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Project Title:  Countermeasures Against Adverse Effects of Space Radiation Reduce
Images: icon  Fiscal Year: FY 2021 
Division: Human Research 
Research Discipline/Element:
HRP SR:Space Radiation
Start Date: 01/31/2019  
End Date: 05/30/2022  
Task Last Updated: 12/31/2020 
Download report in PDF pdf
Principal Investigator/Affiliation:   Rithidech, Kanokporn  Ph.D. / State University New York at Stony Brook 
Address:  Department of Pathology 
BHS T9 Health Sciences Center 
Stony Brook , NY 11794-8691 
Email: Kanokporn.Rithidech@sbumed.org 
Phone: (631) 444-3446  
Congressional District:
Web:  
Organization Type: UNIVERSITY 
Organization Name: State University New York at Stony Brook 
Joint Agency:  
Comments:  
Project Information: Grant/Contract No. 80NSSC19K0435 
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.: 80NSSC19K0435 
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) Cancer:Risk of Radiation Carcinogenesis
Human Research Program Gaps: (1) Cancer-502:Systematically identify safe and effective countermeasures to reduce radiation carcinogenesis (IRP Rev M)
Flight Assignment/Project Notes: NOTE: End date changed to 5/30/2022 per NSSC information (Ed., 3/29/21)

Task Description: This is the task book for the Phase 1 study of our project entitled “Countermeasures against adverse effects of space radiation” in which only male mice are included. The primary goal of our Phase 1 study is to test the efficacy of apigenin (AP) for the prevention and mitigation of cancer in male mice due to exposure to space radiation. We gave food containing AP to male mice before and after exposure to 28Si ions. There are four groups of mice. These are sham controls (Group 1, no AP diet, no radiation), mice receiving 0.5 Gy of 260 MeV/n 28Si ions radiation only and without AP diet (Group 2), mice receiving AP only with no radiation exposure (Group 3), and mice receiving both AP and radiation (Group 4). Groups of mice from each treatment were used for a serial sacrifice schedule at 1-week and 1-year post-irradiation. This will test the ability of AP to counteract heavy-ion-induced early- and late-occurring inflammation in various tissues linked to cancer that are the focus of our study, i.e. bone marrow (BM) and lung. All remaining mice will be observed for morbidity and mortality until they reach about 600-700 days of age. Our data enable the evaluation of countermeasure efficacy of AP across tissues at risk for cancer induction, i.e. BM and the lung. This multi-tissue of the same exposed individual approach has not been used in space research. At 1-week (wk) post-irradiation, a total of six mice from each treatment group were randomly selected for sample collection. We collected blood, BM, lung, spleen, and thymus from the same individual mouse for further analyses. A fraction of blood was used to evaluate the hematological parameters, e.g. white blood cells, red blood cells, and platelets. The remainder of each blood sample was used for plasma preparation, to be used for future molecular analyses (i.e. inflammation and oxidative damage). We also investigated the countermeasure effectiveness of AP against 28Si-ion-induced damage to the hematopoietic stem cell (HSC) compartment of exposed mice. We used the well-established colony-forming unit assay (CFU-A) as a tool for this purpose. This is important because the HSCs are believed to be cells most at risk for leukemia induction. The BM cells from each mouse were used to determine the levels of activated nuclear factor-kappa B (NF-kappa B), and NF-kappa B-regulated pro-inflammatory cytokines (i.e. TNF-alpha, IL-1alpha, IL-1 beta, and IL-6). Further, we investigated the effectiveness of AP in reducing the frequencies of chromosome aberrations (determined by the in vivo blood erythrocytes micronucleus assay) since a high frequency of chromosome aberrations (CAs) is linked to the induction of genomic instability. It is known that a high level of genomic instability is associated with a high risk of cancer induction.

