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Project Title:  Space Relevant Radiation-Induced Cardiovascular Disease Risk Thresholds: Effect of Gender on the Outcome Reduce
Images: icon  Fiscal Year: FY 2024 
Division: Human Research 
Research Discipline/Element:
HRP SR:Space Radiation
Start Date: 04/10/2019  
End Date: 02/15/2024  
Task Last Updated: 02/09/2024 
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Principal Investigator/Affiliation:   Goukassian, David A M.D., Ph.D. / Icahn School of Medicine at Mount Sinai 
Address:  Zena & Michael A. Weiner Cardiovascular Institute 
One Gustave L. Levy Place, Box 1030 
New York , NY 10029 
Email: david.goukassian@mssm.edu 
Phone: 617-480-3890  
Congressional District: 12 
Web:  
Organization Type: UNIVERSITY 
Organization Name: Icahn School of Medicine at Mount Sinai 
Joint Agency:  
Comments: NOTE: PI moved to Icahn School of Medicine at Mount Sinai from Temple University in October 2018.  
Key Personnel Changes / Previous PI: PI notes additional collaborators who are assisting with the project: Lahouaria Hadri, Kenneth Walsh, and Venkata Naga SrikanthGarikpati (Ed., 5/26/23).
Project Information: Grant/Contract No. 80NSSC19K1079 
Responsible Center: NASA JSC 
Grant Monitor: Elgart, Robin  
Center Contact: 281-244-0596 (o)/832-221-4576 (m) 
shona.elgart@nasa.gov 
Unique ID: 12726 
Solicitation / Funding Source: 2016-2017 HERO NNJ16ZSA001N-SRHHC. Appendix E: Space Radiobiology and Human Health Countermeasures Topics 
Grant/Contract No.: 80NSSC19K1079 
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) Cardiovascular:Risk of Cardiovascular Adaptations Contributing to Adverse Mission Performance and Health Outcomes
Human Research Program Gaps: (1) CV-102:Determine whether space radiation induces cardiovascular structural and functional changes and/or oxidative stress & damage (OSaD)/inflammation, that can contribute to development of disease.
Flight Assignment/Project Notes: NOTE: Continuation of "Space Relevant Radiation-Induced Cardiovascular Disease Risk Thresholds: Effect of Gender on the Outcome," grant 80NSSC18K0921, due to PI move to Icahn School of Medicine at Mount Sinai from Temple University. (Ed., 2/10/2020)

NOTE: End date changed to 02/15/2024 per NSSC information (Ed., 5/26/23)

Task Description: Ed. note 2/10/2020: Continuation of "Space Relevant Radiation-Induced Cardiovascular Disease Risk Thresholds: Effect of Gender on the Outcome," grant 80NSSC18K0921 with the same Principal Investigator Dr. David Goukassian, due to PI move to Icahn School of Medicine at Mount Sinai from Temple University.

During the future Moon, near Earth asteroids, and Mars missions, astronauts will be exposed to higher total doses of space irradiation (IR) (~0.4-0.5 Gy) from galactic cosmic rays (GCR). Most of what we know about harmful effects of IR on cardiovascular (CV) system is from epidemiological studies of long-term survivors of cancer radiotherapy (RT). A recent study of 2,168 women who underwent RT for breast cancer has shown that the rates of major coronary events increased linearly with the mean dose to the heart by 7.4% per Gy, with no apparent lower or upper threshold. In this study, it was determined that average of the mean doses to the whole heart was 4.9 Gy with the range of 0.03 - 27.72 Gy. Furthermore, metabolomics studies, in patients undergoing hematopoietic stem cell (HSC) transplantation as part of cancer treatment (1.25 Gy total-body irradiated), identified seven urine-based biomarkers with distinct differences between pre- and post-exposure samples. The levels of these markers were found to be gender-dependent suggesting that separate biomarker signatures may exist for males and females.

Hypotheses: Our central hypothesis is that low-dose proton and HZE (high energy) particle IR-induced biological responses are long-lasting, IR type- and dose-dependent and may augment excess relative risk (ERR) estimates for the development of cardiovascular diseases (CVDs) during and after long-duration space missions. In addition, we hypothesize that gender differences could further modify radio-biologically effective (RBE) IR thresholds for CV risk estimates. Gene expression and epigenetic modifications in protein and microRNA (miRNA) in exosomes from the blood (e.g., plasma/serum) may be altered before the onset of the cardiac symptoms, which could be used as potential biomarkers to predict the CVD risks. We will test our hypotheses with the following specific aims:

AIM 1. Determine the longitudinal effect of IR type, dose, and gender on cardiovascular physiology in wild type mice and ApoE null mice after full-body 5-ion simplified mixed field and gamma radiation.

AIM 2. Determine space-type IR mediated modulations in exosomal cargo in the blood, and determine whether these changes are associated with alterations in the heart function, structure, and vasculature before the manifestation of clinical symptoms.

AIM 3. Utilize known and newly identified biomarkers in the blood to develop human-relevant point-of-care tests (POCT) for predicting and monitoring possible CV alterations before and during space flights.

We anticipate that the results of our proposed work may be beneficial for human space exploration and could (1) Determine single whole body mixed field dose-response, radio-biologically effective IR thresholds in the heart and cardiac vasculature, and whether gender differences could modify radio-biologically effective IR thresholds for CV risk estimates; 2) Determine whether space radiation leads to modifications in the circulating exosomal cargo contents and whether IR-induced exosomal cargo modulations are reflective of subclinical changes in the cells and organs of origin; 3) Ascertain if modulations of exosomal cargo may be representative of chronic oxidative stress and inflammation and could serve as early biomarkers of IR-induced CVD initiation and progression; 4) Integrate physiological CV endpoint data sets with gene expression and epigenetic data to identify biomarkers in bio-fluids that could be used for prediction of asymptomatic CVD in the setting of space IR, which will include known early and intermediate biomarkers of cardiac damage, inflammation, and oxidative stress, as well as currently unknown novel radiation-associated cardiac biomarkers.

Research Impact/Earth Benefits: We anticipate that the results of our work could be beneficial for human space exploration as well as for the Earth-based applications on several levels -- (1) determine whether low dose space-type and terrestrial IR may present an increased risk for CVD development during and after prolonged space missions, as well as after conventional and particle cancer radiotherapy; (2) determine the underlying molecular signaling of CV alterations; (3) identify biomarkers in the blood that could be used for prediction of asymptomatic CV disease, which will include known early and intermediate biomarkers of cardiac damage, as well as currently unknown novel cardiac biomarkers; (4) the identification of sub-clinical CV disease biomarkers that could be used for monitoring the effectiveness of mitigating factors for prevention and treatment of IR-induced CVDs in space and in Earth-bound civilian population, in general.

Task Progress & Bibliography Information FY2024 
Task Progress: Our new findings for the reporting period are organized below by four sub-titles containing corresponding background, methodology, main findings, and the summary.

Sub-project 1:

Title: "Radiation-Induced Clonal Hematopoiesis as an Independent Risk Factor for Carcinogenesis and Heart Disease"

Background. Acquiring and accumulating somatic mutations is a hallmark of aging and can be accelerated by space irradiation (IR). While most mutations are silent, others can confer advantageous phenotypes leading to clonal events in normal tissues. In HSCs, the expansion of mutated cells is termed clonal hematopoiesis (CH). In the absence of concomitant malignancy, the presence of mutations in these known CH "driver" genes, with a variant allele fraction (VAF) of at least 2%, is termed CH of indeterminate potential (CHIP). While mutations in leukemogenic "driver" genes represent an early step in the progression toward hematologic malignancy, unexpectedly, CHIP also predisposed patients to an increased risk of cardiovascular disease (CVD), including a 2-4-fold increased risk of coronary artery disease, early-onset myocardial infarction, and thrombotic stroke when adjusted for other covariates (age, sex, type 2 diabetes, etc.). Our group analyzed the somatic mutational profile in 14 astronauts (binned age ~42) and identified 34 nonsynonymous mutations of relatively low VAF in CHIP-driver genes in leukocytes, predominantly in TP53 and DNMT3A, which is consistent with the development of an early stage of CHIP. While these clones were small, there is a possibility for additional clonal instability with longer duration missions, which may be facilitated by aging and many other extrinsic factors in space. Thus, longitudinal lifetime murine studies assessing the effects of space-type IR on CH, cancer, and CVD would provide a mechanistic framework to investigate the direct connection between CH, cancer, and CVD pathophysiology.

Hypothesis. We hypothesize that exposure to space-type IR will increase the lifetime accumulation of somatic mutations within known CHIP "driver" gene candidates. Further, we hypothesize that the aberrant clonal events resulting from these mutations will be associated with accelerated carcinogenesis, particularly evident in the later stages of life. In addition, these processes may be IR exposure type-dependent, i.e., acute or chronic/intermittent.

Methodology. We exposed 3-month-old male age-matched C57Bl/6J wild type (WT) mice to 137Cs-?-IR at 100 cGy and simGCRsim-IR at 50 cGy 500 MeV/nucleon. During this study mice were observed for gross tumor development in all internal organs, cardiac function was assessed by echocardiography (ECHO) and blood was collected at 14, 28 days and 12, 16, 22 months post-IR. Genomic DNA was isolated from white blood cells (WBC) and processed for whole exome sequencing (WES). The sequencing was performed on the Illumina NovaSeq-6000 platform, using 150bp paired ends sequencing with an average of ~24 million raw reads/sample and with a depth of 50x. Sequencing reads were aligned to mm10 reference mouse genome with BWA mem aligner. Somatic variant calling was performed with the GATK Mutect2 pipeline. Mutation data was further analyzed with the maftools R package. The left ventricles of mice, from the same experiments, were bisected at 16- and 22-months post-IR and total RNA was isolated and sequenced with Illumina NGS. RNA-seq reads were spliced-aligned to the mm10 mouse reference genome using the STAR aligner. Raw read counts were converted to log2 CPM values with the DESeq2 R package. Normalized gene expression data were then analyzed using a machine learning-based Self-Organizing Map (SOM) algorithm implemented in the oposSOM R package.

Main findings for longitudinal mouse lifetime cardiovascular studies in male and female C57bl/6j mice.

In male C57BL/6J mice we found acute “in-flight” cardiac function changes - 1) global LV systolic function (LVEF) is impaired in all IR groups and doses at 14 and 28 days; 2) at 14 days, reduced LV systolic function is paired with structural alterations (reduced LV size, mass, and stroke volume) in 50 cGy simGCRsim-IR mice.

In male C57BL/6J mice we found longitudinal/degenerative cardiac changes - 1) at 365 days global LV systolic function remains reduced in all IR groups and doses; 2) at 440 days there is no significant difference in LV structure and function in all IR groups; 3) at 660 days there is no significant alteration in LV function or structure in y-IR mice compared to no-IR ND-fed mice; 4) in 50 cGy simGCRsim-IR mice decrease in diastolic wall strain (DWS), smaller overall LV size, and LV mass, suggests that these mice may exhibit diastolic dysfunction.

In female mice LV function was evaluated at 28, 180, 365, 440, and 550 days post-IR following the same cohort of mice for each treatment condition longitudinally. There was no significant alteration in global LV systolic function across any treatment groups at 28, 180, 365, 440, and 550 days post-IR in female mice.

Main findings in longitudinal mouse lifetime carcinogenesis studies in male and female C57bl/6j mice.

- The incidence of macroscopic tumors is 4.5-times higher in male WT compared to female WT mice after the same doses of ?- and simGCRsim-IR or Western diet (WD) suggesting underlying genotypic variance may attenuate pathways involved in tumorigenesis. - The incidence of IR-induced internal organ tumors was higher in 100 cGy gamma- versus 50 cGy simGCRsim-IR, suggesting higher carcinogenic potential of gamma-IR at these doses. - The liver is the most affected organ by tumor growth, followed by the spleen then the lung. - Pathologic evaluation of macroscopic tumors revealed the highest number of malignant tumors during the lifetime of WT mice was detected in the WD-fed group, but not in either of the IR groups. - The incidence of malignant tumors of internal organs (liver, spleen, lungs) was 3-times higher in male (N=21) vs female (N=7) mice (i.e., macroscopic tumors). - All microscopic tumors in both male and female mice at all time points and treatment conditions were diagnosed exclusively as lymphomas.

Findings in whole exome sequencing of WBC in male mice.

In animals with pathologically confirmed liver tumors, nonsynonymous mutations in somatic genes were the most prevalent, followed by stop-gain, nonframeshift, and one frameshift mutations. The mutation count and type were similar for both types of IR for hepatocellular carcinoma, their mutations in mice with histiocytic sarcoma were exclusively in simGCGsim IR mice, whereas mutations in mice with hemangiosarcoma were exclusively in ?-IR mice. The majority of somatic variations observed were nonsynonymous SNVs regardless of age and exposure type. Transition and transversion mutations were more frequent in ?-IR group. Mutations in 6 genes (Cdh11, Muc4, Vmn2r116, Sp110, Zfp987, Gm2022) had the highest frequency in all studied groups. Cdh11 is overexpressed in 15% of breast cancers and seems essential to tumor progression in some other cancer types. Muc-4 plays a role in cancer progression by repressing apoptosis and increasing tumor cell proliferation via downregulation of Cdkn1b. Also stabilizes Her2 signaling.

In summary, our results provide compelling scientific evidence that gamma and/or space IR exposure induces “long-lasting” effects in the hearts of male but not female C57BL/6J mice. Moreover, murine lifetime carcinogenesis studies in various internal organs showed a 4.5-fold higher number of malignant tumors in male but not female mice after exposure to exactly the same doses of gamma and simGCRsim IR. Further, whole exome sequencing of leukocytes collected from male C57BL/6J mice showed that mutations-affected genes are mainly implicated in cancer and liver and kidney cancer were the top disease types across all groups. In animals with pathologically confirmed liver tumors, nonsynonymous mutations in somatic genes were the most prevalent, followed by stop-gain, nonframeshift, and one frameshift mutations. The mutation count and type were similar for both types of IR for hepatocellular carcinoma, but mutations in mice with histiocytic sarcoma were exclusively in simGCGsim IR mice, whereas mutations in mice with hemangiosarcoma were exclusively in ?-IR mice. There was a small number of known CHIP gene mutations observed. This data could provide a well-controlled genotype/phenotype system in which IR-induced changes in clonal hematopoiesis (i.e., CHIP) and expression of these genes in the heart and other organs can be assessed for their contributions to the development of clinical phenotypes over the lifetime.

