Bibliography Type: Description: (Last Updated: 11/11/2021)  Show Cumulative Bibliography Listing
 
Articles in Peer-reviewed Journals Upadhyay M, Rajagopal M, Gill K, Li Y, Bansal S, Sridharan V, Tyburski JB, Boerma M, Cheema AK. "Identification of plasma lipidome changes associated with low dose space-type radiation exposure in a murine model." Metabolites. 2020 Jun 17;10(6):E252. https://doi.org/10.3390/metabo10060252 ; PMID: 32560360; PMCID: PMC7345467 , Jun-2020
Articles in Peer-reviewed Journals Sridharan V, Seawright JW, Landes RD, Cao M, Singh P, Davis CM, Mao XW, Singh SP, Zhang X, Nelson GA, Boerma M. "Effects of single-dose protons or oxygen ions on function and structure of the cardiovascular system in male Long Evans rats." Life Sci Space Res (Amst). 2020 Aug;26:62-8. https://doi.org/10.1016/j.lssr.2020.04.002 ; PMID: 32718688; PMCID: PMC7387753 , Aug-2020
Project Title:  Gamma-Tocotrienol as a Countermeasure against High-Energy Charged Particle-Induced Carcinogenesis, Cardiovascular Disease, and Central Nervous System Effects Reduce
Images: icon  Fiscal Year: FY 2020 
Division: Human Research 
Research Discipline/Element:
HRP SR:Space Radiation
Start Date: 01/31/2019  
End Date: 03/31/2022  
Task Last Updated: 11/12/2019 
Download report in PDF pdf
Principal Investigator/Affiliation:   Boerma, Marjan  Ph.D. / University of Arkansas, Little Rock 
Address:  4301 W. Markham Street, Slot 522-10 
Slot 522-10 
Little Rock , AR 72205-7101 
Email: mboerma@uams.edu 
Phone: 501-686-6599  
Congressional District:
Web:  
Organization Type: UNIVERSITY 
Organization Name: University of Arkansas, Little Rock 
Joint Agency:  
Comments:  
Co-Investigator(s)
Affiliation: 
Landes, Reid  Ph.D. University of Arkansas, Little Rock 
Weil, Michael  Ph.D. Colorado State University 
Pathak, Rupak  Ph.D. University of Arkansas, Little Rock 
Key Personnel Changes / Previous PI: November 2019 report: No changes.
Project Information: Grant/Contract No. 80NSSC19K0437 
Responsible Center: NASA JSC 
Grant Monitor:  
Center Contact:   
Solicitation / Funding Source: 2017-2018 HERO 80JSC017N0001-BPBA Topics in Biological, Physiological, and Behavioral Adaptations to Spaceflight. Appendix C 
Grant/Contract No.: 80NSSC19K0437 
Project Type: GROUND 
Flight Program:  
TechPort: No 
No. of Post Docs:  
No. of PhD Candidates:  
No. of Master's Candidates:  
No. of Bachelor's Candidates:  
No. of PhD Degrees:  
No. of Master's Degrees:  
No. of Bachelor's Degrees:  
Human Research Program Elements: (1) SR:Space Radiation
Human Research Program Risks: (1) Bmed:Risk of Adverse Behavioral Conditions and Psychiatric Disorders
(2) Cancer:Risk of Radiation Carcinogenesis
(3) CVD:Risk of Spaceflight Induced Cardiovascular Disease (IRP Rev L)
Human Research Program Gaps: (1) BMed-103:What are the validated, efficacious treatments (individual or Team-based) and/or countermeasures to prevent adverse behavioral conditions, CNS/neurological, and/or psychiatric disorders caused by either single and/or integrated exposures to spaceflight hazards during exploration class missions? (IRP Rev L)
(2) BMed-104:Given the potentially negative spaceflight associated CNS changes and behavioral experiences of stressors during long-duration missions (e.g., isolation, confinement, reduced sensory stimulation, altered gravity, space radiation), what are validated modifications to habitat/vehicle to mitigate stressors impacting on CNS / cognition / behavioral health? (IRP Rev L)
(3) BMed-105:Given the potentially negative spaceflight associated CNS/cognitive changes and behavioral experiences of stressors during long-duration missions (e.g., isolation, confinement, reduced sensory stimulation, altered gravity, space radiation), what are validated medical or dietary countermeasures to mitigate stressors impacting on CNS / cognition / behavioral health? (IRP Rev L)
(4) Cancer-302:Identify tissue-specific surrogate end-points for space radiation induced pre-malignancy and shared biology with other degenerative diseases (IRP Rev L)
(5) Cancer-501:Identify and translate countermeasures to reduce radiation carcinogenesis and degenerative risks with shared biology (IRP Rev L)
(6) CVD-202:Develop and ground-test countermeasures against the spaceflight-induced changes in the cardiovascular system of importance for development of disease (IRP Rev L)
Flight Assignment/Project Notes: NOTE: End date changed to 3/31/2022 per NSSC information (Ed., 11/4/20)