Research Impact/Earth Benefits: Despite significant efforts, advances in developing radiation countermeasures, both those given before (protectors) and after (mitigators) radiation exposure are still an unmet need. Hence, the search for efficient countermeasures is at high priority to protect the victims in the event of nuclear terrorism or accident, as well as in the battlefield (in the event of radiological explosive devices are used), as well as astronauts and space travelers. In this project, our primary goal is to test the efficacy of AP for the prevention and mitigation of cancer due to space radiation exposure. It has been well characterized that radiation-induced hematopoietic failure is the major detrimental biological effects. This is mostly due to the extensive suppression of lymphocytes, platelets, including damage to stem and progenitor cells. Such shortages increase the risk of infection, inflammation, hemorrhage, and death. Further, any induced damage in the HSC compartment, if not repaired, will be carried onto the next generation and adversely impacted self-renewal, proliferation, as well as untoward health outcomes later in life. Our resulting data obtained from the analyses of samples collected from groups of mice at 1-wk post-irradiation are the first set of data demonstrating the countermeasure efficacy of AP given as a diet supplement to irradiated mice. Our results indicate that AP prevents a loss of white blood cells (leukopenia), inhibits the depletion of platelets (thrombocytopenia), enhances the production of red blood cells (erythropoiesis), and increases the proliferation capacity of hematopoietic stem/progenitor cells (HSPCs). Moreover, we also found that AP consumption reduces the frequencies of radiation-induced chromosome aberrations (CAs) in the BM cells of exposed mice. It is known that the occurrence of CAs is closely linked to the induction of genomic instability (a critical event in cancer induction). Therefore, our findings are of paramount significance in radiation protection during the space mission and on earth. Further, our data on the efficacy of AP in protection/prevention and/or mitigation of radiation-induced cancer will have a significant impact on the future development of a novel therapeutic strategy to prevent or mitigate the acute or long-term effects of radiation during a space mission, in the event of radiobiological events on earth, (e.g. a nuclear accident or terrorisms) or in the battlefield.

Task Progress & Bibliography Information FY2021 
Task Progress: Our data from samples collected at 1-wk post-irradiation from groups of mice show the efficacy of AP in protection and mitigation against radiation-induced injuries in hematopoietic cells of exposed mice. The first set of our data demonstrate for the first time the effectiveness of AP given to mice via food consumption (AP 20 mg/kg/bw) in counteracting injuries to the hematopoietic tissues induced by space radiation (28Si ions). The highlights of our data are: AP prevents a loss of white blood cells (leukopenia), AP prevents the depletion of platelets (thrombocytopenia), AP enhances the production of red blood cells (erythropoiesis), and AP enhances the proliferation capacity of hematopoietic stem/progenitor cells.. Further, we found that AP is very effective in the suppression of inflammation. Our results suggest that AP given as a diet supplement protects 28Si-ion-induced damage in the hematopoietic tissues of irradiated male C57BL/6 mice via its anti-inflammation activity. In summary, our data clearly show the efficacy of AP in counteracting radiation-induced harmful effects on the hematopoietic system. Further, consumption of AP at 20 mg/kg body weight does not induce damage to the hematopoietic system of exposed mice. In contrast, AP consumption significantly enhances HSPC proliferation. These findings strongly suggested that daily consumption of AP is safe.

Bibliography Type: Description: (Last Updated: 01/01/2021) 

Show Cumulative Bibliography Listing
 
Abstracts for Journals and Proceedings Rithidech K, Peanlikhit T, Honikel L, Zimmerman T. "Countermeasure efficacy of apigenin given as a diet supplement before and after exposure of mice to silicon ions on hematopoietic tissues." To be presented at the virtual 2021 NASA Human Research Program Investigators' Workshop, February 1st 2021.

2021 NASA Human Research Program Investigators’ Workshop, Virtual, February 1-4, 2021. , Feb-2021

Abstracts for Journals and Proceedings Peanlikhit T, Honikel L, Rithidech K. "Apigenin as a countermeasure for chromosome aberrations induced by whole-body exposure to silicon (28Si) ion." To be presented at the virtual 2021 NASA Human Research Program Investigators’ Workshop, Virtual, February 1-4, 2021.

2021 NASA Human Research Program Investigators’ Workshop, Virtual, February 1-4, 2021. , Feb-2021

Abstracts for Journals and Proceedings Rithidech K, Peanlikhit T, Zimmerman T, Honikel L, Whorton E. "Apigenin counteracts adverse effects of space radiation to the hematopoietic system." Presented at the 2020 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 27-30, 2020.