Sub-project 2:

Title: “Evaluation of Mosaic Loss of Y Chromosome and Y-Linked Gene Mutations after Exposure to Gamma and Simgcrsim Radiation during Lifespan of Male C57bl6/J Mice”

Background. The Y chromosome carries a mere 154 genes - less than one-tenth of the X chromosome. The vast majority of these 154 genes are not even characterized. Until this year, the Y chromosome has been the last human chromosome to be fully sequenced. Nevertheless, researchers have found the Y chromosome is missing from at least some white blood cells (WBC) in about 40% of 70-year-olds and 57% of 93-year-olds. In some older men, more than 80% of the cells can be short of the Y chromosome. Further, random microdeletions in the azoospermia factor (AZF) a, b, and c regions were detected in >90%, and tandem duplication and copy number polymorphism (CNP) of an additional 11 different Y-linked genes were detected in about 80% of males exposed to natural background radiation in Kerala, India. Interestingly, large structural clonal mosaicism of the X chromosome was analyzed in 38,303 women from cancer genome-wide association studies (20,878 cases and 17,425 controls) and detected 124 mosaic X events 42 Mb in 97 (0.25%) women. However, a small X chromosome mosaicism frequency increased with age (0.11% in 50-year-olds; 0.45% in 75-year-olds). These findings may suggest that the Y chromosome undergoes mosaic events ~ 90 times more frequently than the X chromosome in females. This could have substantial implications in the higher prevalence of men dying on average about 5 years earlier than women in the United States due to aging-related ailments such as cancer and cardiovascular disease.

Hypothesis. We hypothesize that gamma (?-IR) or simplified Galactic Cosmic Ray simulated radiation (simGCRsim-IR) of mice at a younger age may increase the rate of mutations in Y chromosome-linked genes and lead to mosaic loss of Y (mLOY) chromosome during their lifetime.

Methodology. We exposed 3-month-old male C57B1/6J wild-type (WT) mice to a single dose of 100 cGy, 0.662 MeV of 137Cs gamma-IR (?-IR) and 50 cGy, 500 MeV/n simGCRsim-IR. All control (no-IR), ?- and simGCRsim-IR were housed at 12/12h light cycle, and food and water were provided ad libitum for 22 months post-IR at which time mice were approaching the end of their lifespan. During this study, mice were observed for gross tumor development, all internal organs and blood as well as assessment of cardiac function by transthoracic echocardiography (ECHO) was performed at 14, 28 days and 12, 16, 22 months post-IR. Genomic DNA was isolated from white blood cells (WBC) and processed for whole exome sequencing (WES) on the Illumina NovaSeq-6000 platform, achieving an average coverage of 92% at a depth of 50x in the target region. Sequencing reads were aligned to the mm10 reference mouse genome using the BWA mem aligner and deduplicated PicardTools. Somatic variant calling was performed with the GATK Mutect2 pipeline. The detection of copy number changes was performed using the Control-FREEC tool.

Main Findings. Distribution of somatic mutation types in all study groups revealed that exonic mutations in the Y chromosome were detected only in irradiated groups, 11% in simGCRsim and 16.6% in Gamma. Distribution of the copy number variations (CNVs) across the genome in studied animals reveals that natural aging in non-IR samples leads to gain of CNVs on the Y chromosome, whereas IR samples showed a loss of CVNs in the Y chromosome. Exploration CNVs data revealed that IR led to a decline in copy numbers for the following 12 Y-linked genes: Usp9y, Uty, Ddx3y, Kdm5d, Eif2s3y, Tspy-ps, Uba1y, Zfy1, Gm16501, Gm6026, Zfy2, and Sry. The average copy numbers for the non-IR 12 and 22-month groups were 3 and 12.1, respectively. For the simGCRsim-IR groups at 12 and 16 months, the averages were 2.33 and 1.58, and for the 12, 16, and 22 months for gamma-IR groups, the averages were 1.83, 3.45, and 1.16. simGCRsim and gamma-IR induced CNV that were found in Y-linked genes in our studies are known to regulate male sex-related processes, such as spermatogenesis, initiation of male sex determination, spermatogonial stem cells via Wnt6/ß-catenin pathway. A set of the affected genes have been linked to various cancer such as colorectal cancer (Kdm5d, a histone demethylase), gonadoblastoma, testicular and prostate cancer (Tspy-ps) as well as in the pathophysiology of pulmonary hypertension (Uty) through negative regulation of proinflammatory cytokine levels. The most frequent type of mutation is IGR, however, exonic mutations are observed only in IR groups: 0.5 Mix (Gm21677) and gamma (Zfy2).

It must be noted that CNVs affect more nucleotides in the human genome than SNPs and can arise via several mechanisms including non-allelic homologous recombination (HR), and non-homologous end joining (NHEJ), both, are DNA repair mechanisms known to remove IR-induced damage, and retroelement insertions. As the fidelity of the HR and NHEJ are low and tend to introduce various mistakes into DNA sequence, CNVs can also lead to many negative consequences and have been implicated in intellectual disability, epilepsy, cancer, and other degenerative disease processes.

In summary, our findings suggest that both terrestrial and space-type IR led to a decline in copy number of protein-coding genes as early as 12 months after a single exposure which continues to decline towards the end of mice's lifespan. We strongly believe that well-designed and in-depth studies of the effects of IR are warranted to extend mLOY studies from discovery to mechanistic studies. An improved understanding of IR-mediated mLOY will allow advance determination of individual susceptibility and provide an early opportunity for the development of personalized mitigation of a wide spectrum of human diseases including cancer, neuro-, and cardiovascular diseases.

Sub-project 3:

Title: “Female and Male Hearts Respond Differently to Same Doses of Gamma and Simgcrsim Radiation – Sex Matters”

Background. Space radiation (IR) from Solar Particle Events (SPE) and Galactic Cosmic Rays (GCR), also known as high charge and energy (HZE) IR, is a primary risk associated with deep-space missions. There are limited animal and human studies on the risk of cardiovascular disease (CVD) development due to space-IR. During future exploration-type space missions, astronauts could be exposed to doses of space-type radiation (IR) (~0.4–0.5 Gy) from galactic cosmic rays (GCR). The cardiac effects induced by space-type IR, specifically simplified GCR simulated (simGCRsim)-IR, are not well-known. Sex-specific differences in response to gamma and simGCRsim IR are yet to be discovered.

Hypothesis. We hypothesize that there may be sex-specific differences in long-term gamma and simGCRsim-associated alterations in differential gene expression in the heart tissue. We also hypothesized that gamma and simGCRsim IR-induced biological responses are chronic, IR type-dependent, and may increase the relative risk for developing CVD.

Methodology. To test our hypotheses, we exposed 3-month-old male and female age-matched C57Bl/6J wild-type (WT) mice to 137Cs-?-IR at 100 cGy, 0.662 MeV, and simGCRsim-IR at 50 cGy 500 MeV/n. We assessed cardiac function by transthoracic echocardiography (ECHO) at 28 days, and 12, 16, 22/18.5 (male/female)-months post-IR. To evaluate sex-associated differences in the regulation of the transcriptional landscape, total RNA isolated from male and female LV hearts was sequenced with Illumina NGS. Sequenced reads were splice-aligned to the mm10 mouse reference genome using the STAR aligner. Raw read counts were normalized with the DESeq2 R package and converted to log2 CPM values. Differential expression analysis and downstream bioinformatics analysis were performed using oposSOM R package.

Main findings. Longitudinal Mouse Lifetime Echocardiography. Compared to no-IR controls, in male WT mice, ECHO data revealed that a single full-body ?- and simGCRsim-IR, lead to a 25-30% decrease (p<0.01) in Fractional Shortening % (FS%) and Ejection Fraction % (EF%) of the heart 28 days post-IR. Interestingly, the EF% and FS% were not affected in female mice, indicating no change in systolic function 28 days after exactly the same exposure doses of ?- or simGCRsim-IR. The EF% and FS% decrease in male mice were associated with a 10-15% decrease (p<0.05) in LV posterior wall thickness (PWth) in systole and an increase in end-systolic volume (ESV), indicating that decreases in FS% and EF% are starting to affect cardiac morphology and function in male mice. No change in these parameters was observed in female mice at 28 days. These early time point findings suggest that at these doses female mice do not reveal any CV functional and structural changes, whereas male mice show significant decreases in global systolic function that are also associated with structural changes. There were no additional degenerative IR-induced changes relative to normal aging at 12 and 16 months post-IR. Interestingly, at 22 months, 50 cGy simGCRsim-IR male mice exhibited preserved LV systolic function but altered LV size and mass, which were associated with elevated levels of cardiac fibrosis, inflammation, and hypertrophy markers Tgfß1, Mcp1, Mmp9, and ßMhc in LV tissue (qPCR), suggesting that space-type IR may induce the cardiac remodeling processes that are commonly associated with diastolic dysfunction. Again, no alteration in LV systolic function or LV size and mass was detected in female mice at 18.5 months (the last time point examined for females).

Main findings. RNAseq Analyses of Male and Female LV Tissue. RNA-seq analyses of male and female LV tissue at 16 and 22/18.5 (male/female) months revealed genes that were upregulated in response to IR in mice of both sexes. Enrichment analysis of the upregulated genes in LV from both male and female mice showed an overlap with pathways such as sarcolemma, cardiac muscle contraction, and regulation of heart rate. Interestingly, LV tissue isolated from male mice exhibited down-regulation of hemoglobin alpha and beta chain genes in response to both simGCGsim- and gamma-IR, while no change in the expression of these genes was observed in LVs from female mice. In male LVs, the top enriched pathways were chloride transmembrane transport and cytokine activity. In addition, a set of ribosomal genes was upregulated only in simGCRsim-IR LVs of male mice, while females showed only age-related changes for the same set of ribosomal genes.

Differential gene expression in males - 1) changes in LV transcriptome at 16 months observed only for simGCRsim; 2) gamma radiation results only in downregulation of a small number of genes at 22 months. Differential gene expression in females - 1) simGCRsim and gamma irradiation resulted in a comparable number deferentially expressed genes (DEGs) in LV at 16 months; 2) changes in LV transcriptome at 18.5 months observed only for simGCRsim. Therefore, simGCRsim causes a substantially higher number of differentially expressed genes than gamma radiation at all time points.

More than 95% of DEGs are sex specific. There were only 6 overlapping DEGs between male and female groups at all times and IR types examined. Specific overlapping DEGs are: Tspan4: tetraspanin 4 regulation of cell development, regulates activation, growth, and motility. Or5m3b: olfactory receptor family 5 subfamily M member 3B sensory perception of smell. Arntl: aryl hydrocarbon receptor nuclear translocator-like involved in abnormal circadian regulation of heart rate, decreased heart rate, decreased heart weight. Spon2: Spondin 2 cell adhesion protein essential in the innate immune responses, macrophage phagocytosis. Tef: thyrotroph embryonic factor circadian clock associated gene, has a role in the smooth muscle cell and blood pressure regulation. Mid1ip1: Midline 1 interacting protein 1 involved in liver lipogenesis, HCC metastasis via MMP9.

We also observed shared DEGs within gender comparison groups. There are 7 shared DEGs between 18.5 female gamma and simGCRsim radiated groups, Dbp, Bhlhe41, Picalm, Unc119b, Tcap, Ppfla1, and Mapk4. In addition, there was one intersection between 16-month and 22-month simGCRsim male groups which is the St6galnac3 gene.

The set of upregulated DEGs in male hearts at 16 and 22 months indicate a regulation of negative processes such as abnormal heart morphology, abnormal myocardial fiber morphology, cardiac fibrosis, small heart, decreased heart weight, and abnormal circadian regulation of heart rate. Interestingly, in female mice heart tissue a single gene (Hsd17b4) responsible for the enlarged heart was upregulated at 16 months, suggesting that the heart may be compensating by hypertrophy. In addition, a few genes regulating immune responses were also upregulated in female mice heart tissue.

In summary, our findings suggest significant and long-lasting IR-induced (both, simGCRsim- and ?-IR) gene expression changes in the LV function in both male and female mice, specifically - 1) most of the differentially expressed genes in radiation groups are sex specific; 2) simGCRsim radiation have more impact on the gene expression of left ventricular tissue; 3) the identification of a small number of shared genes in comparisons across different types of IR and sham treatments suggests an insignificant overlap between radiation exposure type and alterations in the transcriptome.

Bibliography: Description: (Last Updated: 03/06/2024) 

Show Cumulative Bibliography
 
Abstracts for Journals and Proceedings Brojakowska A, Bisserier M, Hakobyan S, Davitavyan S, Stepanyan A, Khlgatian MK, Zhang S, Arakelyan A, Goukassian DA. "Radiation-induced clonal hematopoiesis as an independent risk factor for carcinogenesis and heart disease development." 2024 NASA Human Research Program Investigators' Workshop, Galveston, Texas, February 13-16, 2024.

Abstracts. 2024 NASA Human Research Program Investigators' Workshop, Galveston, Texas, February 13-16, 2024. , Feb-2024

Abstracts for Journals and Proceedings Brojakowska A, Hakobyan S, Davitavyan S, Stepanyan A, Khlgatian MK, Bisserier M, Zhang S, Khachatryan G, Sirunyan T, Garikipati VNS, Tsakanova G, Arakelyan A, Goukassian DA. "Evaluation of mosaic loss of Y chromosome and Y-linked gene mutations after exposure to gamma and simGCRsim radiation during lifespan of male C57BL6/J mice." 2024 NASA Human Research Program Investigators' Workshop, Galveston, Texas, February 13-16, 2024.

Abstracts. 2024 NASA Human Research Program Investigators' Workshop, Galveston, Texas, February 13-16, 2024. , Jan-2024

Abstracts for Journals and Proceedings Brojakowska A, Hakobyan S, Davitavyan S, Stepanyan A, Khlgatian MK, Bisserier M, Zhang S, Hadri L, Garikipati VNS, Kishore R, Arakelyan A, Goukassian DA. "Female and male hearts respond differently to same doses of gamma and simGCRsim radiation – Sex matters." 2024 NASA Human Research Program Investigators' Workshop, Galveston, Texas, February 13-16, 2024.

