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At least 217 records · Page 12
All sourcesNASA NTRSDOE OSTI
NASA NTRS2016

Simulated Space Radiation: Murine Skeletal Responses During Recovery and with Mechanical Stimulation

Simulated space radiation at doses similar to those of solar particle events or a round-trip sojourn to Mars (1-2Gy) may cause skeletal tissue degradation and deplete stem/progenitor cell pools throughout the body. We hypothesized that simulated space radiation (SSR) causes late, time-dependent deficits in bone structure and bone cell function reflected by changes in gene expression in response to anabolic stimuli. We used a unique sequential dual ion exposure (proton and iron) for SSR to investigate time-dependence of responses in gene expression, cell function, and microarchitecture with respect to radiation and an anabolic stimulus of axial loading (AL). Male 16-wk C57BL6/J mice (n=120 total) were exposed to 0Gy (Sham, n=10), 56Fe (2Gy, positive control dose, n=10), or sequential ions for SSR (1Gy 1H/56Fe/1H, n=10) by total body irradiation (IR), and the tissues were harvested 2 or 6 mo. later. Further, to assess the response to anabolic stimuli, we subjected additional Sham-AL (n=15) and SSR-AL (n=15) groups to rest-inserted tibial axial loading (AL) starting at 1 and 5 months post-IR (-9N, 60 cycles/day, 3 days/wk, 4 wks). Exposure to 56Fe caused a significant reduction in cancellous bone volume fraction (BV/TV) compared to Sham (-34%) and SSR (-20%) in the proximal tibia metaphysis at 2-months post-IR; however BV/TV for SSR group was not different than Sham. Both 56Fe and SSR caused significant reduction in trabecular number (Tb.N) compared to Sham (-33% and -16%, respectively). Further, Tb.N for 56Fe (2Gy) was significantly lower than SSR (-21%). Ex vivo culture of marrow cells to assess growth and differentiation of osteoblast lineage cells 6 months post-IR showed that both 56Fe and SSR exposures significantly impaired colony formation compared to Sham (-66% and -54%, respectively), as well as nodule mineralization (-90% and -51%, respectively). Two-way analysis of variance showed that both mechanical loading and radiation reduced BV/TV, mechanical loading reduced trabecular thickness (Tb.Th), and radiation reduced Tb.N, at both time points. To assess acute response to mechanical stimuli, samples were harvested from a subset of Sham-AL (n=5) and SSR-AL (n=5) to measure changes in gene expression levels. Preliminary results indicate that axial loading increased expression of the antioxidant response gene Nfe2l2 and the osteoprogenitor-associated marker Runx2 in the bone marrow cells, and there was an interaction effect between axial loading and radiation at 2-months post-IR. Additional analyses of gene expression levels in the mineralized tissue are in progress. Results indicate that SSR caused persistent impairment of osteoblast colony formation and nodule mineralization 6-mo post-IR. Contrary to our hypothesis, simulated space radiation did not impair the ability of cancellous bone to respond to a mechanical anabolic stimulus, consistent with our previous findings [1]. Hence, compressive loading may be a potential countermeasure against spaceflight-induced bone loss.

Bone Loss↗
NASA NTRS2016

Simulated Space Radiation: Murine Skeletal Responses During Recovery and with Mechanical Stimulation

