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Dysregulation of Human Molecular and Metabolic Mechanisms Resulting in Oxidative Stress and Damage Generation in the Space Environment

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 28231

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Prof. Dr. Melpo Christofidou-Solomidou

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Division of Pulmonary, Allergy, and Critical Care Medicine and the Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
Interests: oxidative stress; antioxidants; botanicals; radiation toxicity; lung inflammation; lung fibrosis; space radiation; radiotherapy
Special Issues, Collections and Topics in MDPI journals

Dr. Thomas J. Goodwin

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Guest Editor

1. Sovaris Aerospace, Research Innovation, Infectious Disease Research Center Colorado State University, Fort Collins, CO 80521, USA
2. The National Aeronautics and Space Administration (NASA Retired) Johnson Space Center, Houston, TX 77058, USA
Interests: ageing; oxidative stress and damage; antioxidants; radiation toxicity; inflammation; genomics; proteomics; metabolomics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues:

The phenomenon of oxidative stress and damage (OSaD) is recognized as an important common denominator in human physiological function and disease occurrence, on Earth and in space, signifying the vital nature of the topic. Advanced and evolving “multi-omics” technologies permit the analyses of essential molecular and metabolic processes in the medical arena, facilitating planning for deep space exploration missions with the intent to discover new habitats and commercial markets for humankind. In the past, the National Aeronautics and Space Administration (NASA) has spearheaded this effort and research into the identification of risks to crew members associated with such lengthy missions. Now, commercial and defense efforts are pioneering promising applications of the space environment in low Earth orbit (LEO). Investigators across the US, Europe, and Asia have identified oxidative damage as a significant risk to organ systems that could pose a threat to the health of astronauts and the success of a variety of missions. This Special Issue of IJMS is dedicated to providing a comprehensive overview of the identified elemental risks and pivotal theme of OSaD impact in major organ systems when exposed to space-relevant conditions, such as cosmic/galactic radiation, solar particle events, hypogravity, hyperoxia, and hypoxia or a combination of these stressors.

Prof. Dr. Melpo Christofidou-Solomidou
Dr. Thomas J. Goodwin
Guest Editors

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Keywords

OSaD
Galactic cosmic radiation (GCR)
Deep space exploration
Low earth orbit commercialization
Health risk mitigation
Tissue toxicity

Published Papers (9 papers)

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Editorial

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6 pages, 3039 KiB

Open AccessEditorial

Editorial to the Special Issue: “Dysregulation of Human Molecular and Metabolic Mechanisms Resulting in Oxidative Stress and Damage Generation in the Space Environment”

by Thomas J. Goodwin and Melpo Christofidou-Solomidou

Int. J. Mol. Sci. 2022, 23(12), 6466; https://doi.org/10.3390/ijms23126466 - 09 Jun 2022

Cited by 1 | Viewed by 1062

Abstract

Commercial space industries are emergent, bolstered by new exciting rocket systems, orbital and landing vehicles, the creation of multi-country orbital platforms, satellite technology, the renewed promise of low Earth orbit (LEO) business opportunities, as well as promised planetary exploration [...] Full article

(This article belongs to the Special Issue Dysregulation of Human Molecular and Metabolic Mechanisms Resulting in Oxidative Stress and Damage Generation in the Space Environment)

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Research

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34 pages, 1857 KiB

Open AccessArticle

Mitochondrial Effects in the Liver of C57BL/6 Mice by Low Dose, High Energy, High Charge Irradiation

by Brooke L. Barnette, Yongjia Yu, Robert L. Ullrich and Mark R. Emmett

Int. J. Mol. Sci. 2021, 22(21), 11806; https://doi.org/10.3390/ijms222111806 - 30 Oct 2021

Cited by 6 | Viewed by 2243

Abstract

Galactic cosmic rays are primarily composed of protons (85%), helium (14%), and high charge/high energy ions (HZEs) such as ⁵⁶Fe, ²⁸Si, and ¹⁶O. HZE exposure is a major risk factor for astronauts during deep-space travel due to the possibility of HZE-induced cancer. A systems biology integrated omics approach encompassing transcriptomics, proteomics, lipidomics, and functional biochemical assays was used to identify microenvironmental changes induced by HZE exposure. C57BL/6 mice were placed into six treatment groups and received the following irradiation treatments: 600 MeV/n ⁵⁶Fe (0.2 Gy), 1 GeV/n ¹⁶O (0.2 Gy), 350 MeV/n ²⁸Si (0.2 Gy), ¹³⁷Cs (1.0 Gy) gamma rays, ¹³⁷Cs (3.0 Gy) gamma rays, and sham irradiation. Left liver lobes were collected at 30, 60, 120, 270, and 360 days post-irradiation. Analysis of transcriptomic and proteomic data utilizing ingenuity pathway analysis identified multiple pathways involved in mitochondrial function that were altered after HZE irradiation. Lipids also exhibited changes that were linked to mitochondrial function. Molecular assays for mitochondrial Complex I activity showed significant decreases in activity after HZE exposure. HZE-induced mitochondrial dysfunction suggests an increased risk for deep space travel. Microenvironmental and pathway analysis as performed in this research identified possible targets for countermeasures to mitigate risk. Full article