2024 NASA Human Research Program Investigators' Workshop, Galveston, Texas, February 13-16, 2024. , Feb-2024

Articles in Peer-reviewed Journals Brojakowska A, Jackson CJ, Bisserier M, Khlgatian MK, Jagana V, Eskandari A, Grano C, Blattnig SR, Zhang S, Fish KM, Chepurko V, Chepurko E, Gillespie V, Dai Y, Kumar Rai A, Garikipati VNS, Hadri L, Kishore R, Goukassian DA. "Lifetime evaluation of left ventricular structure and function in male ApoE null mice after gamma and space-type radiation exposure." Front Physiol. 2023 Nov 20:14:1292033. https://doi.org/10.3389/fphys.2023.1292033 ; PubMed PMID: 38054039; PubMed Central PMCID: PMC10694360 , Nov-2023
Articles in Peer-reviewed Journals Brojakowska A, Jackson CJ, Bisserier M, Khlgatian MK, Grano C, Blattnig SR, Zhang S, Fish KM, Chepurko V, Chepurko E, Gillespie V, Dai Y, Lee B, Garikipati VNS, Hadri L, Kishore R, Goukassian DA. "Lifetime evaluation of left ventricular structure and function in male C57BL/6J mice after gamma and space-type radiation exposure." Int J Mol Sci. 2023 Mar 13;24(6):5451. https://doi.org/10.3390/ijms24065451 ; PubMed PMID: 36982525; PubMed Central PMCID: PMC10049327 , Mar-2023
Project Title:  Space Relevant Radiation-Induced Cardiovascular Disease Risk Thresholds: Effect of Gender on the Outcome Reduce
Images: icon  Fiscal Year: FY 2023 
Division: Human Research 
Research Discipline/Element:
HRP SR:Space Radiation
Start Date: 04/10/2019  
End Date: 02/15/2024  
Task Last Updated: 02/27/2023 
Download report in PDF pdf
Principal Investigator/Affiliation:   Goukassian, David A M.D., Ph.D. / Icahn School of Medicine at Mount Sinai 
Address:  Zena & Michael A. Weiner Cardiovascular Institute 
One Gustave L. Levy Place, Box 1030 
New York , NY 10029 
Email: david.goukassian@mssm.edu 
Phone: 617-480-3890  
Congressional District: 12 
Web:  
Organization Type: UNIVERSITY 
Organization Name: Icahn School of Medicine at Mount Sinai 
Joint Agency:  
Comments: NOTE: PI moved to Icahn School of Medicine at Mount Sinai from Temple University in October 2018.  
Co-Investigator(s)
Affiliation: 
Kishore, Raj  Temple University School of Medicine 
Key Personnel Changes / Previous PI: PI notes additional collaborators who are assisting with the project: Lahouaria Hadri, Kenneth Walsh, and Venkata Naga SrikanthGarikpati (Ed., 5/26/23).
Project Information: Grant/Contract No. 80NSSC19K1079 
Responsible Center: NASA JSC 
Grant Monitor: Elgart, Robin  
Center Contact: 281-244-0596 (o)/832-221-4576 (m) 
shona.elgart@nasa.gov 
Unique ID: 12726 
Solicitation / Funding Source: 2016-2017 HERO NNJ16ZSA001N-SRHHC. Appendix E: Space Radiobiology and Human Health Countermeasures Topics 
Grant/Contract No.: 80NSSC19K1079 
Project Type: GROUND 
Flight Program:  
TechPort: No 
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Human Research Program Elements: (1) SR:Space Radiation
Human Research Program Risks: (1) Cardiovascular:Risk of Cardiovascular Adaptations Contributing to Adverse Mission Performance and Health Outcomes
Human Research Program Gaps: (1) CV-102:Determine whether space radiation induces cardiovascular structural and functional changes and/or oxidative stress & damage (OSaD)/inflammation, that can contribute to development of disease.
Flight Assignment/Project Notes: NOTE: Continuation of "Space Relevant Radiation-Induced Cardiovascular Disease Risk Thresholds: Effect of Gender on the Outcome," grant 80NSSC18K0921, due to PI move to Icahn School of Medicine at Mount Sinai from Temple University. (Ed., 2/10/2020)

NOTE: End date changed to 02/15/2024 per NSSC information (Ed., 5/26/23)

Task Description: Ed. note 2/10/2020: Continuation of "Space Relevant Radiation-Induced Cardiovascular Disease Risk Thresholds: Effect of Gender on the Outcome," grant 80NSSC18K0921 with the same Principal Investigator Dr. David Goukassian, due to PI move to Icahn School of Medicine at Mount Sinai from Temple University.

During the future Moon, near Earth asteroids, and Mars missions, astronauts will be exposed to higher total doses of space irradiation (IR) (~0.4-0.5 Gy) from galactic cosmic rays (GCR). Most of what we know about harmful effects of IR on cardiovascular (CV) system is from epidemiological studies of long-term survivors of cancer radiotherapy (RT). A recent study of 2,168 women who underwent RT for breast cancer has shown that the rates of major coronary events increased linearly with the mean dose to the heart by 7.4% per Gy, with no apparent lower or upper threshold. In this study, it was determined that average of the mean doses to the whole heart was 4.9 Gy with the range of 0.03 - 27.72 Gy. Furthermore, metabolomics studies, in patients undergoing hematopoietic stem cell (HSC) transplantation as part of cancer treatment (1.25 Gy total-body irradiated), identified seven urine-based biomarkers with distinct differences between pre- and post-exposure samples. The levels of these markers were found to be gender-dependent suggesting that separate biomarker signatures may exist for males and females.

Hypotheses: Our central hypothesis is that low-dose proton and HZE (high energy) particle IR-induced biological responses are long-lasting, IR type- and dose-dependent and may augment excess relative risk (ERR) estimates for the development of cardiovascular diseases (CVDs) during and after long-duration space missions. In addition, we hypothesize that gender differences could further modify radio-biologically effective (RBE) IR thresholds for CV risk estimates. Gene expression and epigenetic modifications in protein and microRNA (miRNA) in exosomes from the blood (e.g., plasma/serum) may be altered before the onset of the cardiac symptoms, which could be used as potential biomarkers to predict the CVD risks. We will test our hypotheses with the following specific aims:

AIM 1. Determine the longitudinal effect of IR type, dose, and gender on cardiovascular physiology in wild type mice and ApoE null mice after full-body 5-ion simplified mixed field and gamma radiation.

AIM 2. Determine space-type IR mediated modulations in exosomal cargo in the blood, and determine whether these changes are associated with alterations in the heart function, structure, and vasculature before the manifestation of clinical symptoms.

AIM 3. Utilize known and newly identified biomarkers in the blood to develop human-relevant point-of-care tests (POCT) for predicting and monitoring possible CV alterations before and during space flights.

We anticipate that the results of our proposed work may be beneficial for human space exploration and could (1) Determine single whole body mixed field dose-response, radio-biologically effective IR thresholds in the heart and cardiac vasculature, and whether gender differences could modify radio-biologically effective IR thresholds for CV risk estimates; 2) Determine whether space radiation leads to modifications in the circulating exosomal cargo contents and whether IR-induced exosomal cargo modulations are reflective of subclinical changes in the cells and organs of origin; 3) Ascertain if modulations of exosomal cargo may be representative of chronic oxidative stress and inflammation and could serve as early biomarkers of IR-induced CVD initiation and progression; 4) Integrate physiological CV endpoint data sets with gene expression and epigenetic data to identify biomarkers in bio-fluids that could be used for prediction of asymptomatic CVD in the setting of space IR, which will include known early and intermediate biomarkers of cardiac damage, inflammation, and oxidative stress, as well as currently unknown novel radiation-associated cardiac biomarkers.

Research Impact/Earth Benefits: We anticipate that the results of our work could be beneficial for human space exploration as well as for the Earth-based applications on several levels -- (1) determine whether low dose space-type and terrestrial IR may present an increased risk for CVD development during and after prolonged space missions, as well as after conventional and particle cancer radiotherapy; (2) determine the underlying molecular signaling of CV alterations; (3) identify biomarkers in the blood that could be used for prediction of asymptomatic CV disease, which will include known early and intermediate biomarkers of cardiac damage, as well as currently unknown novel cardiac biomarkers; (4) the identification of sub-clinical CV disease biomarkers that could be used for monitoring the effectiveness of mitigating factors for prevention and treatment of IR-induced CVDs in space and in Earth-bound civilian population, in general.

Task Progress & Bibliography Information FY2023 
Task Progress: Our new findings for the reporting period are organized below by four sub-titles containing corresponding background, methodology, main findings, and the summary.

Sub-project 1:

Title: "Lifetime Evaluation of Cardiac Function and Structure in C57bl/6j Mice after Gamma and Space-Type Radiation Exposure"

Background. The lifetime effects of space irradiation (IR) on left ventricular (LV) function are unknown. The cardiac effects induced by space-type IR, specifically simplified galactic cosmic ray simulation (simGCRsim), are yet to be discovered. This study aimed to - (1) determine the effects of (terrestrial) and simGCRsim (space) IR on LV function; (2) identify disease spectrum and latency following single, whole-body IR exposure; (3) establish whether dose thresholds for gamma (y) and simGCRsim IR exist; and (4) describe the comparative impact of y and simGCRsim IR by calculating Relative Biological Effectiveness (RBE) and Radiation Effects Ratio (RER).

Methods. Three-month-old, age-matched, male C57BL/6J mice were irradiated with 137Cs gamma (gamma; 100, 200 cGy) and 5-ion simplified GCR simulation (simGCRsim; 50, 100 cGy). LV function was assessed by transthoracic echocardiography at 14, 28 days (early), and 365, 440, 660 (late) days post-IR. We measured endothelial function markers of brain natriuretic peptide in plasma at three late time points. We assessed the mRNA expression of genes involved in cardiac remodeling, fibrosis, inflammation, and calcium handling in LVs harvested at 660 days post IR. RBE and RER estimates were calculated for LV ejection fraction and LV fractional shortening, on which IR had a statistically significant effect.

Main Findings. All IR groups had impaired global LV systolic function at 14, 28, and, 365 days. At 660 days, 50 cGy simGCRsim-IR mice exhibited preserved LV systolic function with altered LV size and mass. At this time point, simGCRsim-IR mice had elevated levels of cardiac fibrosis, inflammation, and hypertrophy markers TGFß1, MCP1, MMP9, and ßMHC, suggesting that space-type IR may induce cardiac remodeling processes commonly associated with diastolic dysfunction. IR groups showing statistical significance were modeled to calculate the Relative Biological Effectiveness (RBE) and Radiation Effects Ratio (RER). The observed dose-response shape did not indicate a lower threshold at these IR doses.

Summary. Our work is the first to assess in mice the lifetime longitudinal effects of simGCRsim-IR at doses of 50 and 100 cGy and y-IR at doses of 100 and 200 cGy on LV function and structure using echocardiography, serum biomarkers, and cardiac tissue structure alterations. Our findings can be summarized as follows: - (1) LV systolic function is impaired in simGCRsim (50, 100 cGy) and y-IR (100, 200 cGy) wild-type C57BL/6J male mice as early as 14 and 28 days post IR, as well as 365 and 440 days post–IR; (2) at 660 days post IR, simGCRsim-IR male mice appear to have developed a HFpEF cardiac phenotype, though diastolic dysfunction cannot be ruled out, while the cardiac function is recovered in y-IR mice; (3) cardiac function alterations at 660 days post IR appear to be associated with increased expression of markers of cardiac fibrosis (TGFß1, MMP9), inflammation (MCP-1), and hypertrophy (ßMHC), results that suggest simGCRsim-IR may dynamically affect cardiac remodeling processes throughout a lifetime; and (4) no clear dose-response was observed.

Sub-project 2:

Title: "Lifetime Risk of Tumor Development in C57b1/6j Mice Exposed to a Single Full Body Gamma and C57B1/6J MICE EXPOSED TO A SINGLE FULL BODY GAMMA AND simGCRsim Radiation"

Background: Radiation-induced cancer is one of the primary risks associated with exposure to space radiation (IR) during deep-space missions. There is limited data in humans and in animal models for high charge and energy (HZE)-induced carcinogenesis over the murine lifetime. We hypothesize that exposure to space-type IR may increase the risk of cancer development, especially in association with aging processes.

Methods: As part of our NASA-funded mouse-lifetime studies to evaluate the effect of space-type and gamma (y)-IR on cardiovascular disease (CVD) development, mice were examined for tumor development during scheduled tissue collections over 22 months post-IR. Three-month-old male ApoE null and C57B1/6J wild-type (WT) mice were exposed to 100 cGy of 137Cs y-IR and 50 cGy, 500 MeV/nucleon of 5-ion simplified GCR simulation-IR (simGCRsim). Control ApoE null and WT mice were fed with mouse chow (normal diet-ND) and one group in each genotype was fed Western diet (WD) without IR. Note, all IR mice were fed with a ND for 22 months. All neoplasms were fully bisected with visibly unaffected tissue. Formalin-fixed tissues were submitted for routine H&E staining and evaluation by two pathologists blindfolded to treatment conditions.

Main Findings: At all time points and treatment conditions examined, a total of 9 neoplasms were detected in ApoE null mice, including ND-fed mice. Therefore, we focused our further studies only on WT mice. A single WT mouse developed a lymphoma in control No-IR mice at 22 months. In WT mice, the prevalence of neoplasms (liver, lung, spleen) was the highest in no-IR, WD-fed mice with 9/15 (60%) and 7/17 (41%) animals developing neoplasms at 16 and 22 months, respectively. A small number of WD-fed and 100 cGy y-IR mice developed more than one distinct tumor. At 16 months, tumors in WD-fed mice were represented by 7 liver tumors (2 - hepatocellular carcinomas, 1 - hemangiosarcoma, 4 - metastatic lymphomas), 1 lung (lymphoma), and 1 spleen (hemangiosarcoma) tumors. In WT IR mice, higher tumor prevalence represented by lymphoma, hemangiosarcoma, hepatoblastoma, early carcinoma (all liver) and hemangiosarcoma, lymphoma (spleen) was found in 100 cGy y-IR mice 2/16 (12.5%) and 8/16 (50%) at 16 and 22 months, respectively. At the same respective time points, there were 1/15 (6.7%) and 6/15 (40%) tumors represented by lymphoma, hepatocellular carcinoma, histiocytic sarcoma (all liver) in 50 cGy simGCRsim-IR WT mice. Lung tumors were not observed at 22 months in any treatment group, though hepatic and splenic tumors were higher in all groups.

Summary: Our studies revealed that – i) the incidence of tumors is higher in WT compared to ApoE null mice after the same doses of y- and simGCRsim-IR suggesting underlying genotypic variance may attenuate pathways involved in tumorigenesis; ii) the highest number of tumors during the lifetime of WT mice was detected in the WD-fed group, but not in either of IR groups, iii) in WT mice, the incidence of IR-induced internal organ tumors was higher in 100 cGy y- versus 50 cGy simGCRsim-IR, suggesting higher carcinogenic potential of y-IR at these doses; iv) the liver is the most affected organ by tumor growth, followed by the spleen. These results suggest that age-related metabolic changes and IR-induced mutagenesis may drive carcinogenesis.