Simulated space radiation at doses similar to those of solar particle events or a round-trip sojourn to Mars (1-2Gy) may cause skeletal tissue degradation and deplete stem/progenitor cell pools throughout the body. We hypothesized that simulated space radiation (SSR) causes late, time-dependent deficits in bone structure and bone cell function reflected by changes in gene expression in response to anabolic stimuli. We used a unique sequential dual ion exposure (proton and iron) for SSR to investigate time-dependence of responses in gene expression, cell function, and microarchitecture with respect to radiation and an anabolic stimulus of axial loading (AL). Male 16-wk C57BL6/J mice (n=120 total) were exposed to 0Gy (Sham, n=10), 56Fe (2Gy, positive control dose, n=10), or sequential ions for SSR (1Gy 1H/56Fe/1H, n=10) by total body irradiation (IR), and the tissues were harvested 2 or 6 mo. later. Further, to assess the response to anabolic stimuli, we subjected additional Sham-AL (n=15) and SSR-AL (n=15) groups to rest-inserted tibial axial loading (AL) starting at 1 and 5 months post-IR (-9N, 60 cycles/day, 3 days/wk, 4 wks). Exposure to 56Fe caused a significant reduction in cancellous bone volume fraction (BV/TV) compared to Sham (-34%) and SSR (-20%) in the proximal tibia metaphysis at 2-months post-IR; however BV/TV for SSR group was not different than Sham. Both 56Fe and SSR caused significant reduction in trabecular number (Tb.N) compared to Sham (-33% and -16%, respectively). Further, Tb.N for 56Fe (2Gy) was significantly lower than SSR (-21%). Ex vivo culture of marrow cells to assess growth and differentiation of osteoblast lineage cells 6 months post-IR showed that both 56Fe and SSR exposures significantly impaired colony formation compared to Sham (-66% and -54%, respectively), as well as nodule mineralization (-90% and -51%, respectively). Two-way analysis of variance showed that both mechanical loading and radiation reduced BV/TV, mechanical loading reduced trabecular thickness (Tb.Th), and radiation reduced Tb.N, at both time points. To assess acute response to mechanical stimuli, samples were harvested from a subset of Sham-AL (n=5) and SSR-AL (n=5) to measure changes in gene expression levels. Preliminary results indicate that axial loading increased expression of the antioxidant response gene Nfe2l2 and the osteoprogenitor-associated marker Runx2 in the bone marrow cells, and there was an interaction effect between axial loading and radiation at 2-months post-IR. Additional analyses of gene expression levels in the mineralized tissue are in progress. Results indicate that SSR caused persistent impairment of osteoblast colony formation and nodule mineralization 6-mo post-IR. Contrary to our hypothesis, simulated space radiation did not impair the ability of cancellous bone to respond to a mechanical anabolic stimulus, consistent with our previous findings. Hence, compressive loading may be a potential countermeasure against spaceflight-induced bone loss.

MURINE SKELETAL↗
NASA NTRS2000

Identification of genes regulated during mechanical load-induced cardiac hypertrophy

Cardiac hypertrophy is associated with both adaptive and adverse changes in gene expression. To identify genes regulated by pressure overload, we performed suppressive subtractive hybridization between cDNA from the hearts of aortic-banded (7-day) and sham-operated mice. In parallel, we performed a subtraction between an adult and a neonatal heart, for the purpose of comparing different forms of cardiac hypertrophy. Sequencing more than 100 clones led to the identification of an array of functionally known (70%) and unknown genes (30%) that are upregulated during cardiac growth. At least nine of those genes were preferentially expressed in both the neonatal and pressure over-load hearts alike. Using Northern blot analysis to investigate whether some of the identified genes were upregulated in the load-independent calcineurin-induced cardiac hypertrophy mouse model, revealed its incomplete similarity with the former models of cardiac growth. Copyright 2000 Academic Press.

NASA Discipline Cardiopulmonary↗
NASA NTRS1996

Sense and antisense transcripts of the developmentally regulated murine hsp70.2 gene are expressed in distinct and only partially overlapping areas in the adult brain

We have examined the spatial pattern of expression of a member of the hsp70 gene family, hsp70.2, in the mouse central nervous system. Surprisingly, RNA blot analysis and in situ hybridization revealed abundant expression of an 'antisense' hsp70.2 transcript in several areas of adult mouse brain. Two different transcripts recognized by sense and antisense riboprobes for the hsp70.2 gene were expressed in distinct and only partially overlapping neuronal populations. RNA blot analysis revealed low levels of the 2.7 kb transcript of hsp70.2 in several areas of the brain, with highest signal in the hippocampus. Abundant expression of a slightly larger (approximately 2.8 kb) 'antisense' transcript was detected in several brain regions, notably in the brainstem, cerebellum, mesencephalic tectum, thalamus, cortex, and hippocampus. In situ hybridization revealed that the sense and antisense transcripts were both predominantly neuronal and localized to the same cell types in the granular layer of the cerebellum, trapezoid nucleus of the superior olivary complex, locus coeruleus and hippocampus. The hsp70.2 antisense transcripts were particularly abundant in the frontal cortex, dentate gyrus, subthalamic nucleus, zona incerta, superior and inferior colliculi, central gray, brainstem, and cerebellar Purkinje cells. Our findings have revealed a distinct cellular and spatial localization of both sense and antisense transcripts, demonstrating a new level of complexity in the function of the heat shock genes.