Abstracts. 2020 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 27-30, 2020. , Jan-2020

Articles in Peer-reviewed Journals Rithidech KN, Mortazavi SMJ, Brooks AL. "Letter to Editor Re: Fang et al. entitled 'Assessment of genomic instability in medical workers exposed to chronic low-dose X-Rays in Northern China.' " Dose Response. 2020 Apr-Jun;18(2):1559325820922101. https://doi.org/10.1177/1559325820922101 ; PMID: 32577116; PMCID: PMC7288825 [The authors comment on the article by Fang et al. in Dose Response. 2019 Nov 28;17(4):1559325819891378. PMID: 31819742] , Apr-2020
Project Title:  Countermeasures Against Adverse Effects of Space Radiation Reduce
Images: icon  Fiscal Year: FY 2020 
Division: Human Research 
Research Discipline/Element:
HRP SR:Space Radiation
Start Date: 01/31/2019  
End Date: 05/30/2021  
Task Last Updated: 12/12/2019 
Download report in PDF pdf
Principal Investigator/Affiliation:   Rithidech, Kanokporn  Ph.D. / State University New York at Stony Brook 
Address:  Department of Pathology 
BHS T9 Health Sciences Center 
Stony Brook , NY 11794-8691 
Email: Kanokporn.Rithidech@sbumed.org 
Phone: (631) 444-3446  
Congressional District:
Web:  
Organization Type: UNIVERSITY 
Organization Name: State University New York at Stony Brook 
Joint Agency:  
Comments:  
Project Information: Grant/Contract No. 80NSSC19K0435 
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.: 80NSSC19K0435 
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) Cancer:Risk of Radiation Carcinogenesis
Human Research Program Gaps: (1) Cancer-502:Systematically identify safe and effective countermeasures to reduce radiation carcinogenesis (IRP Rev M)
Task Description: The space environment consists of various types of radiation that are different from those found in the Earth's atmosphere. These include particles with high mass and high energy (heavy particles) such as silicon. Hence, exposure to radiation in space is the greatest hazard to astronauts venturing beyond Earth. It is therefore important to protect astronauts in space environments. To date, the use of shielding materials to prevent radiation exposure in space is inadequate. Consequently, the search for efficient medical countermeasures (protectors, those given prior to exposure; mitigators, those given after exposure) is at high priority in radiation protection in space, as well as on Earth.

This is the first task book for Phase 1 study of our project entitled “Countermeasures against adverse effects of space radiation.” The primary goal of our Phase 1 study is to test the efficacy of apigenin (AP) for the prevention and mitigation of cancer in male mice due to exposure to space radiation as measured by incidence, aggressiveness, burden, and latency. Our main hypothesis is that AP exhibits its beneficial effects by suppression of radiation-induced inflammation and oxidative stress during the initiation/promotion steps of carcinogenesis. Although the emphasis will be on the mitigation of lung cancer and lymphoma/leukemia, other types of cancer will be recorded.

In this project, we will give food containing AP to male mice before and after exposure to heavy silicon (28Si) ions. There are four groups of mice. These are sham controls (Group 1, no AP diet, no radiation), mice receiving 0.5 Gy of 260 MeV/n 28Si ions radiation only and without AP diet (Group 2), mice receiving AP only with no radiation exposure (Group 3), and mice receiving both AP and radiation (Group 4). Groups of mice from each treatment will be used for a serial sacrifice schedule at 1 week and 6 months post-irradiation. This will test the ability of AP to counteract heavy-ion-induced early- and late-occurring inflammation and oxidative damage in various tissues linked to cancer that are the focus of our study (i.e., bone marrow, lung, thymus, spleen). All remaining mice will be observed for morbidity and mortality until they reach about 700 days of age. Our data enable the evaluation of countermeasure efficacy of AP across tissues at risk for cancer induction, i.e., bone marrow and the lung. This multi-tissue of the same exposed individual approach has not been used in space research.