Sub-project 3:

Title: "Space Radiation Induced Clonal Hematopoiesis: Lifetime Disease Susceptibility Risks and Identification of Biomarkers"

Background: Recent epidemiological studies have documented the prevalence of somatic mutations within the cells of the hematopoietic system in healthy individuals. These acquired DNA mutations accumulate with age and, in some instances, can provide a competitive advantage to the mutant cell thus allowing for its clonal expansion, a phenomenon known as clonal hematopoiesis of indeterminate potential (CHIP). The recent NASA Twin Study provided a detailed analysis of how prolonged, low-orbit space travel may contribute to genotoxic stress and genomic instability in leukocytes. The observed genomic instability during and after flight suggests that the ionizing radiation (IR) exposure caused DNA damage to hematopoietic stem cells that replenish blood cells throughout life. In our recent study, we used leukocytes collected 21-24 years ago from 14 relatively young astronauts who flew space Shuttle missions between 1998-2001 to assay, retrospectively, somatic mutations in CHIP-driver genes. We identified 34 nonsynonymous SNVs in 17 known CHIP-driver genes, of which TP53 and DNMT3A were the most frequent. It is conceivable that these genetic alterations may be particularly magnified when traveling beyond Earth’s geomagnetic field where there is increased exposure to high atomic number and high energy IR.

Methodology: Of particular interest to the proposed studies are findings in our preliminary mouse lifespan space IR studies. As part of our NASA Human Research Program/HRP-funded mouse-lifetime studies to evaluate the effects of space-type and gamma IR on cardiovascular disease (CVD) development, 3-month-old male C57BL6/J mice were systematically examined for tumor development over 22 months after 100 cGy, of gamma (y)- and 50 cGy (500 MeV/n) of 5-ion simplified GCR simulation (simGCRsim)-IR. Both types of IR showed deleterious effects on the left and right ventricular structure and function. Moreover, in y- and simGCRsim-IR mice, detectable neoplasms of internal organs (liver, spleen, lungs, lymph nodes) were observed at 16- and 22 months post-IR, but only one mouse developed a lymphoma in non-IR mice at 16 months and none at 22 months. To study the effects of aging and IR on the development of malignancies (hematopoietic and solid cancers) and CVD, We performed mouse whole-exome sequencing (mWES) of white blood cells and paired tumor tissues to assess somatic mutations on a focused cohort of WT mice that develop liver tumors. Somatic variants were called with a variant allele frequency (VAF) > 0.1%, and annotation was performed using ANNOVAR and MuTect.

Main Findings: At 22 months post-IR mWES analysis revealed a higher incidence (8%) of non-frameshift deletions in both IR groups compared to none in no-IR and WD-fed groups, suggesting this could be an IR-specific mutational signature. In addition, there was an age-associated increase in frameshift deletions (3%) that was increased (to 5%) in simGCRsim-IR mice, suggesting that frameshift deletions are common for aging and are increased after space-type exposure. Interestingly, stop-gain mutations were increased due to aging (7%) and WD-fed mice showed an additional increase (10%) in stop-gain mutation, suggesting that these types of mutations are common for aging and increased by WD. Among all treatment conditions, several genes with identified mutations were associated with various cancers (hematopoietic and solid) and cardiovascular diseases. Comparing mutation-type versus cancer pathology revealed that hepatocellular carcinoma was specific for both types of IR, and histiocytic sarcoma only for space-type IR. Interestingly, hemangiosarcoma was found in WD-fed and y-IR mice but not in simGCRsim-IR mice. Common signaling pathways that were affected by aging (no-IR) or exposure to either IR type include - 1) NF-kB pathway, 2) WNT/beta-catenin signaling pathway, and 3) different mediators of cell cycle checkpoints. Additional studies are underway to study mWES in paired tumor samples and to perform spatial transcriptomics assay (Visium) using adjacent tumor section of the paired tumor samples.

Summary: While the impact of space travel on CHIP is completely unknown, it is reasonable to speculate that space IR in combination with other space travel-related stresses may lead to IR-specific and gene-specific accelerations of clonal hematopoiesis. Our studies identified specific somatic mutations in known CHIP "driver" genes during the lifetime of mice that could provide a framework for the identification of individual susceptibility, predictive genetic biomarkers and development of mitigation strategies before and after future deep space exploration missions. In addition, our studies provided scientific evidence, in animal models, on whether the CHIP-related mutant clone expansions may be the shared underlying biology for space IR-associated cancer and CVD development.

Sub-project 4:

Title: "Lifetime Evaluation of Cardiac Function and Structure in Female C57bl/6j and Apoe Null Mice after Gamma and Space-Type Radiation Exposure"

Background: Space radiation (IR) from Solar Particle Events (SPE) and Galactic Cosmic Rays, also known as high charge and energy (HZE) ionizing IR, is a primary risk associated with deep-space missions. There are limited animal and human studies on the risk of cardiovascular disease (CVD) development due to space-IR. Our longitudinal studies in male mice showed a reduction in global systolic function in Apolipoprotein-E (ApoE) null and C57BL6/J wild type (WT) male mice exhibit reduced global systolic function at 14 and 28 days after exposure to gamma (y) and simplified GCR simulated (simGCRsim)-IR. No significant changes were observed between the control and all other remaining IR groups over the next up to 400 days of the follow-up post-IR. At 22 months, both WT and ApoE null y-IR male mice showed significant cardiac dysfunction paired with structural alterations. To assess for any sex-specific effects following IR exposure, we hypothesized similar alterations in CV function in female ApoE and WT mice following the same IR exposure.

Methods: Three-month-old female age-matched WT and ApoE null mice were irradiated with 137Cs-y -IR (100 cGy, 0.662 MeV) and simGCRsim (25 and 50 cGy, 500 MeV/n). Control ApoE null and WT mice were fed with mouse chow (normal diet-ND) and Western diet (WD) without irradiation. ApoE null mice are predisposed to atherosclerosis development when fed a WD mouse chow due to impaired clearance of elevated plasma low-density lipoproteins (LDL) levels, however, WT mice do not develop atherosclerosis. We assessed left ventricular (LV) function by transthoracic echocardiography at 14, 28, 365, 440, and 580 days post-IR following the same cohort of mice for each treatment condition longitudinally.

Main Finding: At 28 days post-IR, 50 cGy simGCRsim-IR ApoE null and WT mice exhibit reduced Left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS), which paired with decreased posterior wall thickness (LVPWd) may suggest an early but mild effect of IR on systolic function. By 180-, 365-, 440-, and 580 days post-IR, no alteration in LVEF or LVFS was observed in non-IR WD-fed mice and two IR groups of both genotypes. However, in WT mice LV internal diameter (LVIDd), stroke volume (SV), and LV mass were minimally reduced in 50 cGy simCRsim-IR mice at 365 days suggesting possible compensation of the altered diastolic function. In female ApoE null mice, there was no significant alteration in global LV systolic function across any treatment groups at 28-, 180-, 365-, 440-, and 580 days post-IR.

Summary: Our lifetime longitudinal echocardiography findings showed minimal and not statistically significant radiation-associated alterations in global systolic function or structural cardiac alterations in both female WT and ApoE null mice across any treatment group. Compared to our findings in similarly treated male mice cohort the female cohort studies showed substantially decreased in sex-specific CVD risks after space and terrestrial IR over the lifetime of female mice. These findings do not exclude the possibility of increased acute or degenerative CVD risks at lower than 25 and 50 cGy simGCGsim doses of space-type IR and/or when combined with other space travel-associated stressors.

Bibliography: Description: (Last Updated: 03/06/2024) 

Show Cumulative Bibliography
 
Abstracts for Journals and Proceedings Brojakowska A, Fish K, Khlgatian MK, Grano C, Bisserier M, Zhang S, Chepurko V, Chepurko E, Gillespie V, Dai Y, Hadri L, Kishore R, Goukassian DA. "Longitudinal evaluation of cardiac function and structure in apoe null and c57bl/6j mice after gamma and space-type radiation exposure." 2021 NASA Human Research Program Investigators' Workshop, Galveston, Texas, February 1-4, 2021.

Abstracts. 2021 NASA Human Research Program Investigators' Workshop, Galveston, Texas, February 1-4, 2021. , Feb-2021

Abstracts for Journals and Proceedings Bisserier M, Khlgatian MK, Grano C, Zhang S, Brojakowska A, Fish K, Goukassian DA, Hadri L. "Longitudinal evaluation of right ventricular cardiac function after full space radiation exposure." 2021 NASA Human Research Program Investigators' Workshop, Galveston, Texas, February 1-4, 2021.

Abstracts. 2021 NASA Human Research Program Investigators' Workshop, Galveston, Texas, February 1-4, 2021. , Feb-2021

Abstracts for Journals and Proceedings Brojakowska A, Bisserier M, Khlgatian MK, Zhang S, Gillespie V, Dai Y, Hadri L, Goukassian DA. "Lifetime risk of tumor development in c57b1/6j mice exposed to a single full body gamma and simgcrsim radiation." 2021 NASA Human Research Program Investigators' Workshop, Galveston, Texas, February 1-4, 2021.

Abstracts. 2021 NASA Human Research Program Investigators' Workshop, Galveston, Texas, February 1-4, 2021. , Feb-2021