Task Description: Recent evidence shows that radiation encountered during deep space travel is associated with increased risks of cancer. Administration of a dietary radiation countermeasure before and/or during the mission is an attractive option to reduce the carcinogenesis risk. Gamma-tocotrienol is one of the strongest radiation protectors of all natural compounds tested so far. It is safe, non-toxic and well tolerated, exhibits no interactions with other medications and requires no special storage conditions. It has anti-oxidant and anti-inflammatory properties and protects against endothelial dysfunction. Moreover, studies with tocotrienol administration in human subjects and animal models have shown cancer prevention. In our preliminary studies, gamma-tocotrienol reduced radiation-induced genomic instability, as detected by studying chromosomal aberrations, in human endothelial cells and in bone marrow cells of gamma-ray exposed mice. Altogether, based on its safety profile, biological properties, and our preliminary results, gamma-tocotrienol has high potential as radiation countermeasure during space travel. Here, we use a mouse model to test whether gamma-tocotrienol protects against radiation-induced carcinogenesis. For this purpose, genetically modified mice will be used that show a low spontaneous cancer rate, but increased tumor incidence in response to low-dose radiation. Male and female adult mice will be exposed to mixed charged particle beams to mimic galactic cosmic rays at the NASA Space Radiation Laboratory. Twenty-four hours before each radiation exposure, mice will be administered gamma-tocotrienol. Mice will be followed for 18 months after irradiation and inspected daily for tumor formation. In addition, bone marrow cells will be collected to assess the effects of gamma-tocotrienol on genomic instability by cytogenetic analysis. These studies will advance the countermeasure readiness level of gamma-tocotrienol against carcinogenesis risks of space radiation.

Research Impact/Earth Benefits: There is concern about increased carcinogenesis risk after chronic exposures to low-dose ionizing radiation, such as from medical treatments, occupational low-dose exposures, and radiological accidents. The current project will provide evidence for gamma-tocotrienol as a safe countermeasure against radiation-induced carcinogenesis. This information will not only contribute to reducing the risk of radiation exposure during deep-space travel, but also the risks of carcinogenesis from exposure to low-dose rate radiation exposures on Earth.

Task Progress & Bibliography Information FY2020 
Task Progress: This is the progress report of year 1 of this project. The project is on schedule.

This project makes use of a transgenic mouse model with a mutation in the p53 gene (P53 deltaP mice) on a mixed 129/SvJ and C57BL/6J background. These mice are not commercially available and need to be bred in-house. A breeding colony was established and is on schedule to produce >500 male and female mice as required for this project in year 2.

In year 2 of the project, we plan to transport >500 mice to Brookhaven National Laboratory for exposure to simulated galactic cosmic rays at the NASA Space Radiation Laboratory. Twenty-four hours before irradiation, mice will be administered gamma-tocotrienol or vehicle. After irradiation, mice will be shipped to Colorado State University and the University of Arkansas for Medical Sciences for follow-up.

Bibliography Type: Description: (Last Updated: 11/11/2021)  Show Cumulative Bibliography Listing
 