NASA Discipline Developmental Biology↗
DOE OSTI2025

Single-nuclei transcriptome analysis of IgM+ cells isolated from channel catfish (Ictalurus punctatus) spleen

Catfish production is the primary aquaculture sector in the United States, and the key cultured species is channel catfish (Ictalurus punctatus). The major causes of production losses are pathogenic diseases, and the spleen, an important site of adaptive immunity, is implicated in these diseases. To examine the channel catfish immune system, single-nuclei transcriptomes of sorted and captured IgM + cells were produced from adult channel catfish. Three channel catfish (~1 kg) were euthanized, the spleen dissected, and the tissue dissociated. The lymphocytes were isolated using a Ficoll gradient and IgM + cells were then sorted with flow cytometry. The IgM + cells were lysed and single-nuclei libraries generated using a Chromium Next GEM Single Cell 3’ GEM Kit and the Chromium X Instrument (10x Genomics) and sequenced with the Illumina NovaSeq X Plus sequencer. The reads were aligned to theI. punctatusreference assembly (Coco_2.0) using Cell Ranger, and normalization, cluster analysis, and differential gene expression analysis were carried out with Seurat. Across the three samples, approximately 753.5 million reads were generated for 18,686 cells. After filtering, 10,637 cells remained for the cluster analysis. The cluster analysis identified 16 clusters which were classified as B cells (10,276), natural killer-like (NK-like) cells (178), T cells or natural killer cells (45), hematopoietic stem and progenitor cells (HSPC)/megakaryocytes (MK) (66), myeloid/epithelial cells (40), and plasma cells (32). The B cell clusters were further defined as different populations of mature B cells, cycling B cells, and plasma cells. The plasma cells highly expressedighmand we demonstrated that the secreted form of the transcript was largely being expressed by these cells. This atlas provides insight into the gene expression of IgM + immune cells in channel catfish. The atlas is publicly available and could be used garner more important information regarding the gene expression of splenic immune cells.

Immunology↗
DOE OSTI2024

Design and Characterization of a Transcriptional Repression Toolkit for Plants

Regulation of gene expression is essential for all life. Tools to manipulate the gene expression level have therefore proven to be very valuable in efforts to engineer biological systems. However, there are few well-characterized genetic parts that reduce gene expression in plants, commonly known as transcriptional repressors. We characterized the repression activity of a library consisting of repression motifs from approximately 25% of the members of the largest known family of repressors. Combining sequence information with our trans-regulatory function data, we next generated a library of synthetic transcriptional repression motifs with function predicted in advance. After characterizing our synthetic library, we demonstrated not only that many of our synthetic constructs were functional as repressors but also that our advance predictions of repression strength were better than random guesses. Finally, we assessed the functionality of known transcriptional repression motifs from a wide range of eukaryotes. Our study represents the largest plant repressor motif library experimentally characterized to date, providing unique opportunities for tuning transcription in plants.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2026

Constitutive and inducible oleoresin defenses share genetic architectures and mechanisms in Pinus taeda

The oleoresin defense system of loblolly pine (Pinus taeda) protects trees from insects and pathogens and is an important source of renewable biofuels and chemicals, but the genetic basis of oleoresin production is poorly understood. We characterized the genetic architecture of oleoresin flow, resin canal number, stem wood terpene content, and monoterpene composition in two clonal populations of P. taeda. We used quantitative genetic analyses, genome-wide association studies (GWASs), multiplex network learning, and gene expression profiling to elucidate shared gene networks underlying defense traits and to identify high-quality candidates for breeding and engineering loblolly pine. Genetic analyses revealed polygenic inheritance and trait-to-trait correlations provide strong evidence for shared genes regulating constitutive and induced oleoresin flow. We identified 236 single nucleotide polymorphisms associated with oleoresin flow, resin canal number, and terpene composition and highlight candidate genes likely involved in terpene biosynthesis, cambial meristem reprogramming, and pathogen perception and immune signaling. Fourteen GWAS candidates were methyl jasmonate-responsive in tissues where resin canals initiate and terpene production occurs. Integrating quantitative genetics, GWAS, gene expression, and multiplex network analyses enabled the prioritization of high-quality candidate genes. This work advances the development of more resilient loblolly pine optimized for ecological performance, renewable chemical, and biofuel production.

genome-wide association study↗
NASA NTRS2018

Genomics and Proteomics Based Security Protocols for Secure Network Architectures

A hardware design that integrates live and algorithmic inhabitants to produce patterns of gene expression in vivo and in silico Protocols and algorithms based upon the processes of regulation of gene expression to produce cryptographic representations of genes, RNA, proteins, and gene expression to perform authentication and confidentiality functions for computers and networks. A network concept of operations integrating all of the above into existing legacy networks.