Articles in Peer-reviewed Journals Bisserier M, Saffran N, Brojakowska A, Sebastian A, Evans AC, Coleman MA, Walsh K, Mills PJ, Garikipati VNS, Arakelyan A, Hadri L, Goukassian DA. "Emerging role of exosomal long non-coding RNAs in spaceflight-associated risks in astronauts." Front Genet. 2022 Jan 17;12:812188. eCollection 2021. https://doi.org/10.3389/fgene.2021.812188 ; PMID: 35111205 PMCID: PMC8803151 , Jan-2022
Articles in Peer-reviewed Journals Goukassian D, Arakelyan A, Brojakowska A, Bisserier M, Hakobyan S, Hadri L, Rai AK, Evans A, Sebastian A, Truongcao M, Gonzalez C, Bajpai A, Cheng Z, Dubey PK, Addya S, Mills P, Walsh K, Kishore R, Coleman M, Garikipati VNS. "Space flight associated changes in astronauts’ plasma-derived small extracellular vesicle microRNA: Biomarker identification." Clin Transl Med. 2022 Jun;12(6):e845. https://doi.org/10.1002/ctm2.845 ; PMID: 35653543 PMCID: PMC9162436 , Jun-2022
Articles in Peer-reviewed Journals Bisserier M, Brojakowska A, Saffran N, Rai AK, Lee B, Coleman M, Sebastian A, Evans A, Mills PJ, Addya S, Arakelyan A, Garikipati VNS, Hadri L and Goukassian DA. "Astronauts plasma-derived exosomes induced aberrant EZH2-mediated H3K27me3 epigenetic regulation of the vitamin D receptor." Front Cardiovasc Med. 2022 Jun 16;9:855181. eCollection 2022. https://doi.org/10.3389/fcvm.2022.855181 ; PMID: 35783863 PMCID: PMC9243458 , Jun-2022
Articles in Peer-reviewed Journals Rai AK, Rajan KS, Bisserier M, Brojakowska A, Sebastian A, Evans AC, Coleman MA, Mills PJ, Arakelyan A, Uchida S, Hadri L, Goukassian DA and Garikipati VNS. "Spaceflight-associated changes of snoRNAs in peripheral blood mononuclear cells and plasma exosomes-A pilot study." Front Cardiovasc Med. 2022 Jun 24;9:886689. eCollection 2022. https://doi.org/10.3389/fcvm.2022.886689 ; PMID: 35811715 PMCID: PMC9267956 , Jun-2022
Articles in Peer-reviewed Journals Brojakowska A, Kour A, Thel MC, Park E, Bisserier M, Garikipati VNS, Hadri L, Mills PJ, Walsh K, Goukassian DA. "Retrospective analysis of somatic mutations and clonal hematopoiesis in astronauts." Commun Biol. 2022 Aug 17;5(1):828. https://doi.org/10.1038/s42003-022-03777-z ; PMID: 35978153 PMCID: PMC9385668. , Aug-2023
Articles in Peer-reviewed Journals Brojakowska A, Jackson CJ, Bisserier M, Khlgatian MK, Grano C, Blattnig SR, Zhang S, Fish KM, Chepurko V, Chepurko E, Gillespie V, Dai Y, Lee B, Garikipati VNS, Hadri L, Kishore R, Goukassian DA. "Lifetime evaluation of left ventricular structure and function in male C57BL/6J mice after gamma and space-type radiation exposure." Int J Mol Sci. 2023 Mar 13;24(6):5451. https://doi.org/10.3390/ijms24065451 ; PubMed PMID: 36982525; PubMed Central PMCID: PMC10049327 , Mar-2023
Significant Media Coverage Gasparini A. (Goukassian DA interview). "“Astronaut Blood Samples Could Reveal Health Risks Posed By Space Flight”. Dr. Goukassian interview by Forbes Science Reporter." FORBES March 10, 2022. https://www.forbes.com/sites/allisongasparini/2022/03/10/astronaut-blood-could-reveal-space-flight-risks/?sh=2a85529e7d85 , Mar-2022
Significant Media Coverage Howell E. (Goukassian DA interview). "“Astronauts' blood shows signs of DNA mutations due to spaceflight”. Dr. Goukassian interviewed by space.com reporter." Space.com September 5, 2022. https://www.space.com/astronaut-spaceflight-cancer-dna-mutations-study , Sep-2022
Significant Media Coverage Byrne J. (Brojakowska A and Goukassian DA interview) "Spaceflight may be linked to somatic mutations, increased risk for cancer, heart disease. Ms. Brojakowska and Dr. Goukassian interviewed by HemOncologyToday." HemOnctoday December 12, 2022. https://www.healio.com/news/hematology-oncology/20221212/spaceflight-may-be-linked-to-somatic-mutations-increased-risk-for-cancer-heart-disease , Dec-2022
Significant Media Coverage Christensen T. (Goukassian DA interview). "DNA to leak out of astronauts' cell powerhouse”, American Heart Association News. Dr. Goukassian interviewed AHA News reporter." American Heart Association News”, October 20, 2021, https://www.heart.org/en/news/2021/10/20/spaceflight-caused-dna-to-leak-out-of-astronauts-cell-powerhouse , Oct-2021
Significant Media Coverage Clarke V. (Goukassian DA interview). "Spaceflight can cause mutations in human DNA. Astronauts safe? Dr. Goukassian interviewed by UK Daily News reporter." UK Daily News, September 2, 2022, https://ukdaily.news/spaceflight-can-cause-mutations-in-human-dna-astronauts-safe-68485.html , Sep-2022
Significant Media Coverage McFarland F. (Goukassian DA interview). "Astronauts’ blood shows signs of DNA mutation due to spaceflight may have a cancer risk. Dr. Goukassian interviewed by US Sun reporter." The US Sun, September 6, 2022, https://www.the-sun.com/tech/6164149/astronauts-dna-blood-mutation-in-space/ , Sep-2022
Significant Media Coverage Arianne G. (Goukassian DA interview). "DNA Mutations Found In Astronauts' Blood: Study. Dr. Goukassian interviewed by Business Times reporter." Business Times, September 6, 2022, https://www.btimesonline.com/articles/156158/20220906/dna-mutations-found-astronauts-blood-study.htm , Sep-2022
Significant Media Coverage Porterfield C. (Goukassian DA interview). "Spaceflight Could Increase Risk Of Cancer And Heart Disease In Astronauts, Study Suggests. Dr. Goukassian interviewed by Forbes Africa reporter." FORBES Africa, September 1, 2022, https://www.forbesafrica.com/health/2022/09/01/spaceflight-could-increase-risk-of-cancer-and-heart-disease-in-astronauts-study-suggests/ , Sep-2022
Significant Media Coverage Nikravesh I. (Goukassian DA Press Release). "Researchers Find Spaceflight May Be Associated With DNA Mutations and Increased Risk of Developing Heart Disease and Cancer. Dr. Goukassian interviewed by Mount Sinai Press release office." Mount Sinai Newsroom. August 31, 2022. https://www.mountsinai.org/about/newsroom/2022/fesearchers-find-spaceflight-may-be-associated-with-dna-mutations-and-increased-risk-of-developing-heart-disease-and-cancer , Aug-2022
Significant Media Coverage Martin M. (Goukassian DA interview). "NASA Astronauts' Blood Shows Signs of DNA Mutation After Returning From Space. Dr. Goukassian interviewed by Finance.yahoo reporter." Finance.yahoo, September 11, 2022, https://finance.yahoo.com/news/nasa-astronauts-blood-shows-signs-155823841.html?guccounter=1&guce_referrer=aHR0cHM6Ly93d3cuZ29vZ2xlLmNvbS8&guce_referrer_sig=AQAAAGHKBGza4wTsfcuBnCrN_-T-grOY3ccR_ZahppuSp66aZWbcDbkFmr8AG66M5NxhQK_IcMxrLiHPbz6elbeI99ItIgkWQL4BXLFLXJ5dy6sgrtYvrBVso9r5KSaNbeilmSoxtY7iQCP-t6urRhgwTKcFJrKxKdQqnqIoHgBz69LY , Sep-2022
Significant Media Coverage William. (Goukassian DA interview). "NASA Astronauts’ Blood Shows Signs Of DNA Mutations Due To Spaceflight And They Must Be Monitored. Dr. Goukassian interviewed by NY Breaking reporter." NY Breaking, September 5, 2022, https://nybreaking.com/nasa-astronauts-blood-shows-signs-of-dna-mutations-due-to-spaceflight-and-they-must-be-monitored/ , Sep-2022
Significant Media Coverage Melillo G. (Goukassian interview). "Spaceflight may increase the risk of heart disease, cancer: study. Dr. Goukassian interviewed by The Hill reporter." The Hill, August 31, 2022, https://thehill.com/changing-america/well-being/prevention-cures/3622854-spaceflight-may-increase-the-risk-of-heart-disease-cancer-study/ , Aug-2022
Significant Media Coverage The Universe Today. (Goukassian DA interview). "Space travel changes astronauts' DNA. Dr. Goukassian interviewed by The Universe Today reporter." Technologie et science, October 19, 2022. https://www.speakdating.io/fr-fr/activity-space-travel-changes-astronauts-dna , Oct-2022
Significant Media Coverage Carbone C. (Goukassian DA interview). "NASA astronauts' blood shows signs of DNA mutations due to spaceflight and they must be monitored for cancer risk, new study reveals. Dr. Goukassian interviewed by Daily Mail reporter." Daily Mail September 5, 2022. https://www.dailymail.co.uk/sciencetech/article-11182509/NASA-astronauts-blood-shows-signs-DNA-mutations-spaceflight-monitored.html , Sep-2022
Significant Media Coverage Quach K. (Goukassian DA interview). "Astronaut blood reveals genetic mutations for cancer and heart disease. Dr. Goukassian interviewed by The Register reporter." The Register, September 1, 2022. https://www.theregister.com/2022/09/01/astronauts_blood_space_health/ , Sep-2022
Significant Media Coverage Sharma B. (Goukassian DA interview). "Study Finds Astronauts' Blood Develops DNA Mutations Due To Spaceflight. Dr. Goukassian interviewed by IndiaTimes reporter." IndiaTimes September 10, 2022, https://www.indiatimes.com/technology/science-and-future/astronauts-blood-develops-dna-mutations-due-to-spaceflight-study-578991.html , Sep-2022
Significant Media Coverage Antidote H. (Goukassian DA interview). "Astronauts' blood shows signs of DNA mutations due to spaceflight. Dr. Goukassian interviewed by reporter." Pakistan Defense, September 5, 2022, https://defence.pk/pdf/threads/astronauts-blood-shows-signs-of-dna-mutations-due-to-spaceflight.750331/ , Sep-2022
Significant Media Coverage Leitch C. (Goukassian DA interview). "Spaceflight Seems to Raise Levels of Circulating Cell-Free Mitochondrial DNA. Dr. Goukassian interviewed by LabRoots reporter." LabRoots, October 25, 2021, https://www.labroots.com/trending/space/21548/spaceflight-raise-levels-circulating-cell-free-mitochondrial-dna , Oct-2021
Significant Media Coverage Press Release (Goukassian DA interview). "Researchers find spaceflight may be associated with DNA mutations and increased risk of developing heart disease and cancer. Dr. Goukassian interviewed by Mount Sinai Hospital Press Release Office." The Mount Sinai Hospital / Mount Sinai School of Medicine, August 31, 2022. https://www.sciencedaily.com/releases/2022/08/220831113642.htm , Aug-2022
Significant Media Coverage Felicity T. (Goukassian DA interview). "Spaceflights ‘Most Likely’ Linked to DNA Mutations Putting Astronauts at Risk of Cancer. Dr. Goukassian interviewed by TechTimes reporter." TechTimes, August 31, 2022, https://www.techtimes.com/articles/279921/20220831/spaceflights-most-likely-linked-to-dna-mutations-putting-astronauts-at-risk-of-cancer.htm , Aug-2022
Significant Media Coverage Martin M. (Goukassian DA interview). "NASA Astronauts' Blood Shows Signs of DNA Mutation After Returning From Space. Dr. Goukassian interviewed by MSN reporter." MSN, September 11, 2022, https://www.msn.com/en-us/health/medical/nasa-astronauts-blood-shows-signs-of-dna-mutation-after-returning-from-space/ss-AA11HK8v?li=BBnba9O , Sep-2022
Significant Media Coverage Shirole T. (Goukassian DA interview). "Astronauts Prone to DNA Mutations That Increases Risk of Cancer and Heart Disease. Dr. Goukassian interviewed by MedIndia reporter." Medindia, September 5, 2022, https://www.medindia.net/news/healthwatch/astronauts-prone-to-dna-mutations-that-increases-risk-of-cancer-heart-disease-208504-1.htm , Sep-2022
Significant Media Coverage Voytovich K. (Goukassian DA interview). "Scientists have discovered mutations in the DNA of astronauts’ cells. Dr. Goukassian interviewed by Mezha Media reporter." Mezha Media September 13, 2022. https://mezha.media/en/2022/09/13/scientists-have-discovered-mutations-in-the-dna-of-astronauts-cells/ , Sep-2022
Significant Media Coverage Tangermann V. (Goukassian DA interview). "Scientists Found Genetic Mutations in Every Astronaut Blood Sample They Studied. Dr. Goukassian interviewed by Futurism reporter." Futurism, September 6, 2022. https://futurism.com/neoscope/scientists-genetic-mutations-every-astronaut-blood-sample , Sep-2022
Significant Media Coverage Bayard J-G. (Goukassian DA interview). "Can spaceflight damage our DNA? Dr. Goukassian interviewed by Pourquoi Doctor reporter." Pourquoi doctor, FR, October 21, 2021, https://www.pourquoidocteur.fr/Articles/Question-d-actu/37603-Les-vols-spatiaux-peuvent-ils-endommager-ADN , Oct-2021
Significant Media Coverage Henderson E. (Goukassian DA interview). "Spaceflight increases the risk of developing cancer and heart disease. Dr. Goukassian interviewed by AZO Life Sciences reporter." AZO Life Sciences, September 2, 2022 https://www.azolifesciences.com/news/20220902/Spaceflight-increases-the-risk-of-developing-cancer-and-heart-disease.aspx , Sep-2022
Significant Media Coverage Micu A. (Goukassian DA interview). "Space flight seems to be causing one specific mutation in the blood of astronauts. Dr. Goukassian interviewed by ZME Science reporter." ZME Science, September 7, 2022. https://www.zmescience.com/science/space-flight-astronauts-blood-mutation-22645/ , Sep-2022
Significant Media Coverage Al Mayadeen. (Goukassian DA interview). "DNA mutation from spaceflight may increase cancer risk in astronauts. Dr. Goukassian interviewed by almayaden.net reporter." Almayaden.net, September 6, 2022, https://english.almayadeen.net/news/technology/dna-mutation-from-spaceflight-may-increase-cancer-risk-in-as , Sep-2022
Significant Media Coverage Goyal N. (Goukassian DA interview). "Spaceflight Could Increase Risk of Cancer and Heart Disease in Astronauts. Dr. Goukassian interviewed by Industry Tap into News reporter." Industry Tap into News, September 12, 2022, https://www.industrytap.com/spaceflight-could-increase-risk-of-cancer-and-heart-disease-in-astronauts/63829 , Sep-2022
Project Title:  Space Relevant Radiation-Induced Cardiovascular Disease Risk Thresholds: Effect of Gender on the Outcome Reduce
Images: icon  Fiscal Year: FY 2022 
Division: Human Research 
Research Discipline/Element:
HRP SR:Space Radiation
Start Date: 04/10/2019  
End Date: 04/09/2023  
Task Last Updated: 03/07/2022 
Download report in PDF pdf
Principal Investigator/Affiliation:   Goukassian, David A M.D., Ph.D. / Icahn School of Medicine at Mount Sinai 
Address:  Zena & Michael A. Weiner Cardiovascular Institute 
One Gustave L. Levy Place, Box 1030 
New York , NY 10029 
Email: david.goukassian@mssm.edu 
Phone: 617-480-3890  
Congressional District: 12 
Web:  
Organization Type: UNIVERSITY 
Organization Name: Icahn School of Medicine at Mount Sinai 
Joint Agency:  
Comments: NOTE: PI moved to Icahn School of Medicine at Mount Sinai from Temple University in October 2018.  
Project Information: Grant/Contract No. 80NSSC19K1079 
Responsible Center: NASA JSC 
Grant Monitor: Elgart, Robin  
Center Contact: 281-244-0596 (o)/832-221-4576 (m) 
shona.elgart@nasa.gov 
Unique ID: 12726 
Solicitation / Funding Source: 2016-2017 HERO NNJ16ZSA001N-SRHHC. Appendix E: Space Radiobiology and Human Health Countermeasures Topics 
Grant/Contract No.: 80NSSC19K1079 
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) Cardiovascular:Risk of Cardiovascular Adaptations Contributing to Adverse Mission Performance and Health Outcomes
Human Research Program Gaps: (1) CV-102:Determine whether space radiation induces cardiovascular structural and functional changes and/or oxidative stress & damage (OSaD)/inflammation, that can contribute to development of disease.
Flight Assignment/Project Notes: NOTE: Continuation of "Space Relevant Radiation-Induced Cardiovascular Disease Risk Thresholds: Effect of Gender on the Outcome," grant 80NSSC18K0921, due to PI move to Icahn School of Medicine at Mount Sinai from Temple University. (Ed., 2/10/2020)

Task Description: Ed. note 2/10/2020: Continuation of "Space Relevant Radiation-Induced Cardiovascular Disease Risk Thresholds: Effect of Gender on the Outcome," grant 80NSSC18K0921 with the same Principal Investigator Dr. David Goukassian, due to PI move to Icahn School of Medicine at Mount Sinai from Temple University.

During the future Moon, near Earth asteroids, and Mars missions, astronauts will be exposed to higher total doses of space irradiation (IR) (~0.4-0.5 Gy) from galactic cosmic rays (GCR). Most of what we know about harmful effects of IR on cardiovascular (CV) system is from epidemiological studies of long-term survivors of cancer radiotherapy (RT). A recent study of 2,168 women who underwent RT for breast cancer has shown that the rates of major coronary events increased linearly with the mean dose to the heart by 7.4% per Gy, with no apparent lower or upper threshold. In this study, it was determined that average of the mean doses to the whole heart was 4.9 Gy with the range of 0.03 - 27.72 Gy. Furthermore, metabolomics studies, in patients undergoing hematopoietic stem cell (HSC) transplantation as part of cancer treatment (1.25 Gy total-body irradiated), identified seven urine-based biomarkers with distinct differences between pre- and post-exposure samples. The levels of these markers were found to be gender-dependent suggesting that separate biomarker signatures may exist for males and females.

Hypotheses: Our central hypothesis is that low-dose proton and HZE (high energy) particle IR-induced biological responses are long-lasting, IR type- and dose-dependent and may augment excess relative risk (ERR) estimates for the development of cardiovascular diseases (CVDs) during and after long-duration space missions. In addition, we hypothesize that gender differences could further modify radio-biologically effective (RBE) IR thresholds for CV risk estimates. Gene expression and epigenetic modifications in protein and microRNA (miRNA) in exosomes from the blood (e.g., plasma/serum) may be altered before the onset of the cardiac symptoms, which could be used as potential biomarkers to predict the CVD risks. We will test our hypotheses with the following specific aims:

AIM 1. Determine the longitudinal effect of IR type, dose, and gender on cardiovascular physiology in wild type mice and ApoE null mice after full-body 5-ion simplified mixed field and gamma radiation.

AIM 2. Determine space-type IR mediated modulations in exosomal cargo in the blood, and determine whether these changes are associated with alterations in the heart function, structure, and vasculature before the manifestation of clinical symptoms.

AIM 3. Utilize known and newly identified biomarkers in the blood to develop human-relevant point-of-care tests (POCT) for predicting and monitoring possible CV alterations before and during space flights.