We will also determine the hematological parameters [i.e., white blood cells (WBCs), red blood cells (RBCs), and platelets] collected from the same individual mouse included in the serial sacrifice schedule. It is important to evaluate the hematological parameters after exposure to radiation since it has been well characterized that radiation [either low or high LET (linear energy transfer) radiation found on Earth or in the space environment] induces hematological changes that can further induce the impairment of the immune system enabling susceptibility to infection and inflammation. Ultimately, such detrimental effects from exposure to radiation can lead to cancer and other chronic diseases.

Further, we will evaluate the efficacy of AP in protection/mitigation against 28Si-ion-induced damage in the hematopoietic stem cell (HSC) compartment in mice included in the serial sacrifice schedule. Our approach is important since the hallmark properties of the hematopoietic stem cells (HSCs) are the capability of self-renewal and proliferation with pluripotent potentials to give rise to various types of differentiated and functional progenitor cells. Hence, any induced damage in the HSC compartment, if not repair, will be carried onto the next generation an adversely impacted self-renewal and proliferation. Further, it has been well recognized that the HSC compartment is the site of the target cells for radiation-induced leukemia.

Research Impact/Earth Benefits: To date, intense efforts have been made to identify agents that can attenuate radiation injuries when given before and after exposure to radiation found on Earth and those found in the space environment. However, novel radiation-countermeasures remain an unmet need for counteracting radiation-induced injuries in exposed individuals. Hence, the search for agents that are safe, easily administered, and effective in diminishing adverse health effects to exposed individuals are urgently needed. In this project, our primary goal is to test the efficacy of AP for the prevention and mitigation of cancer due to space radiation exposure. Our results will fill such a gap of knowledge in radiation countermeasures during the space mission or on Earth.

It has been well characterized that radiation-induced hematopoietic failure is the major detrimental biological effects. This is mostly due to the substantial suppression of lymphocytes, platelets, including damage to stem and progenitor cells. Such shortages increase the risk of infection, inflammation, hemorrhage, and death. Further, any induced damage in the HSC compartment, if not repaired, will be carried onto the next generation and adversely impacted self-renewal, proliferation, as well as untoward health outcomes later in life. Our first set of data strongly demonstrate that AP (given before and after irradiation) prevents a loss of white blood cells (leukopenia), inhibits the depletion of platelets (thrombocytopenia), enhances the production of red blood cells (erythropoiesis), and increases the proliferation capacity of hematopoietic stem/progenitor cells (HSPCs). Hence, our findings are of paramount significance not only in radiation protection during the space mission but also in the improvement of radiation therapy on Earth.

Further, our data on the efficacy of AP in protection/prevention and/or mitigation of radiation-induced cancer will have a significant impact on the future development of a novel therapeutic strategy to prevent or mitigate the acute or long-term effects of radiation in the event of radiobiological events on Earth, (e.g. a nuclear accident, or terrorisms) or from combats in the battlefield.

Task Progress & Bibliography Information FY2020 
Task Progress: We completed the exposure of male C57BL/6 mice to 0 (sham controls) or 0.5 Gy of 260 MeV/n 28Si ions (delivered at 0.5 Gy/min) on November 21, 2019. We also completed the collection of several tissues for further molecular analyses from the same individual mice included in the sacrifice schedule at d 7 post-irradiation. These samples are blood, BM, lung, spleen, and thymus. A fraction of blood was used to evaluate the hematological parameters, e.g., white blood cells (WBCs), red blood cells (RBCs), and platelets (PLTs). The resulting data are used to determine the efficacy of AP in the protection and mitigation of 28Si-ion-induced damage to the hematopoietic tissue. The remaining of each blood sample was used for plasma preparation and stored in a -80oC freezer for future molecular analyses. To date, we have completed the analyses of hematological parameters and the countermeasure effectiveness of AP against 28Si ion-induced damage in the hematopoietic stem cell compartment in samples collected at 1 wk post-irradiation.

The highlights of our findings are:

(1) AP prevents a loss of white blood cells (leukopenia),

(2) AP enhances the production of red blood cells (erythropoiesis),

(3) AP prevents depletion of platelets (thrombocytopenia),

(4) AP protects and enhances the proliferation capacity of hematopoietic stem/progenitor cells (HSPCs), and

(5) AP maintains homeostasis of the hematopoietic system.