Security Genomics↗
DOE OSTI2025

Too dim, too bright, and just right: Systems analysis of the Chlamydomonas diurnal program under limiting and excess light

Photosynthetic organisms coordinate their metabolism and growth with diurnal light, which can range in intensity from limiting to excessive. Little is known about how light intensity impacts the diurnal program in Chlamydomonas reinhardtii, or how diurnal rhythms in gene expression and metabolism shape photoprotective responses at different times of day. To address these questions, we performed a systems analysis of synchronized Chlamydomonas populations acclimated to low, moderate, and high diurnal light. Transcriptomic and proteomic data revealed that the Chlamydomonas rhythmic gene expression program is resilient to limiting and excess light: genome-wide, waves of transcripts, and proteins peak at the same times in populations acclimated to stressful light intensities as in populations acclimated to moderate light. Yet, diurnal photoacclimation gives rise to hundreds of gene expression changes, even at night. Time course measurements of photosynthetic efficiency and pigments responsive to excess light showed that high light-acclimated cells partially overcome photodamage in the latter half of the day prior to cell division. Although gene expression and photodamage are dynamic over the diurnal cycle, Chlamydomonas populations acclimated to low and high diurnal light maintain altered photosystem abundance, thylakoid architecture, and non-photochemical quenching capacity through the night phase. This suggests that cells remember or anticipate the light intensities that they have typically encountered during the day. The integrated data constitute an excellent resource for understanding photoacclimation in eukaryotes under environmentally relevant conditions.

Dupuis, Sunnyjoy↗
NASA NTRSDate not supplied

GL4U: Training the next generation of bioinformaticians, one omics datatype at a time

Spaceflight modifies gene expression in every organism examined to date, including humans. Understanding how these gene expression changes affect physiology is crucial for the development of countermeasures to enable long-duration manned missions. NASA’s GeneLab project provides researchers open access to multi-omics data, including genetic and gene expression data, from spaceflight experiments that can be mined to understand the effects of spaceflight on biological systems. To ensure new knowledge generation through data re-use, it is important to maximize the number of scientists who utilize GeneLab data. Training students on the GeneLab platform is the best way to create long-term adopters of this NASA database and its tools. Turning students into future instructors and advocates will also accelerate the dissemination of these data and tools to the broader scientific community. Therefore, in collaboration with the GeneLab Educational Working Group (EWG), GeneLab has created GeneLab for Colleges and Universities (GL4U). GL4U provides space biology-relevant training in bioinformatics to the next generation of scientists through direct and indirect approaches. The GeneLab team plans to host two annual data processing bootcamps, one for college-level students (direct) and one for college educators (indirect – training of trainers), in which participants learn to analyze GeneLab’s space-relevant omics data. During the bootcamp, educators will receive materials and training to enable them to run the bootcamp at their home institutions or alternatively to adapt the content to implement within existing courses, thereby extending the reach of this initiative. The GL4U direct training pilot program was conducted in June 2021 in collaboration with USRA and San Jose State University (SJSU). During the pilot, SJSU students participated in a week-long bootcamp consisting of space biology-specific lectures and hands-on instruction using Jupyter Notebooks to analyze RNA sequence data. This pilot demonstrates the capacity of GL4U for training young scientists and encouraging data re-use.