We anticipate that the results of our proposed work may be beneficial for human space exploration and could (1) Determine single whole body mixed field dose-response, radio-biologically effective IR thresholds in the heart and cardiac vasculature, and whether gender differences could modify radio-biologically effective IR thresholds for CV risk estimates; 2) Determine whether space radiation leads to modifications in the circulating exosomal cargo contents and whether IR-induced exosomal cargo modulations are reflective of subclinical changes in the cells and organs of origin; 3) Ascertain if modulations of exosomal cargo may be representative of chronic oxidative stress and inflammation and could serve as early biomarkers of IR-induced CVD initiation and progression; 4) Integrate physiological CV endpoint data sets with gene expression and epigenetic data to identify biomarkers in bio-fluids that could be used for prediction of asymptomatic CVD in the setting of space IR, which will include known early and intermediate biomarkers of cardiac damage, inflammation, and oxidative stress, as well as currently unknown novel radiation-associated cardiac biomarkers.

Research Impact/Earth Benefits: We anticipate that the results of our work could be beneficial for human space exploration as well as for the Earth-based applications on several levels -- (1) determine whether low dose space-type and terrestrial IR may present an increased risk for CVD development during and after prolonged space missions, as well as after conventional and particle cancer radiotherapy; (2) determine the underlying molecular signaling of CV alterations; (3) identify biomarkers in the blood that could be used for prediction of asymptomatic CV disease, which will include known early and intermediate biomarkers of cardiac damage, as well as currently unknown novel cardiac biomarkers; (4) the identification of sub-clinical CV disease biomarkers that could be used for monitoring the effectiveness of mitigating factors for prevention and treatment of IR-induced CVDs in space and in Earth-bound civilian population, in general.

Task Progress & Bibliography Information FY2022 
Task Progress: In late September 2018, we irradiated at the NASA Space Radiation Laboratory (NSRL) and the Brookhaven National Laboratory (BNL) gamma facility 660 ApoE null male mice and 480 C57Bl/6J male mice, the first two cohorts of our longitudinal lifetime studies. We completed and performed cardiac function analyses and harvested tissues and blood for 5 harvesting time points (14, 28, 365, 440, and 660 days post-irradiation). In terms of selection of radiation parameters, we utilized the following doses, energies, and ions, as recommended by Space Radiation Element Management:

(i) Gamma IR - 1, 2, and 4 Gy, using ApoE null MALE mice for all time points indicated above. (ii) 5-Ion Simplified Mixed field IR - 0.5, 1.0 and 1.5 Gy, adjusted to 500 MeV/n, using ApoE null MALE mice for all time points indicated above. (iii) Gamma IR – 1, 2 Gy, using WT-C57BL/6J MALE mice for all time points indicated in section above. (iv) 5-Ion Simplified Mixed field IR - 0.5, 1.0 Gy, adjusted to 500 MeV/n, using WT-C57BL/6J MALE mice for all time points indicated above.

Lifetime tumor burden As part of our study to assess the effects of space radiation on cardiovascular disease (CVD) risks, male mice were systematically examined for tumor development during scheduled tissue collections over 660 days after initial radiation (IR) exposure. We report:

• The incidence of tumors is higher in wild type (WT) compared to ApoE null male mice after the same doses of gamma- and simGCRsim-IR suggesting underlying genotypic variance may attenuate pathways involved in tumorigenesis;

• The highest number of tumors during the lifetime of WT male mice was detected in the no-IR, Western diet-fed (WD-fed) group, suggesting the role of high fat diet in the development of internal organ tumors, especially in the liver;

• In WT male mice, the incidence of IR-induced internal organ tumors was higher in 100 cGy gamma-IR versus 50 cGy simGCRsim-IR, suggesting higher carcinogenic potential of gamma-IR at these doses;

• In WT male mice, the liver is the most affected organ by tumor growth, followed by the spleen, and lung;

• There was a higher incidence of hepatic and splenic tumors in mice fed with WD or exposed to both types of IR in WT mice approaching end of life;

• In ApoE null male mice, the incidence of IR-induced tumors was higher in 50 cGy simCGRsim -IR mice with a higher prevalence of lung tumors.

In October 2020, we have irradiated at the NSL and the BNL gamma facility an additional 160 ApoE null female mice and 300 C57BL/6J female mice. This longitudinal life-time study is designed to have 5 harvesting time points (28, 180, 365, 440, and 660 days). We have already performed cardiac function analyses and harvested tissues for 4 of our harvesting time points (28, 180, 365, and 440 days). The final collecting time point is scheduled for July 2022. In terms of selection of radiation parameters, we utilized the following doses, energies, and ions, as recommended by Space Radiation Element Management:

(i) Gamma IR – 1 Gy, using ApoE null and WT FEMALE mice for all time points indicated above. (ii) 5-Ion Simplified Mixed field IR - 0.5 Gy, adjusted to 500 MeV/n, using ApoE null FEMALE mice. (iii) 5-Ion Simplified Mixed field IR - 0.25, 0.50 cGy adjusted to 500 MeV/n, using WT-C57BL/6J FEMALE mice for all time points indicated above.

Left ventricular (LV) cardiac response to IR.

Cardiac function was assessed non-invasively in all control and irradiated ApoE null and C57BL/6J female mice by transthoracic echocardiography at 28, 180, and 365 days post-IR. Each mouse is microchipped and followed longitudinally.

To briefly summarize our male cohort echocardiography findings:

• A single full-body IR at doses of 100-200 cGy for gamma- IR and 50-100 cGy for simGCRsim-IR decreases global LV systolic function in WT male mice at 14, 28, and 365 days post-IR.

• At 660 days post-IR, 50 cGy simGCRsim-IR WT male mice exhibited increased diastolic stiffness paired with alterations in LV size and mass, suggesting these mice may be exhibiting additional diastolic dysfunction and compensation as a result of pressure overload.

• In ApoE null male mice, global LV systolic function is impaired as early as 14 and 28 days post-IR in both simGCRsim (100, 200, 400 cGy) and gamma- IR (100, 200 cGy) mice. Interestingly, there is no intermediate time point (365, 440 days) where LV dysfunction is noted.

• By 660 days post-IR, gamma-IR ApoE null male mice exhibit significant systolic dysfunction with reduction in Left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), and increases in stroke volume (SV), LV mass, and LV dimensions suggesting compensation for likely volume overload. No significant changes in LV function were noted in simGCRsim-IR ApoE null male mice at 660 days.

• No clear dose-response was observed in these studies.

In our female longitudinal cohort:

• A single full-body IR at doses of 100 cGy for gamma-IR and 25 or 50 cGy for simGCRsim-IR decreases the global systolic function of the heart in both ApoE null and WT female mice at 28 days post-IR.

• At later time points (180, 365 days), no significant alterations in global LV systolic function are noted; however, in WT female mice, there is evidence of alterations in LV structure suggesting ongoing remodeling.

• Further work is underway to collect additional data to assess long-term degenerative effects of IR (440, 660 days) in female WT and ApoE null mice. Analysis of additional echocardiography parameters to assess LV remodeling are underway.

These findings do not exclude the possibility of increased acute or degenerative CVD risks at lower doses of space-type IR and/or when combined with other space travel-associated stressors, such as microgravity.

Bibliography: Description: (Last Updated: 03/06/2024) 

Show Cumulative Bibliography
 
Abstracts for Journals and Proceedings Brojakowska A, Fish K, Khlgatian M, Grano C, Bisserier M, Zhang S, Saffran N, Chepurko V, Chepurko E, Gillespie V, Dai Y, Hadri L, Kishore R, Goukassian D. "Longitudinal evaluation of cardiac function and structure in C57BL/6J mice after gamma and space-type radiation exposure." 2022 NASA Human Research Program Investigators’ Workshop, Virtual, February 7-10, 2022.

Abstracts. 2022 NASA Human Research Program Investigators’ Workshop, Virtual, February 7-10, 2022, Abstract #1133-000167. , Feb-2022

Abstracts for Journals and Proceedings Brojakowska A, Bisserier M, Elmas A, Khlgatian M, Zhang S, Gillespie V, Dai Y, Hadri L, Goukassian D. "Lifetime risk of tumor development in C56B1/6J mice fed with Western diet or exposed to a single full body gamma or simGCRsim radiation." 2022 NASA Human Research Program Investigators’ Workshop, Virtual, February 7-10, 2022.

Abstracts. 2022 NASA Human Research Program Investigators’ Workshop, Virtual, February 7-10, 2022, Abstract #1133-000425. , Feb-2022

Abstracts for Journals and Proceedings Jackson C, Brojakowska A, Blattnig S, Khlgatian M, Grano C, Fish K, Chepurko V, Chepurko E, Kishore R, Goukassian D. "The comparative effect of gamma and simplified GCR simulation irradiation on cardiac response in ApoE null mice. " NASA Human Research Program Investigators’ Workshop, Virtual, February 7-10, 2022.

Abstracts. 2022 NASA Human Research Program Investigators’ Workshop, Virtual, February 7-10, 2022, Abstract #1133-000142. , Feb-2022

Articles in Peer-reviewed Journals Bisserier M, Saffran N, Brojakowska A, Sebastian A, Evans AC, Coleman MA, Walsh K, Mills PJ, Garikipati VNS, Arakelyan A, Hadri L, Goukassian DA. "Emerging role of exosomal long non-coding RNAs in spaceflight-associated risks in astronauts." Front Genet. 2022 Jan 17;12:812188. https://doi.org/10.3389/fgene.2021.812188 , Jan-2022
Project Title:  Space Relevant Radiation-Induced Cardiovascular Disease Risk Thresholds: Effect of Gender on the Outcome Reduce
Images: icon  Fiscal Year: FY 2021 
Division: Human Research 
Research Discipline/Element:
HRP SR:Space Radiation
Start Date: 04/10/2019  
End Date: 04/09/2023  
Task Last Updated: 04/01/2021 
Download report in PDF pdf
Principal Investigator/Affiliation:   Goukassian, David A M.D., Ph.D. / Icahn School of Medicine at Mount Sinai 
Address:  Zena & Michael A. Weiner Cardiovascular Institute 
One Gustave L. Levy Place, Box 1030 
New York , NY 10029 
Email: david.goukassian@mssm.edu 
Phone: 617-480-3890  
Congressional District: 12 
Web:  
Organization Type: UNIVERSITY 
Organization Name: Icahn School of Medicine at Mount Sinai 
Joint Agency:  
Comments: NOTE: PI moved to Icahn School of Medicine at Mount Sinai from Temple University in October 2018.  
Project Information: Grant/Contract No. 80NSSC19K1079 
Responsible Center: NASA JSC 
Grant Monitor: Elgart, Robin  
Center Contact: 281-244-0596 (o)/832-221-4576 (m) 
shona.elgart@nasa.gov 
Unique ID: 12726 
Solicitation / Funding Source: 2016-2017 HERO NNJ16ZSA001N-SRHHC. Appendix E: Space Radiobiology and Human Health Countermeasures Topics 
Grant/Contract No.: 80NSSC19K1079 
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) Cardiovascular:Risk of Cardiovascular Adaptations Contributing to Adverse Mission Performance and Health Outcomes
Human Research Program Gaps: (1) CV-102:Determine whether space radiation induces cardiovascular structural and functional changes and/or oxidative stress & damage (OSaD)/inflammation, that can contribute to development of disease.
Flight Assignment/Project Notes: NOTE: Continuation of "Space Relevant Radiation-Induced Cardiovascular Disease Risk Thresholds: Effect of Gender on the Outcome," grant 80NSSC18K0921, due to PI move to Icahn School of Medicine at Mount Sinai from Temple University. (Ed., 2/10/2020)

Task Description: Ed. note 2/10/2020: Continuation of "Space Relevant Radiation-Induced Cardiovascular Disease Risk Thresholds: Effect of Gender on the Outcome," grant 80NSSC18K0921 with the same Principal Investigator Dr. David Goukassian, due to PI move to Icahn School of Medicine at Mount Sinai from Temple University.

During the future Moon, near Earth asteroids, and Mars missions, astronauts will be exposed to higher total doses of space irradiation (IR) (~0.4-0.5 Gy) from galactic cosmic rays (GCR). Most of what we know about harmful effects of IR on cardiovascular (CV) system is from epidemiological studies of long-term survivors of cancer radiotherapy (RT). A recent study of 2,168 women who underwent RT for breast cancer has shown that the rates of major coronary events increased linearly with the mean dose to the heart by 7.4% per Gy, with no apparent lower or upper threshold. In this study, it was determined that average of the mean doses to the whole heart was 4.9 Gy with the range of 0.03 - 27.72 Gy. Furthermore, metabolomics studies, in patients undergoing hematopoietic stem cell (HSC) transplantation as part of cancer treatment (1.25 Gy total-body irradiated), identified seven urine-based biomarkers with distinct differences between pre- and post-exposure samples. The levels of these markers were found to be gender-dependent suggesting that separate biomarker signatures may exist for males and females.

Hypotheses: Our central hypothesis is that low-dose proton and HZE (high energy) particle IR-induced biological responses are long-lasting, IR type- and dose-dependent and may augment excess relative risk (ERR) estimates for the development of CV diseases during and after long-duration space missions. In addition, we hypothesize that gender differences could further modify radio-biologically effective (RBE) IR thresholds for CV risk estimates. Gene expression and epigenetic modifications in protein and microRNA (miRNA) in exosomes from the blood (e.g., plasma/serum) may be altered before the onset of the cardiac symptoms, which could be used as potential biomarkers to predict the CV disease risks. We will test our hypotheses with the following specific aims:

AIM 1. Determine the longitudinal effect of IR type, dose, and gender on cardiovascular physiology in wild type mice and ApoE null mice after full-body 5-ion simplified mixed field and gamma radiation.

AIM 2. Determine space-type IR mediated modulations in exosomal cargo in the blood, and determine whether these changes are associated with alterations in the heart function, structure, and vasculature before manifestation of clinical symptoms.

AIM 3. Utilize known and newly identified bio-markers in the blood to develop human-relevant point-of-care tests (POCT) for predicting and monitoring possible CV alterations before and during the space flights.

We anticipate that the results of our proposed work may be beneficial for human space exploration and could (1) Determine single, low-dose 1H, 56Fe, and mixed field dose-responses, radio-biologically effective IR thresholds in the heart and cardiac vasculature, and whether gender differences could modify radio-biologically effective IR thresholds for CV risk estimates; 2) Determine whether space radiation leads to modifications in the circulating exosomal cargo contents and whether IR-induced exosomal cargo modulations are reflective of subclinical changes in the cells and organs of origin; 3) Ascertain if modulations of exosomal cargo may be representative of chronic oxidative stress and inflammation and could serve as early bio-markers of IR-induced CV disease initiation and progression; 4) Integrate physiological CV endpoint data sets with gene expression and epigenetic data to identify bio-markers in bio-fluids that could be used for prediction of asymptomatic CV disease in the setting of space IR, which will include known early and intermediate bio-markers of cardiac damage, inflammation, and oxidative stress, as well as currently unknown novel radiation-associated cardiac bio-markers.