 None in FY 2020
Project Title:  Gamma-Tocotrienol as a Countermeasure against High-Energy Charged Particle-Induced Carcinogenesis, Cardiovascular Disease, and Central Nervous System Effects Reduce
Images: icon  Fiscal Year: FY 2019 
Division: Human Research 
Research Discipline/Element:
HRP SR:Space Radiation
Start Date: 01/31/2019  
End Date: 01/30/2021  
Task Last Updated: 03/29/2019 
Download report in PDF pdf
Principal Investigator/Affiliation:   Boerma, Marjan  Ph.D. / University of Arkansas, Little Rock 
Address:  4301 W. Markham Street, Slot 522-10 
Slot 522-10 
Little Rock , AR 72205-7101 
Email: mboerma@uams.edu 
Phone: 501-686-6599  
Congressional District:
Web:  
Organization Type: UNIVERSITY 
Organization Name: University of Arkansas, Little Rock 
Joint Agency:  
Comments:  
Co-Investigator(s)
Affiliation: 
Landes, Reid  Ph.D. University of Arkansas, Little Rock 
Weil, Michael  Ph.D. Colorado State University 
Pathak, Rupak  Ph.D. University of Arkansas, Little Rock 
Project Information: Grant/Contract No. 80NSSC19K0437 
Responsible Center: NASA JSC 
Grant Monitor: Simonsen, Lisa  
Center Contact:  
lisa.c.simonsen@nasa.gov 
Solicitation / Funding Source: 2017-2018 HERO 80JSC017N0001-BPBA Topics in Biological, Physiological, and Behavioral Adaptations to Spaceflight. Appendix C 
Grant/Contract No.: 80NSSC19K0437 
Project Type: GROUND 
Flight Program:  
TechPort: No 
No. of Post Docs:  
No. of PhD Candidates:  
No. of Master's Candidates:  
No. of Bachelor's Candidates:  
No. of PhD Degrees:  
No. of Master's Degrees:  
No. of Bachelor's Degrees:  
Human Research Program Elements: (1) SR:Space Radiation
Human Research Program Risks: (1) Bmed:Risk of Adverse Behavioral Conditions and Psychiatric Disorders
(2) Cancer:Risk of Radiation Carcinogenesis
(3) CVD:Risk of Spaceflight Induced Cardiovascular Disease (IRP Rev L)
Human Research Program Gaps: (1) BMed-103:What are the validated, efficacious treatments (individual or Team-based) and/or countermeasures to prevent adverse behavioral conditions, CNS/neurological, and/or psychiatric disorders caused by either single and/or integrated exposures to spaceflight hazards during exploration class missions? (IRP Rev L)
(2) BMed-104:Given the potentially negative spaceflight associated CNS changes and behavioral experiences of stressors during long-duration missions (e.g., isolation, confinement, reduced sensory stimulation, altered gravity, space radiation), what are validated modifications to habitat/vehicle to mitigate stressors impacting on CNS / cognition / behavioral health? (IRP Rev L)
(3) BMed-105:Given the potentially negative spaceflight associated CNS/cognitive changes and behavioral experiences of stressors during long-duration missions (e.g., isolation, confinement, reduced sensory stimulation, altered gravity, space radiation), what are validated medical or dietary countermeasures to mitigate stressors impacting on CNS / cognition / behavioral health? (IRP Rev L)
(4) Cancer-302:Identify tissue-specific surrogate end-points for space radiation induced pre-malignancy and shared biology with other degenerative diseases (IRP Rev L)
(5) Cancer-501:Identify and translate countermeasures to reduce radiation carcinogenesis and degenerative risks with shared biology (IRP Rev L)
(6) CVD-202:Develop and ground-test countermeasures against the spaceflight-induced changes in the cardiovascular system of importance for development of disease (IRP Rev L)
Task Description: Recent evidence shows that radiation encountered during deep space travel is associated with increased risks of cancer, cardiovascular disease, and adverse effects in the central nervous system. Administration of a dietary radiation countermeasure before and/or during the mission is an attractive option to reduce the risk of carcinogenesis and degenerative effects in the heart and brain. Gamma-tocotrienol is one of the strongest radiation protectors of all natural compounds tested so far. It is safe, non-toxic and well tolerated, exhibits no interactions with other medications and requires no special storage conditions. It has anti-oxidant and anti-inflammatory properties and protects against endothelial dysfunction. Moreover, studies with tocotrienol administration in human subjects and animal models have shown cancer prevention and protection against brain white matter lesions. In our preliminary studies, gamma-tocotrienol reduced radiation-induced genomic instability, as detected by studying chromosomal aberrations, in human endothelial cells and in bone marrow cells of gamma-ray exposed mice. Moreover, gamma-tocotrienol reduced changes in behavior and cardiac function in a mouse model of exposure to high-energy oxygen ions. Altogether, based on its safety profile, biological properties, and our preliminary results, gamma-tocotrienol has high potential as radiation countermeasure during space travel. Here, we aim to use a mouse model of exposure to modeled galactic cosmic rays to test whether gamma-tocotrienol protects against 1) carcinogenesis, 2) changes in behavior, dendritic morphology, and synaptic plasticity, and 3) changes in cardiac and vascular function and structure. Carcinogenesis will be assessed in genetically modified mice that show a low spontaneous cancer rate but increased tumor incidence in response to low-dose radiation. Degenerative tissue effects will be assessed in wild-type mice. Male and female adult mice will be exposed to mixed charged particle beams or gamma-rays as a reference radiation, in five once-a-day fractions at the NASA Space Radiation Laboratory. Twenty-four hours before each radiation exposure, mice will receive an oral dose of gamma-tocotrienol. Mice will be followed for 18 months after irradiation and inspected daily for tumor formation. Bone marrow cells will be collected to assess the effects of gamma-tocotrienol on genomic instability by cytogenetic analysis. Additional cohorts of mice will be used to assess cognitive and cardiovascular function. At 12 months after irradiation, mice in these subcohorts will be sacrificed to collect blood samples, and brain and heart tissue for histological analysis. These studies will advance the countermeasure readiness level of gamma-tocotrienol against risks of both carcinogenesis and degenerative tissue effects of space radiation.

Research Impact/Earth Benefits:

Task Progress & Bibliography Information FY2019 
Task Progress: New project for FY2019.

Bibliography Type: Description: (Last Updated: 11/11/2021)  Show Cumulative Bibliography Listing
 
 None in FY 2019