This set of data is the first and significant indicator of protective and mitigative effectiveness of AP against hematopoietic failure. The data strongly supports our hypothesis in using AP as a countermeasure against space-radiation-induced harmful effects during spaceflights. We will present this set of data at the 2020 NASA Human Research Program, to be held in January 2020, Galveston TX.

Plan for the next fiscal year: (1) Monitoring of mice for morbidity and mortality and histological evaluation, (2) Measurements of the levels of multiple cytokines with various biological functions in various tissues collected at d 7 post-irradiation from the same individual mouse, (3) Measurements of the levels of NF-kB, and p38 MAPK activation. In the same tissues that will be used for measuring cytokines, (4) Measurements the levels of enzymes involved in oxidative damage, and (5) Serial sacrifice at 6 mos post-irradiation for further molecular analyses.

Bibliography Type: Description: (Last Updated: 01/01/2021) 

Show Cumulative Bibliography Listing
 
Abstracts for Journals and Proceedings Rithidech K, Peanlikhit T, Whorton EB. "Countermeasures against adverse effects of space radiation." Space Radiation session. To be presented at 2020 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 27-30, 2020.

Abstracts. 2020 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 27-30, 2020. , Jan-2020

Project Title:  Countermeasures Against Adverse Effects of Space Radiation Reduce
Images: icon  Fiscal Year: FY 2019 
Division: Human Research 
Research Discipline/Element:
HRP SR:Space Radiation
Start Date: 01/31/2019  
End Date: 05/30/2021  
Task Last Updated: 03/12/2019 
Download report in PDF pdf
Principal Investigator/Affiliation:   Rithidech, Kanokporn  Ph.D. / State University New York at Stony Brook 
Address:  Department of Pathology 
BHS T9 Health Sciences Center 
Stony Brook , NY 11794-8691 
Email: Kanokporn.Rithidech@sbumed.org 
Phone: (631) 444-3446  
Congressional District:
Web:  
Organization Type: UNIVERSITY 
Organization Name: State University New York at Stony Brook 
Joint Agency:  
Comments:  
Project Information: Grant/Contract No. 80NSSC19K0435 
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.: 80NSSC19K0435 
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) Cancer:Risk of Radiation Carcinogenesis
Human Research Program Gaps: (1) Cancer-502:Systematically identify safe and effective countermeasures to reduce radiation carcinogenesis (IRP Rev M)
Task Description: Our primary goal is to test the efficacy of apigenin (AP) for prevention and mitigation of cancer due to space radiation exposure as measured by incidence, aggressiveness, burden, and latency. Our main hypothesis is that AP exhibits its beneficial effects by suppression of radiation-induced inflammation and oxidative stress during the initiation/promotion steps of carcinogenesis. Although the emphasis will be the mitigation of lung cancer and lymphoma/leukemia, other types of cancer will be recorded.

Apigenin (AP) is a dietary supplement known to possess potent antioxidant, anti-inflammatory, and anti-cancer activities in various tissues. We are the first to report that AP protects human lymphocytes from exposure to radiation in vitro and that AP attenuates inflammation and oxidative damage in bone marrow cells of mice exposed to radiation. These findings lay the groundwork for this project.

We will give food containing AP to mice (males and females) before and after exposure to silicon (Si) ions. Subsequently, the mixed-beam (protons + Si) experiment will be designed. Oxidative stress and inflammation are highly relevant not only to carcinogenesis but also to cardiovascular and nervous disorders. Hence, groups of mice from each treatment will be used for a serial sacrifice schedule at 1 week and 3 months post-irradiation. This will test the ability of AP to counteract heavy-ion-induced early- and late-occurring inflammation and oxidative damage in various tissues linked to cancer that are the focus of our study (i.e., bone marrow, lung, thymus, spleen), including the heart and the brain of the same mouse. All remaining mice will be observed for morbidity and mortality until they reach about 800 days of age. Our data enable the evaluation of countermeasure efficacy of AP not only across tissues at risk for cancer but also across risk areas. This multi-tissue approach has not been used in space research.

Research Impact/Earth Benefits:

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

Bibliography Type: Description: (Last Updated: 01/01/2021) 

Show Cumulative Bibliography Listing
 
 None in FY 2019