Research Impact/Earth Benefits: We anticipate that the results of our work could be beneficial for human space exploration as well as for the Earth-based applications on several levels -- (1) determine whether low dose space-type and terrestrial IR may present an increased risks for CV disease development during and after prolonged space missions, as well as after conventional and particle cancer radiotherapy; (2) determine the underlying molecular signaling of CV alterations; (3) identify bio-markers in the blood that could be used for prediction of asymptomatic CV disease, which will include known early and intermediate bio-markers of cardiac damage, as well as currently unknown novel cardiac biomarkers; (4) the identification of sub-clinical CV disease biomarkers that could be used for monitoring the effectiveness of mitigating factors for prevention and treatment of IR-induced CV diseases in space and in Earth-bound civilian population, in general.

Task Progress & Bibliography Information FY2021 
Task Progress: In late September 2018, we irradiated at the NASA Space Radiation Laboratory (NSRL) and the Brookhaven National Laboratory (BNL) gamma facility 660 ApoE null male mice and 480 C57Bl/6J male mice, first two cohorts of our longitudinal lifetime studies. In terms of selection of radiation parameters, we utilized the following doses, energies, and ions, as recommended by Radiation Biology Element Management:

(i) Gamma IR - 100, 200, and 400 cGy, using ApoE null MALE mice for all time points indicated above.

(ii) 5-Ion Simplified Mixed field (simGCRsim) IR – 50, 100, and 150 cGy, adjusted to 500 MeV/n, using ApoE null MALE mice for all time points indicated above.

(iii) Gamma IR – 100 and 200 cGy, using WT-C57BL/6J MALE mice for all time points indicated in section above.

(iv) 5-Ion Simplified Mixed field (simGCRsim) IR – 50 and 100 cGy, adjusted to 500 MeV/n, using WT-C57BL/6J MALE mice for all time points indicated above.

At the time of this report, we have collected functional cardiac echocardiography data as well as various tissues and blood from animals at all five designated time points (14 days and 28 days post IR as well as 12-, 16-, and 22- months post IR). Our updated findings are as follows:

With regards to left ventricular (LV) cardiac function: Cardiac function was assessed non-invasively in all control and irradiated ApoE null and C57Bl/6J mice by transthoracic echocardiography (ECHO) at baseline (before IR) as well as at acute time points post IR (14 and 28 days) and chronic time points (12-, 16- and 22-months post IR). To summarize our findings:

A single full-body IR at doses of 100-400 cGy for gamma- IR and 50-150 cGy for simGCRsim-IR decreases the global systolic function of the heart in both ApoE null and WT mice at 14 and 28 days after exposure. Histological analyses of H&E stained slides at 28 days after radiation showed – (i) multifocal myofiber disarray with mildly increased variation in myofiber diameter; (ii) swollen myocytes; (iii) mild to moderate sarcoplasmic swelling; (iv) minimal multifocal mineralization of few myofibers within papillary muscles. This suggests inducible alterations in cardiac tissues morphology are detectible early on in response to altered LV function.

Our lifetime study reveals that at these doses, cardiac function is significantly affected at 22 months post-IR in both mouse genotypes. Interestingly, WT mice have an intermediate time point (12 months) where impairment in LV function is observed. Our data suggests, WT IR-mice may be exhibiting more diastolic dysfunction and compensation due to pressure overload, while our ApoE null mice LV functional impairment appears more consistent with a volume overloaded system as noted by increased LV dimensions and size. At 22 months, ApoE null gamma-IR mice exhibit significant systolic dysfunction; however, this does not exclude possibility of diastolic dysfunction in remining IR groups and mouse genotypes. Cardiac tissue responses, morphology, structure, and underlying molecular mechanisms are being analyzed for later time points. Overall, these findings do not exclude the possibility of increased acute or degenerative CV disease risks at lower doses of space-type IR and/or when combined with other space travel-associated stressors, such as microgravity.

Vascular plaque burden: We assessed the effects of gamma- and simGCRsim-IR on vascular plaque burden along with fibrosis development and progression in ApoE null mice. We collected the aortic root with ascending aorta, and aortic arch with carotids and descending aorta from ApoE null and WT mice at 14 and 28 days, as well as 12-, 16-, and 22-months post-IR. ApoE null en face aortas were stained with Oil-Red-O to quantify plaque burden.

To summarize our findings, the highest plaque burden is observed in non-IR western diet (WD)-fed mice at 12 months compared to remaining treatment groups. However, there was an ~1.5-fold increase plaque burden in the descending aorta and full aorta from 16 to 22 months in 50 cGy simGCRsim-IR mice. Progression in full aortic and descending aorta plaque burden is also seen in gamma-IR mice from 12 to 22 months, with a 2-fold increase in vascular plaque over a 10-month period. These findings further suggest that simGCRsim- and gamma-IR may accelerate plaque progression and suggest simGCRsim-IR may be doing so at a higher rate compared to gamma-IR. Our data suggests there is potential IR induced acceleration in plaque progression between the 16- and 22-month time points that is possibly more pronounced with simGCRsim-IR, and that could make the long-term effects of IR comparable to that of a WD. Further work is underway for quantification of fibrosis in both the aorta as well as the aortic root for all treatment groups. Further analyses including in WT mice is underway.

Right ventricular (RV) function: We hypothesize that space-type IR may potentiate pulmonary hypertension and lung fibrosis, therefore inducing vascular remodeling and affecting the right ventricular (RV) morphology and function. Thus, we assessed the effects of gamma-IR (100, 200 cGy) and simGCRsim-IR (50, 100, 150 cGy) on the structure and the function of the heart and lungs over a 22-month post-IR follow up.

Our results showed that full-body gamma- and simGCRsim-IR potentiates the mRNA expression of proliferation, oxidative stress, and inflammation gene markers, as well as vascular remodeling and fibrosis in lung tissue as early as 28 days post IR. Compared to controls, morphometric measurements revealed an increase of the intima-media thickness of the distal pulmonary arteries after both types of IR. In addition, there was a significant increase in perivascular inflammatory infiltration in the lung tissue after simGCGsim radiation with a substantial perivascular fibrosis of pulmonary arteries. Concomitantly, compared to controls, a significant increase in right ventricular systolic pressure (RVSP) after exposure to gamma-IR 200 cGy or simGCRsim 100 cGy was observed at 12-month post IR exposure. Echo analyses at 22-months revealed significant increases in RV internal diameter (RVIDs) in ApoE null mice after all doses of simGCRsim, whereas WT mice revealed 2-fold decreases in RV diameter at mid-level after all doses and types of radiation. However, the structural and functional changes such as increases in pulmonary artery diameter and pulmonary valve maximum velocity were detected only in mice exposed to 50 cGy of simGCRsim and 200 cGy of gamma-IR. Collectively, these findings indicate that both types of radiation may have deleterious effects on the RV and lung structure and function that may lead to the development of pulmonary arterial hypertension.

Bibliography: Description: (Last Updated: 03/06/2024) 

Show Cumulative Bibliography
 
Abstracts for Journals and Proceedings Brojakowska A, Bisserier M, Khlgatian MK, Zhang S. Gillespie V, Dai Y, Hadri, Goukassian DA. "Lifetime risk of tumor development in c57b1/6j mice exposed to a single full body gamma and simGCRsim radiation." Presented at the 2021 NASA Human Research Program Investigators’ Workshop, Virtual, February 1-4, 2021.

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

Abstracts for Journals and Proceedings Bisserier M, Khlgatian MK, Grano C, Zhang S, Brojakowska A, Fish K, Goukassian DA, Hadri L. "Longitudinal evaluation of right ventricular cardiac function after full space radiation exposure." Presented at the 2021 NASA Human Research Program Investigators’ Workshop, Virtual, February 1-4, 2021.

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

Abstracts for Journals and Proceedings Fish K, Khlgatian MK, Grano C, Bisserier M, Zhang S, Brojakowska A, Chepurko V, Chepurko E, Gillespie V, Dai Y, Hadri L, Kishore R, Goukassian DA. " Longitudinal evaluation of cardiac function and structure in ApoE null and C57BL/6J mice after gamma and space-type radiation exposure." Presented at the 2021 NASA Human Research Program Investigators’ Workshop, Virtual, February 1-4, 2021.

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

Articles in Peer-reviewed Journals Garikipati VNS, Arakelyan A, Blakely EA, Chang PY, Truongcao MM, Cimini M, Malaredy V, Bajpai A, Addya S, Bisserier M, Brojakowska A, Eskandari A, Khlgatian MK, Hadri L, Fish K, Kishore R, Goukassian DA. "Long-term effects of very low dose particle radiation on gene expression in the heart: Degenerative disease risks." Cells. 2021 Feb 13;10(2):387. https://doi.org/10.3390/cells10020387 ; PMID: 33668521; PMCID: PMC7917872 , Feb-2021
Project Title:  Space Relevant Radiation-Induced Cardiovascular Disease Risk Thresholds: Effect of Gender on the Outcome Reduce
Images: icon  Fiscal Year: FY 2020 
Division: Human Research 
Research Discipline/Element:
HRP SR:Space Radiation
Start Date: 04/10/2019  
End Date: 04/09/2023  
Task Last Updated: 02/21/2020 
Download report in PDF pdf
Principal Investigator/Affiliation:   Goukassian, David A M.D., Ph.D. / Icahn School of Medicine at Mount Sinai 
Address:  Zena & Michael A. Weiner Cardiovascular Institute 
One Gustave L. Levy Place, Box 1030 
New York , NY 10029 
Email: david.goukassian@mssm.edu 
Phone: 617-480-3890  
Congressional District: 12 
Web:  
Organization Type: UNIVERSITY 
Organization Name: Icahn School of Medicine at Mount Sinai 
Joint Agency:  
Comments: NOTE: PI moved to Icahn School of Medicine at Mount Sinai from Temple University in October 2018.  
Project Information: Grant/Contract No. 80NSSC19K1079 
Responsible Center: NASA JSC 
Grant Monitor: Simonsen, Lisa  
Center Contact:  
lisa.c.simonsen@nasa.gov 
Unique ID: 12726 
Solicitation / Funding Source: 2016-2017 HERO NNJ16ZSA001N-SRHHC. Appendix E: Space Radiobiology and Human Health Countermeasures Topics 
Grant/Contract No.: 80NSSC19K1079 
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) Cardiovascular:Risk of Cardiovascular Adaptations Contributing to Adverse Mission Performance and Health Outcomes
Human Research Program Gaps: (1) CV-102:Determine whether space radiation induces cardiovascular structural and functional changes and/or oxidative stress & damage (OSaD)/inflammation, that can contribute to development of disease.
Flight Assignment/Project Notes: NOTE: Continuation of "Space Relevant Radiation-Induced Cardiovascular Disease Risk Thresholds: Effect of Gender on the Outcome," grant 80NSSC18K0921, due to PI move to Icahn School of Medicine at Mount Sinai from Temple University. (Ed., 2/10/2020)

Task Description: Ed. note 2/10/2020: Continuation of "Space Relevant Radiation-Induced Cardiovascular Disease Risk Thresholds: Effect of Gender on the Outcome," grant 80NSSC18K0921 with the same Principal Investigator Dr. David Goukassian, due to PI move to Icahn School of Medicine at Mount Sinai from Temple University.

During the future Moon, near Earth asteroids, and Mars missions, astronauts will be exposed to higher total doses of space irradiation (IR) (~0.4-0.5 Gy) from galactic cosmic rays (GCR). Most of what we know about harmful effects of IR on cardiovascular (CV) system is from epidemiological studies of long-term survivors of cancer radiotherapy (RT). A recent study of 2,168 women who underwent RT for breast cancer has shown that the rates of major coronary events increased linearly with the mean dose to the heart by 7.4% per Gy, with no apparent lower or upper threshold. In this study, it was determined that average of the mean doses to the whole heart was 4.9 Gy with the range of 0.03 - 27.72 Gy. Furthermore, metabolomics studies, in patients undergoing hematopoietic stem cell (HSC) transplantation as part of cancer treatment (1.25 Gy total-body irradiated), identified seven urine-based biomarkers with distinct differences between pre- and post-exposure samples. The levels of these markers were found to be gender-dependent suggesting that separate biomarker signatures may exist for males and females.

Hypotheses: Our central hypothesis is that low-dose proton and HZE (high energy) particle IR-induced biological responses are long-lasting, IR type- and dose-dependent and may augment excess relative risk (ERR) estimates for the development of CV diseases during and after long-duration space missions. In addition, we hypothesize that gender differences could further modify radio-biologically effective (RBE) IR thresholds for CV risk estimates. Gene expression and epigenetic modifications in protein and microRNA (miRNA) in exosomes from the blood (e.g., plasma/serum) may be altered before the onset of the cardiac symptoms, which could be used as potential biomarkers to predict the CV disease risks. We will test our hypotheses with the following specific aims:

AIM 1. Determine the longitudinal effect of IR type, dose, and gender on cardiovascular physiology in wild type mice and ApoE null mice after full-body 5-ion simplified mixed field and gamma radiation.

AIM 2. Determine space-type IR mediated modulations in exosomal cargo in the blood, and determine whether these changes are associated with alterations in the heart function, structure, and vasculature before manifestation of clinical symptoms.

AIM 3. Utilize known and newly identified bio-markers in the blood to develop human-relevant point-of-care tests (POCT) for predicting and monitoring possible CV alterations before and during the space flights.

We anticipate that the results of our proposed work may be beneficial for human space exploration and could (1) Determine single, low-dose 1H, 56Fe, and mixed field dose-responses, radio-biologically effective IR thresholds in the heart and cardiac vasculature, and whether gender differences could modify radio-biologically effective IR thresholds for CV risk estimates; 2) Determine whether space radiation leads to modifications in the circulating exosomal cargo contents and whether IR-induced exosomal cargo modulations are reflective of subclinical changes in the cells and organs of origin; 3) Ascertain if modulations of exosomal cargo may be representative of chronic oxidative stress and inflammation and could serve as early bio-markers of IR-induced CV disease initiation and progression; 4) Integrate physiological CV endpoint data sets with gene expression and epigenetic data to identify bio-markers in bio-fluids that could be used for prediction of asymptomatic CV disease in the setting of space IR, which will include known early and intermediate bio-markers of cardiac damage, inflammation, and oxidative stress, as well as currently unknown novel radiation-associated cardiac bio-markers.