(This article belongs to the Special Issue Dysregulation of Human Molecular and Metabolic Mechanisms Resulting in Oxidative Stress and Damage Generation in the Space Environment)

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19 pages, 3275 KiB

Open AccessArticle

Simulated Galactic Cosmic Rays Modify Mitochondrial Metabolism in Osteoclasts, Increase Osteoclastogenesis and Cause Trabecular Bone Loss in Mice

by Ha-Neui Kim, Kimberly K. Richardson, Kimberly J. Krager, Wen Ling, Pilar Simmons, Antino R. Allen and Nukhet Aykin-Burns

Int. J. Mol. Sci. 2021, 22(21), 11711; https://doi.org/10.3390/ijms222111711 - 28 Oct 2021

Cited by 6 | Viewed by 2250

Abstract

Space is a high-stress environment. One major risk factor for the astronauts when they leave the Earth’s magnetic field is exposure to ionizing radiation from galactic cosmic rays (GCR). Several adverse changes occur in mammalian anatomy and physiology in space, including bone loss. In this study, we assessed the effects of simplified GCR exposure on skeletal health in vivo. Three months following exposure to 0.5 Gy total body simulated GCR, blood, bone marrow and tissue were collected from 9 months old male mice. The key findings from our cell and tissue analysis are (1) GCR induced femoral trabecular bone loss in adult mice but had no effect on spinal trabecular bone. (2) GCR increased circulating osteoclast differentiation markers and osteoclast formation but did not alter new bone formation or osteoblast differentiation. (3) Steady-state levels of mitochondrial reactive oxygen species, mitochondrial and non-mitochondrial respiration were increased without any changes in mitochondrial mass in pre-osteoclasts after GCR exposure. (4) Alterations in substrate utilization following GCR exposure in pre-osteoclasts suggested a metabolic rewiring of mitochondria. Taken together, targeting radiation-mediated mitochondrial metabolic reprogramming of osteoclasts could be speculated as a viable therapeutic strategy for space travel induced bone loss. Full article

(This article belongs to the Special Issue Dysregulation of Human Molecular and Metabolic Mechanisms Resulting in Oxidative Stress and Damage Generation in the Space Environment)

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25 pages, 2047 KiB

Open AccessArticle

Mammalian and Invertebrate Models as Complementary Tools for Gaining Mechanistic Insight on Muscle Responses to Spaceflight

by Thomas Cahill, Henry Cope, Joseph J. Bass, Eliah G. Overbey, Rachel Gilbert, Willian Abraham da Silveira, Amber M. Paul, Tejaswini Mishra, Raúl Herranz, Sigrid S. Reinsch, Sylvain V. Costes, Gary Hardiman, Nathaniel J. Szewczyk and Candice G. T. Tahimic

Int. J. Mol. Sci. 2021, 22(17), 9470; https://doi.org/10.3390/ijms22179470 - 31 Aug 2021

Cited by 11 | Viewed by 4504

Abstract

Bioinformatics approaches have proven useful in understanding biological responses to spaceflight. Spaceflight experiments remain resource intensive and rare. One outstanding issue is how to maximize scientific output from a limited number of omics datasets from traditional animal models including nematodes, fruitfly, and rodents. The utility of omics data from invertebrate models in anticipating mammalian responses to spaceflight has not been fully explored. Hence, we performed comparative analyses of transcriptomes of soleus and extensor digitorum longus (EDL) in mice that underwent 37 days of spaceflight. Results indicate shared stress responses and altered circadian rhythm. EDL showed more robust growth signals and Pde2a downregulation, possibly underlying its resistance to atrophy versus soleus. Spaceflight and hindlimb unloading mice shared differential regulation of proliferation, circadian, and neuronal signaling. Shared gene regulation in muscles of humans on bedrest and space flown rodents suggest targets for mitigating muscle atrophy in space and on Earth. Spaceflight responses of C. elegans were more similar to EDL. Discrete life stages of D. melanogaster have distinct utility in anticipating EDL and soleus responses. In summary, spaceflight leads to shared and discrete molecular responses between muscle types and invertebrate models may augment mechanistic knowledge gained from rodent spaceflight and ground-based studies. Full article