Jonathan Matthew Galazka↗
NASA NTRS2003

Cell Science and Cell Biology Research at MSFC: Summary

The common theme of these research programs is that they investigate regulation of gene expression in cells, and ultimately gene expression is controlled by the macromolecular interactions between regulatory proteins and DNA. The NASA Critical Path Roadmap identifies Muscle Alterations and Atrophy and Radiation Effects as Very Serious Risks and Severe Risks, respectively, in long term space flights. The specific problem addressed by Dr. Young's research ("Skeletal Muscle Atrophy and Muscle Cell Signaling") is that skeletal muscle loss in space cannot be prevented by vigorous exercise. Aerobic skeletal muscles (i.e., red muscles) undergo the most extensive atrophy during long-term space flight. Of the many different potential avenues for preventing muscle atrophy, Dr. Young has chosen to study the beta-adrenergic receptor (betaAR) pathway. The reason for this choice is that a family of compounds called betaAR agonists will preferentially cause an increase in muscle mass of aerobic muscles (i.e., red muscle) in animals, potentially providing a specific pharmacological solution to muscle loss in microgravity. In addition, muscle atrophy is a widespread medical problem in neuromuscular diseases, spinal cord injury, lack of exercise, aging, and any disease requiring prolonged bedridden status. Skeletal muscle cells in cell culture are utilized as a model system to study this problem. Dr. Richmond's research ("Radiation & Cancer Biology of Mammary Cells in Culture") is directed toward developing a laboratory model for use in risk assessment of cancer caused by space radiation. This research is unique because a human model will be developed utilizing human mammary cells that are highly susceptible to tumor development. This approach is preferential over using animal cells because of problems in comparing radiation-induced cancers between humans and animals.

Source record↗
NASA NTRS2008

Non-DBS DNA Repair Genes Regulate Radiation-induced Cytogenetic Damage Repair and Cell Cycle Progression

Changes of gene expression profile are one of the most important biological responses in living cells after ionizing radiation (IR) exposure. Although some studies have shown that genes up-regulated by IR may play important roles in DNA damage repair, the relationship between the regulation of gene expression by IR, particularly genes not known for their roles in DSB repair, and its impact on cytogenetic responses has not been systematically studied. In the present study, the expression of 25 genes selected on the basis of their transcriptional changes in response to IR was individually knocked down by transfection with small interfering RNA in human fibroblast cells. The purpose of this study is to identify new roles of these selected genes on regulating DSB repair and cell cycle progression , as measured in the micronuclei formation and chromosome aberration. In response to IR, the formation of MN was significantly increased by suppressed expression of 5 genes: Ku70 in the DSB repair pathway, XPA in the NER pathway, RPA1 in the MMR pathway, and RAD17 and RBBP8 in cell cycle control. Knocked-down expression of 4 genes (MRE11A, RAD51 in the DSB pathway, SESN1, and SUMO1) significantly inhibited cell cycle progression, possibly because of severe impairment of DNA damage repair. Furthermore, loss of XPA, P21, or MLH1 expression resulted in both significantly enhanced cell cycle progression and increased yields of chromosome aberrations, indicating that these gene products modulate both cell cycle control and DNA damage repair. Most of the 11 genes that affected cytogenetic responses are not known to have clear roles influencing DBS repair. Nine of these 11 genes were up-regulated in cells exposed to gamma radiation, suggesting that genes transcriptionally modulated by IR were critical to regulate the biological consequences after IR.

Zhang, Ye↗
NASA NTRS1999

Cell Culture in Microgravity: Opening the Door to Space Cell Biology

Adaptational response of human cell populations to microgravity is investigated using simulation, short-term Shuttle experiments, and long-term microgravity. Simulation consists of a clinostatically-rotated cell culture system. The system is a horizontally-rotated cylinder completely filled with culture medium. Low speed rotation results in continuous-fall of the cells through the fluid medium. In this setting, cells: 1) aggregate, 2) propagate in three dimensions, 3) synthesize matrix, 4) differentiate, and 5) form sinusoids that facilitate mass transfer. Space cell culture is conducted in flight bioreactors and in static incubators. Cells grown in microgravity are: bovine cartilage, promyelocytic leukemia, kidney proximal tubule cells, adrenal medulla, breast and colon cancer, and endothelium. Cells were cultured in space to test specific hypotheses. Cartilage cells were used to determine structural differences in cartilage grown in space compared to ground-based bioreactors. Results from a 130-day experiment on Mir revealed that cartilage grown in space was substantially more compressible due to insufficient glycosaminoglycan in the matrix. Interestingly, earth-grown cartilage conformed better to the dimensions of the scaffolding material, while the Mir specimens were spherical. The other cell populations are currently being analyzed for cell surface properties, gene expression, and differentiation. Results suggest that some cells spontaneously differentiate in microgravity. Additionally, vast changes in gene expression may occur in response to microgravity. In conclusion, the transition to microgravity may constitute a physical perturbation in cells resulting in unique gene expressions, the consequences of which may be useful in tissue engineering, disease modeling, and space cell biology.