Research Impact/Earth Benefits: We anticipate that the results of our work could be beneficial for human space exploration as well as for the Earth-based applications on several levels -- (1) determine whether low dose space-type and terrestrial IR may present an increased risks for CV disease development during and after prolonged space missions, as well as after conventional and particle cancer radiotherapy; (2) determine the underlying molecular signaling of CV alterations; (3) identify bio-markers in the blood that could be used for prediction of asymptomatic CV disease, which will include known early and intermediate bio-markers of cardiac damage, as well as currently unknown novel cardiac biomarkers; (4) the identification of sub-clinical CV disease biomarkers that could be used for monitoring the effectiveness of mitigating factors for prevention and treatment of IR-induced CV diseases in space and in Earth-bound civilian population, in general.

Task Progress & Bibliography Information FY2020 
Task Progress: At the time of this report preparation we collected functional cardiovascular data and various tissues for 4 time points – 14, 28 days and 12, 16 months. Within this time points we have established five sub-projects and each is reported here separately as sub-project 1-5. The utilized radiation ions, doses, and energies used in these studies as recommended by Radiation Biology Element of the Human Research Program (HRP) and depicted below:

(i) Gamma IR - 1, 2, and 4 Gy, using ApoE null MALE mice.

(ii) 5-Ion Simplified Mixed field IR - 0.5, 1.0, and 1.5 Gy, adjusted to 500 MeV/n, using ApoE null MALE mice.

(iii) Gamma IR - 1 and 2, using WT-C57BL/6J MALE.

(iv) 5-Ion Simplified Mixed field IR - 0.5 and 1.0 Gy, adjusted to 500 MeV/n, using WT-C57BL/6J MALE mice.

SUB-PROJECT 1. Title - "FULL BODY GAMMA AND 5-ION SIMPLIFIED MIXED ION RADIATION AFFECT CARDIAC FUNCTION AND STRUCTURE IN APOE NULL AND C57BL/6 MICE"

Preliminary Summary: Gamma- and 5-ISMF full body radiation, at doses 100-400 cGy for gamma and 50-150 cGy for 5-ISMF-IR, decrease global systolic function of the heart in both ApoE null and C57Bl/6 mice at 14 and 28 days after exposure. Presence of global systolic dysfunction already by 14 and 28 days post-IR determined by echocardiography (ECHO) and identification of the first detectable changes in the heart tissue only by day 28 after IR, may indicate that alterations in cardiac contractile function could be detected in advance of morphological changes in the heart tissue, suggesting that echocardiography may be one of the early tests to identify CV disease risk development. Compared to control non-irradiated mice, the left ventricular global systolic function continued to deteriorate at 12 and 16 month after exposure, with revealing detectable by echocardiography structural alteration in LV septal wall thickness, as well as other functional ECHO parameters. Additional studies are ongoing to confirm these results and further characterize the functional and histological alterations in cardiac structure and function.

SUB-PROJECT 2. Title - "EFFECTS OF FULL BODY SPACE RADIATION ON RIGHT VENTRICULAR CARDIAC FUNCTION AND DEVELOPMENT OF PULMONARY HYPERTENSION"

Preliminary Summary: At this time, our data suggested that both gamma and 5-ion simplified mix field radiation induce lung damage as characterized by vascular remodeling and increased perivascular fibrosis, proliferation, oxidative stress, and inflammation markers in the lung tissue 28 days and 1 year post radiation. Our results suggested that gamma and 5-ion simplified mix field ion radiation may potentiate fibrosis that could results in pulmonary hypertension.

SUB-PROJECT 3. Title - "FULL BODY GAMMA AND 5-ION SIMPLIFIED MIXED ION RADIATION AFFECT VASCULAR PLAQUE BURDEN IN APOE NULL MICE"

Preliminary Summary: SimGCRsim full body radiation, at a dose of 100cGy in ApoE null mice increase plaque burden at 1 year after exposure. The absence of aortic plaque burden was documented at 14 and 28 days post-IR determined by Oil-Red staining, imaging, and image analyses. Identification of the major detectable changes in the aortas and carotid arteries that was documented at one year after IR may accelerate atherosclerotic plaque development and/or progression when combined with natural aging processes. Further analyses including in vascular cells function/dysfunction in aorta and carotids in Wild Type mice, as well as the extended longitudinal studies in Apoe null mice are ongoing.

SUB-PROJECT 4. Title - "PERIPHERAL BLOOD DERIVED EXOSOMAL miRNA AS BIOMARKERS FOR SPACE RADIATION-ASSOCIATED CARDIOVASCULAR DISEASE DEVELOPMENT"

Preliminary Summary: Results of our studies so far indicate that ionizing radiation alters the miRNA content in peripheral blood derived exosomes of gamma and 5-ISMF full body irradiated mice (both, 100 cGy dose), which can be used as a source of potential biomarkers for cardiac tissue damage. Top five miRNAs were represented by miR223-3p, miR503-3p, miR149-5p (upregulated more than 2-fold after both IRs), and miR1964-3p, miR3068-3p (downregulated more than 2-fold after both IRs). The bioinformatics analyses of miRNA-223-3p and miR-503-3p target mRNAs shared common genes in vascular, cardiac, and metabolic regulatory pathways, e.g., BRINP3, LRP8, SOX11, MEF2C, IL6ST, IGF1R and NTSC1, ADAMTSL1, ABCB1, CCL2, NKAIN2, respectively. Therefore, with further functional and structural validation, exosomal miRNAs could prove to be promising candidate biomarkers for identification and validation of tissue specific damage/pathology for space-type radiation-induced cardiovascular diseases.

SUB-PROJECT 5. Title - "SPACE RADIATION AND HIGH LIPID DIET-ASSOCIATED BRAIN DENDRITIC CELL ACTIVATION: IMPLICATIONS FOR NEUROLOGICAL DISEASE DEVELOPMENT"

Preliminary Summary: Gross examination of brains from irradiated Apo-E mice appears to suggest that 5-Ion Simplified Mix Field-IR (5-ISMF IR) results in increased number of melonocyte-like dendritic cells in western diet-fed and 5-ISMF IR exposed mice meninges. We also detected elevated levels of cells appearing in several pyramidal and granular layers of the cerebral cortex in the 100 cGy 5-IMSF irradiated animals. Congo Red staining for amyloid staining was negative, suggesting that there were no hallmark AD lesions present. Further follow up is needed to confirm these results and further characterize the progression of lesions identified.

Bibliography: Description: (Last Updated: 03/06/2024) 

Show Cumulative Bibliography
 
Abstracts for Journals and Proceedings Fish K, Khlgatian MK, Bisserier M, Zhang S, Hadri L, Hajjar R, Kishore R, Goukassian DA. "Full body gamma and 5-ion simplified mixed ion radiation affect vascular plaque burden in apoe null mice." 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

Abstracts for Journals and Proceedings Bisserier M, Zhang S, Khlgatian MK, Fish K, Goukassian DA, Hadri L. "Effects of full body space radiation on right ventricular cardiac function and development of pulmonary hypertension." 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

Abstracts for Journals and Proceedings Khlgatian MK, Bisserier M, Zhang S, Chepurko V, Chepurko V, Gillespie V, Dai Y, Fish K, Hadri L, Hajjar R, Kishore R, Goukassian DA. "Full body gamma and 5-ion simplified mixed ion radiation affect cardiac function and structure in apoe null and c57bl/6 mice." 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

Abstracts for Journals and Proceedings Fish K, Bisserier M, Khlgatian MK, Adamiak M, Mathiyalagan P, Hajjar R, Kishore R, Sahoo S, Goukassian DA. "Peripheral blood derived exosomal miRNA as biomarkers for space radiation-associated cardiovascular disease development." 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

Abstracts for Journals and Proceedings Fish K, Bisserier MM, Zhang S, Hadri H, Khlgatian MK, Goukassian DA. "Space radiation and high lipid diet-associated brain dendritic cell activation: implications for neurological disease development." 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

Project Title:  Space Relevant Radiation-Induced Cardiovascular Disease Risk Thresholds: Effect of Gender on the Outcome Reduce
Images: icon  Fiscal Year: FY 2019 
Division: Human Research 
Research Discipline/Element:
HRP SR:Space Radiation
Start Date: 04/10/2019  
End Date: 04/09/2023  
Task Last Updated: 02/12/2020 
Download report in PDF pdf
Principal Investigator/Affiliation:   Goukassian, David A M.D., Ph.D. / Icahn School of Medicine at Mount Sinai 
Address:  Zena & Michael A. Weiner Cardiovascular Institute 
One Gustave L. Levy Place, Box 1030 
New York , NY 10029 
Email: david.goukassian@mssm.edu 
Phone: 617-480-3890  
Congressional District: 12 
Web:  
Organization Type: UNIVERSITY 
Organization Name: Icahn School of Medicine at Mount Sinai 
Joint Agency:  
Comments: NOTE: PI moved to Icahn School of Medicine at Mount Sinai from Temple University in October 2018.  
Project Information: Grant/Contract No. 80NSSC19K1079 
Responsible Center: NASA JSC 
Grant Monitor: Simonsen, Lisa  
Center Contact:  
lisa.c.simonsen@nasa.gov 
Unique ID: 12726 
Solicitation / Funding Source: 2016-2017 HERO NNJ16ZSA001N-SRHHC. Appendix E: Space Radiobiology and Human Health Countermeasures Topics 
Grant/Contract No.: 80NSSC19K1079 
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) Cardiovascular:Risk of Cardiovascular Adaptations Contributing to Adverse Mission Performance and Health Outcomes
Human Research Program Gaps: (1) CV-102:Determine whether space radiation induces cardiovascular structural and functional changes and/or oxidative stress & damage (OSaD)/inflammation, that can contribute to development of disease.
Flight Assignment/Project Notes: NOTE: Continuation of "Space Relevant Radiation-Induced Cardiovascular Disease Risk Thresholds: Effect of Gender on the Outcome," grant 80NSSC18K0921, due to PI move to Icahn School of Medicine at Mount Sinai from Temple University. (Ed., 2/10/2020)

Task Description: Ed. note 2/10/2020: Continuation of "Space Relevant Radiation-Induced Cardiovascular Disease Risk Thresholds: Effect of Gender on the Outcome," grant 80NSSC18K0921 with the same Principal Investigator Dr. David Goukassian, due to PI move to Icahn School of Medicine at Mount Sinai from Temple University.

During the future Moon, near Earth asteroids, and Mars missions, astronauts will be exposed to higher total doses of space irradiation (IR) (~0.4-0.5 Gy) from galactic cosmic rays (GCR). Most of what we know about harmful effects of IR on cardiovascular (CV) system is from epidemiological studies of long-term survivors of cancer radiotherapy (RT). A recent study of 2,168 women who underwent RT for breast cancer has shown that the rates of major coronary events increased linearly with the mean dose to the heart by 7.4% per Gy, with no apparent lower or upper threshold. In this study, it was determined that average of the mean doses to the whole heart was 4.9 Gy with the range of 0.03 - 27.72 Gy. Furthermore, metabolomics studies, in patients undergoing hematopoietic stem cell (HSC) transplantation as part of cancer treatment (1.25 Gy total-body irradiated), identified seven urine-based biomarkers with distinct differences between pre- and post-exposure samples. The levels of these markers were found to be gender-dependent suggesting that separate biomarker signatures may exist for males and females.

Hypotheses: Our central hypothesis is that low-dose proton and HZE (high energy) particle IR-induced biological responses are long-lasting, IR type- and dose-dependent and may augment excess relative risk (ERR) estimates for the development of CV diseases during and after long-duration space missions. In addition, we hypothesize that gender differences could further modify radio-biologically effective (RBE) IR thresholds for CV risk estimates. Gene expression and epigenetic modifications in protein and microRNA (miRNA) in exosomes from the blood (e.g., plasma/serum) may be altered before the onset of the cardiac symptoms, which could be used as potential biomarkers to predict the CV disease risks. We will test our hypotheses with the following specific aims:

AIM 1. Determine the longitudinal effect of IR type, dose, and gender on cardiovascular physiology in wild type mice and ApoE null mice after full-body 5-ion simplified mixed field and gamma radiation.

AIM 2. Determine space-type IR mediated modulations in exosomal cargo in the blood, and determine whether these changes are associated with alterations in the heart function, structure, and vasculature before manifestation of clinical symptoms.

AIM 3. Utilize known and newly identified bio-markers in the blood to develop human-relevant point-of-care tests (POCT) for predicting and monitoring possible CV alterations before and during the space flights.

We anticipate that the results of our proposed work may be beneficial for human space exploration and could (1) Determine single, low-dose 1H, 56Fe, and mixed field dose-responses, radio-biologically effective IR thresholds in the heart and cardiac vasculature, and whether gender differences could modify radio-biologically effective IR thresholds for CV risk estimates; 2) Determine whether space radiation leads to modifications in the circulating exosomal cargo contents and whether IR-induced exosomal cargo modulations are reflective of subclinical changes in the cells and organs of origin; 3) Ascertain if modulations of exosomal cargo may be representative of chronic oxidative stress and inflammation and could serve as early bio-markers of IR-induced CV disease initiation and progression; 4) Integrate physiological CV endpoint data sets with gene expression and epigenetic data to identify bio-markers in bio-fluids that could be used for prediction of asymptomatic CV disease in the setting of space IR, which will include known early and intermediate bio-markers of cardiac damage, inflammation, and oxidative stress, as well as currently unknown novel radiation-associated cardiac bio-markers.

Research Impact/Earth Benefits: We anticipate that the results of our work could be beneficial for human space exploration as well as for the Earth-based applications on several levels -- (1) determine whether low dose space-type and terrestrial IR may present an increased risks for CV disease development during and after prolonged space missions, as well as after conventional and particle cancer radiotherapy; (2) determine the underlying molecular signaling of CV alterations; (3) identify bio-markers in the blood that could be used for prediction of asymptomatic CV disease, which will include known early and intermediate bio-markers of cardiac damage, as well as currently unknown novel cardiac biomarkers; (4) the identification of sub-clinical CV disease biomarkers that could be used for monitoring the effectiveness of mitigating factors for prevention and treatment of IR-induced CV diseases in space and in Earth-bound civilian population, in general.

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

NOTE: Continuation of "Space Relevant Radiation-Induced Cardiovascular Disease Risk Thresholds: Effect of Gender on the Outcome," grant 80NSSC18K0921 with the same Principal Investigator Dr. David Goukassian, due to PI move to Icahn School of Medicine at Mount Sinai from Temple University. See that project for previous reporting. (Added in February 2020 to Task Book when received information on new grant.)

Bibliography: Description: (Last Updated: 03/06/2024) 

Show Cumulative Bibliography
 
 None in FY 2019