(This article belongs to the Special Issue Dysregulation of Human Molecular and Metabolic Mechanisms Resulting in Oxidative Stress and Damage Generation in the Space Environment)

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17 pages, 1021 KiB

Open AccessArticle

Spaceflight Modulates the Expression of Key Oxidative Stress and Cell Cycle Related Genes in Heart

by Akhilesh Kumar, Candice G. T. Tahimic, Eduardo A. C. Almeida and Ruth K. Globus

Int. J. Mol. Sci. 2021, 22(16), 9088; https://doi.org/10.3390/ijms22169088 - 23 Aug 2021

Cited by 12 | Viewed by 2993

Abstract

Spaceflight causes cardiovascular changes due to microgravity-induced redistribution of body fluids and musculoskeletal unloading. Cardiac deconditioning and atrophy on Earth are associated with altered Trp53 and oxidative stress-related pathways, but the effects of spaceflight on cardiac changes at the molecular level are less understood. We tested the hypothesis that spaceflight alters the expression of key genes related to stress response pathways, which may contribute to cardiovascular deconditioning during extended spaceflight. Mice were exposed to spaceflight for 15 days or maintained on Earth (ground control). Ventricle tissue was harvested starting ~3 h post-landing. We measured expression of select genes implicated in oxidative stress pathways and Trp53 signaling by quantitative PCR. Cardiac expression levels of 37 of 168 genes tested were altered after spaceflight. Spaceflight downregulated transcription factor, Nfe2l2 (Nrf2), upregulated Nox1 and downregulated Ptgs2, suggesting a persistent increase in oxidative stress-related target genes. Spaceflight also substantially upregulated Cdkn1a (p21) and cell cycle/apoptosis-related gene Myc, and downregulated the inflammatory response gene Tnf. There were no changes in apoptosis-related genes such as Trp53. Spaceflight altered the expression of genes regulating redox balance, cell cycle and senescence in cardiac tissue of mice. Thus, spaceflight may contribute to cardiac dysfunction due to oxidative stress. Full article

(This article belongs to the Special Issue Dysregulation of Human Molecular and Metabolic Mechanisms Resulting in Oxidative Stress and Damage Generation in the Space Environment)

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22 pages, 2779 KiB

Open AccessArticle

Acute, Low-Dose Neutron Exposures Adversely Impact Central Nervous System Function

by Peter M. Klein, Yasaman Alaghband, Ngoc-Lien Doan, Ning Ru, Olivia G. G. Drayson, Janet E. Baulch, Enikö A. Kramár, Marcelo A. Wood, Ivan Soltesz and Charles L. Limoli

Int. J. Mol. Sci. 2021, 22(16), 9020; https://doi.org/10.3390/ijms22169020 - 21 Aug 2021

Cited by 8 | Viewed by 2670

Abstract

A recognized risk of long-duration space travel arises from the elevated exposure astronauts face from galactic cosmic radiation (GCR), which is composed of a diverse array of energetic particles. There is now abundant evidence that exposures to many different charged particle GCR components within acute time frames are sufficient to induce central nervous system deficits that span from the molecular to the whole animal behavioral scale. Enhanced spacecraft shielding can lessen exposures to charged particle GCR components, but may conversely elevate neutron radiation levels. We previously observed that space-relevant neutron radiation doses, chronically delivered at dose-rates expected during planned human exploratory missions, can disrupt hippocampal neuronal excitability, perturb network long-term potentiation and negatively impact cognitive behavior. We have now determined that acute exposures to similar low doses (18 cGy) of neutron radiation can also lead to suppressed hippocampal synaptic signaling, as well as decreased learning and memory performance in male mice. Our results demonstrate that similar nervous system hazards arise from neutron irradiation regardless of the exposure time course. While not always in an identical manner, neutron irradiation disrupts many of the same central nervous system elements as acute charged particle GCR exposures. The risks arising from neutron irradiation are therefore important to consider when determining the overall hazards astronauts will face from the space radiation environment. Full article

(This article belongs to the Special Issue Dysregulation of Human Molecular and Metabolic Mechanisms Resulting in Oxidative Stress and Damage Generation in the Space Environment)

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25 pages, 5255 KiB

Open AccessArticle

Chronic Low Dose Neutron Exposure Results in Altered Neurotransmission Properties of the Hippocampus-Prefrontal Cortex Axis in Both Mice and Rats

by Balaji Krishnan, Chandramouli Natarajan, Krystyn Z. Bourne, Leila Alikhani, Juan Wang, Allison Sowa, Katherine Groen, Bayley Perry, Dara L. Dickstein, Janet E. Baulch, Charles L. Limoli and Richard A. Britten

Int. J. Mol. Sci. 2021, 22(7), 3668; https://doi.org/10.3390/ijms22073668 - 01 Apr 2021