Pellis, Neal R.↗
NASA NTRS2001

Plants, plant pathogens, and microgravity--a deadly trio

Plants grown in spaceflight conditions are more susceptible to colonization by plant pathogens. The underlying causes for this enhanced susceptibility are not known. Possibly the formation of structural barriers and the activation of plant defense response components are impaired in spaceflight conditions. Either condition would result from altered gene expression of the plant. Because of the tools available, past studies focused on a few physiological responses or biochemical pathways. With recent advances in genomics research, new tools, including microarray technologies, are available to examine the global impact of growth in the spacecraft on the plant's gene expression profile. In ground-based studies, we have developed cDNA subtraction libraries of rice that are enriched for genes induced during pathogen infection and the defense response. Arrays of these genes are being used to dissect plant defense response pathways in a model system involving wild-type rice plants and lesion mimic mutants. The lesion mimic mutants are ideal experimental tools because they erratically develop defense response-like lesions in the absence of pathogens. The gene expression profiles from these ground-based studies will provide the molecular basis for understanding the biochemical and physiological impacts of spaceflight on plant growth, development and disease defense responses. This, in turn, will allow the development of strategies to manage plant disease for life in the space environment.

NASA Discipline Plant Biology↗
NASA NTRS2002

Do convergent developmental mechanisms underlie convergent phenotypes?

Convergence is a pervasive evolutionary process, affecting many aspects of phenotype and even genotype. Relatively little is known about convergence in developmental processes, however, nor about the degree to which convergence in development underlies convergence in anatomy. A switch in the ecology of sea urchins from feeding to nonfeeding larvae illustrates how convergence in development can be associated with convergence in anatomy. Comparisons to more distantly related taxa, however, suggest that this association may be limited to relatively close phylogenetic comparisons. Similarities in gene expression during development provide another window into the association between convergence in developmental processes and convergence in anatomy. Several well-studied transcription factors exhibit likely cases of convergent gene expression in distantly related animal phyla. Convergence in regulatory gene expression domains is probably more common than generally acknowledged, and can arise for several different reasons. Copyright 2002 S. Karger AG, Basel.

NASA Discipline Evolutionary Biology↗
DOE OSTI2025

Genetic_and_epigenetic_signatures_of_Populus_Trichocarpa_in_response_to_abiotic_stress

Plants respond to abiotic stresses such as drought, heat, and salinity through both shared and stress-specific regulatory pathways. However, the role of epigenetic mechanisms, particularly DNA methylation, in modulating these responses is still underexplored. Here, we integrated transcriptome profiling with whole-genome bisulfite sequencing (WGBS) to investigate the dynamic relationship between gene expression and DNA methylation in Populus trichocarpa during brief early-stage exposure to abiotic stress. Each stress elicited distinct transcriptional and methylation signatures; however, a subset of conserved stress-responsive genes was commonly regulated across treatments. Approximately 5% of differentially expressed genes also displayed differential methylation patterns, suggesting a coordinated role for DNA methylation in regulating gene expression. Motif enrichment analysis of differentially methylated regions revealed binding sites of key transcription factor families, including ERF, bHLH, and ABF, highlighting potential role for methylation in modulating transcription factor targeting. Furthermore, we identified stress-inducible molecular markers with potential applications in early stress detection and functional dissection of gene regulatory pathways. Together, these findings provide new insights into the coordinated genetic and epigenetic responses to abiotic stress and provide a foundation for developing biosensors and breeding strategies to enhance stress resilience woody plants.

CBI↗
NASA NTRSDate not supplied

Cardiovascular Responses to Simulated Spaceflight: Molecular Signatures and Surrogate Outputs to Measure CVD Risk

During extended space missions beyond low Earth orbit, astronauts will encounter prolonged periods of weightlessness and low dose space radiation. Previous studies have shown that exposure to small doses of high LET radiation (< 50 cGy) can lead to both short-term and long-term alterations in heart function, structure and underlying molecular mechanisms. In this study, we aim to identify the molecular signature associated with the cardiovascular response to simulated galactic cosmic radiation (5-ion GCR) alone or in combination with simulated weightlessness at time intervals relevant to mission length and recovery. Additionally, we aim to determine whether sex impacts cardiovascular responses to these spaceflight factors. Our overarching goal is to enhance our understanding of the cardiovascular risks associated with extended space missions and the clinical endpoints they suggest. We hypothesize that exposure to simulated space radiation leads to enduring alterations in the transcriptome, redox signaling and cytokine environment of cardiovascular tissue, some which have known links with reduced cardiovascular performance, aging, and increased risk of cardiovascular disease (CVD). Furthermore, we posit that simulated space radiation exposure in combination with simulated microgravity exacerbates cardiovascular deficits compared to single factor exposure. Female and male C57BL/6J mice, aged 23-24 weeks, were exposed to a single dose of 5, 15, or 50 cGy of 5-ion GCR, or sham-treated (0 cGy). Euthanasia was performed at 14 days and ~4 months post-irradiation. Hearts, aorta and blood plasma were collected shortly thereafter. RNA-sequencing of left ventricles at ~4 months post-GCR exposure revealed sex differences in the heart transcriptome with a few genes showing radiation-dependent changes in expression levels. Notably, some of the differentially expressed genes in 15 and 50 cGy GCR groups are known to play roles in the development of CVD. Analysis of protein levels of a subset of inflammatory cytokines in the heart indicated sex differences but no differences between sham and 50 cGy groups. Results also showed correlations among differentially expressed genes and a subset of inflammatory cytokines, with some correlations altered by GCR exposure. These findings suggest that GCR exposure can modify protein and gene networks linked to inflammation and CVD progression. In the aorta, telomere lengths were comparable across treatment groups sexes. Mitochondrial copy number is a biomarker for mitochondrial function with decreased copy numbers associated with cardiometabolic disease traits. Mitochondrial copy numbers of aorta also showed no sex nor dose differences. In a second study, mice underwent one week of simulated microgravity by hindlimb unloading (HU) and then exposed to a single dose of 15 cGy of 5-ion GCR. HU was conducted for an additional two weeks following GCR exposure. Single factor exposure groups (HU or GCR only) also were included in the study. Euthanasia was then performed and the same tissues were collected. Protein levels of select inflammatory cytokines in the heart showed sex-dependent differences in expression. In the aorta, telomere lengths and mitochondrial copy number also showed sex differences. In summary, our results indicate differences between sexes in biomarkers related to cardiovascular health. Exposure to 5-ion GCR or HU, alone or in combination, did not result in changes in most of the cardiovascular biomarkers that were examined. However, in the heart, simulated space radiation at doses of 15 and 50 cGy led to long-term alterations in the expression levels of a small group of genes known to be associated with the progression of CVD. The long-term transcriptomic changes resulting from exposure to simulated space radiation should be carefully investigated to mitigate adverse cardiovascular events during and after deep space missions. Our results also highlight the importance of sex-specific strategies in monitoring and maintaining cardiovascular health during and after deep space missions.

cardiovascular↗
DOE OSTI2024

Bioactivity Profiling of Chemical Mixtures for Hazard Characterization

Abstract The assessment and regulation of chemical toxicity to protect human health and the environment are done one chemical at a time and seldom at environmentally relevant concentrations. However, chemicals are found in the environment as mixtures, and their toxicity is largely unknown. Understanding the hazard posed by chemicals within the mixture is critical to enforce protective measures. Here, we demonstrate the application of bioactivity profiling of environmental water samples using the sentinel and ecotoxicology model species Daphnia to reveal the biomolecular response induced by exposure to real-world mixtures. We exposed a Daphnia strain to 30 sampled waters of the Chaobai River and measured the gene expression response profiles. Using a multiblock correlation analysis, we establish correlations between chemical mixtures identified in 30 water samples with gene expression patterns induced by these chemical mixtures. We identified 80 metabolic pathways putatively activated by mixtures of inorganic ions, heavy metals, polycyclic aromatic hydrocarbons, industrial chemicals, and a set of biocides, pesticides, and pharmacologically active substances. Our data-driven approach discovered both known bioactivity signatures with previously described modes of action and new pathways linked to undiscovered potential hazards. This study demonstrates the feasibility of reducing the complexity of real-world mixture toxicity to characterize the biomolecular effects of a defined number of chemical components based on gene expression monitoring of the sentinel species Daphnia.

Engineering↗