Cited by 15 | Viewed by 3047

Abstract

The proposed deep space exploration to the moon and later to Mars will result in astronauts receiving significant chronic exposures to space radiation (SR). SR exposure results in multiple neurocognitive impairments. Recently, our cross-species (mouse/rat) studies reported impaired associative memory formation in both species following a chronic 6-month low dose exposure to a mixed field of neutrons (1 mGy/day for a total dose pf 18 cGy). In the present study, we report neutron exposure induced synaptic plasticity in the medial prefrontal cortex, accompanied by microglial activation and significant synaptic loss in the hippocampus. In a parallel study, neutron exposure was also found to alter fluorescence assisted single synaptosome LTP (FASS-LTP) in the hippocampus of rats, that may be related to a reduced ability to insert AMPAR into the post-synaptic membrane, which may arise from increased phosphorylation of the serine 845 residue of the GluA1 subunit. Thus, we demonstrate for the first time, that low dose chronic neutron irradiation impacts homeostatic synaptic plasticity in the hippocampal-cortical circuit in two rodent species, and that the ability to successfully encode associative recognition memory is a dynamic, multicircuit process, possibly involving compensatory changes in AMPAR density on the synaptic surface. Full article

(This article belongs to the Special Issue Dysregulation of Human Molecular and Metabolic Mechanisms Resulting in Oxidative Stress and Damage Generation in the Space Environment)

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16 pages, 12031 KiB

Open AccessArticle

Effects of Low Dose Space Radiation Exposures on the Splenic Metabolome

by Evagelia C. Laiakis, Igor Shuryak, Annabella Deziel, Yi-Wen Wang, Brooke L. Barnette, Yongjia Yu, Robert L. Ullrich, Albert J. Fornace, Jr. and Mark R. Emmett

Int. J. Mol. Sci. 2021, 22(6), 3070; https://doi.org/10.3390/ijms22063070 - 17 Mar 2021

Cited by 12 | Viewed by 3921

Abstract

Future space missions will include a return to the Moon and long duration deep space roundtrip missions to Mars. Leaving the protection that Low Earth Orbit provides will unavoidably expose astronauts to higher cumulative doses of space radiation, in addition to other stressors, e.g., microgravity. Immune regulation is known to be impacted by both radiation and spaceflight and it remains to be seen whether prolonged effects that will be encountered in deep space can have an adverse impact on health. In this study, we investigated the effects in the overall metabolism of three different low dose radiation exposures (γ-rays, ¹⁶O, and ⁵⁶Fe) in spleens from male C57BL/6 mice at 1, 2, and 4 months after exposure. Forty metabolites were identified with significant enrichment in purine metabolism, tricarboxylic acid cycle, fatty acids, acylcarnitines, and amino acids. Early perturbations were more prominent in the γ irradiated samples, while later responses shifted towards more prominent responses in groups with high energy particle irradiations. Regression analysis showed a positive correlation of the abundance of identified fatty acids with time and a negative association with γ-rays, while the degradation pathway of purines was positively associated with time. Taken together, there is a strong suggestion of mitochondrial implication and the possibility of long-term effects on DNA repair and nucleotide pools following radiation exposure. Full article

(This article belongs to the Special Issue Dysregulation of Human Molecular and Metabolic Mechanisms Resulting in Oxidative Stress and Damage Generation in the Space Environment)

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Review

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24 pages, 1266 KiB

Open AccessReview

Genomic Changes Driven by Radiation-Induced DNA Damage and Microgravity in Human Cells

by Afshin Beheshti, J. Tyson McDonald, Megumi Hada, Akihisa Takahashi, Christopher E. Mason and Maddalena Mognato

Int. J. Mol. Sci. 2021, 22(19), 10507; https://doi.org/10.3390/ijms221910507 - 29 Sep 2021

Cited by 17 | Viewed by 4360

Abstract

The space environment consists of a complex mixture of different types of ionizing radiation and altered gravity that represents a threat to humans during space missions. In particular, individual radiation sensitivity is strictly related to the risk of space radiation carcinogenesis. Therefore, in view of future missions to the Moon and Mars, there is an urgent need to estimate as accurately as possible the individual risk from space exposure to improve the safety of space exploration. In this review, we survey the combined effects from the two main physical components of the space environment, ionizing radiation and microgravity, to alter the genetics and epigenetics of human cells, considering both real and simulated space conditions. Data collected from studies on human cells are discussed for their potential use to estimate individual radiation carcinogenesis risk from space exposure. Full article

(This article belongs to the Special Issue Dysregulation of Human Molecular and Metabolic Mechanisms Resulting in Oxidative Stress and Damage Generation in the Space Environment)

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