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DOE OSTI2021

Exposure to an environmental mixture of polycyclic aromatic hydrocarbons induces hepatic cytochrome P450 enzymes in mice

Cytochrome P450 enzymes (CYPs) play an important role in bioactivating or detoxifying polycyclic aromatic hydrocarbons (PAHs), common environmental contaminants. While it is widely accepted that exposure to PAHs induces CYPs, effectively increasing rates of xenobiotic metabolism, dose- and time-response patterns of CYP induction are not well known. In order to better understand dose- and time-response relationships of individual CYPs following induction, we exposed B6129SF1/J mice to single or repeated doses (2-180 µmol/kg/d) of benzo[a]pyrene (BaP) or Supermix-10, a mixture of the top 10 most abundant PAHs found at the Portland Harbor Superfund Site. In hepatic microsomes from exposed mice, we measured amounts of active CYPs using activity-based protein profiling and total CYP expression using global proteomics. We observed rapid Cyp1a1 induction after 6 hr at the lowest PAH exposures and broad induction of many CYPs after 3 daily PAH doses at 72 hr following the first dose. Using samples displaying Cyp1a1 induction, we observed significantly higher metabolic affinity for BaP metabolism (Km reduced 3-fold), 3-fold higher intrinsic clearance, but no changes to the Vmax. Mice dosed with the highest PAH exposures exhibited 1.7 to 5-fold higher intrinsic clearance rates for BaP compared to controls and higher Vmax values indicating greater amounts of enzymes capable of metabolizing BaP. This study demonstrates exposure to PAHs found at Superfund Sites induces enzymes in dose- and time-dependent patterns in mice. Accounting for specific changes in enzyme profiles, and relative rates of PAH bioactivation and detoxification, and resulting risk will help translate internal dosimetry of animal models to humans and improve risk assessments of PAHs at Superfund sites.

Stoddard, Ethan G.↗

DOE OSTI2025

Diet outperforms microbial transplant to drive microbiome recovery in mice

A high-fat, low-fibre Western-style diet (WD) induces microbiome dysbiosis characterized by reduced taxonomic diversity and metabolic breadth, which in turn increases risk for a wide array of metabolic, immune and systemic pathologies. Recent work has established that WD can impair microbiome resilience to acute perturbations such as antibiotic treatment, although little is known about the mechanism of impairment and the specific consequences for the host of prolonged post-antibiotic dysbiosis. Here, in this study, we characterize the trajectory by which the gut microbiome recovers its taxonomic and functional profile after antibiotic treatment in mice on regular chow (RC) or WD, and find that only mice on RC undergo a rapid successional process of recovery. Metabolic modelling indicates that a RC diet promotes the development of syntrophic cross-feeding interactions, whereas in mice on WD, a dominant taxon monopolizes readily available resources without releasing syntrophic byproducts. Intervention experiments reveal that an appropriate dietary resource environment is both necessary and sufficient for rapid and robust microbiome recovery, whereas microbial transplant is neither. Furthermore, prolonged post-antibiotic dysbiosis in mice on WD renders them susceptible to infection by the intestinal pathogen Salmonella enterica serovar Typhimurium. Our data challenge widespread enthusiasm for faecal microbiota transplant (FMT) as a strategy to address dysbiosis, and demonstrate that specific dietary interventions are, at a minimum, an essential prerequisite for effective FMT, and may afford a safer, more natural and less invasive alternative.

Kennedy, M. S. [University of Chicago, IL (United ↗

DOE OSTI2021

Modeling Cell Survival Fraction and Other Dose-Response Relationships for Immunodeficient C.B-17 SCID Mice Exposed to 320-kV X Rays

US homeland security concerns related to potential misuse of γ-ray-emitting radiation sources employed in radiobiological research (eg, shielded cesium-137 irradiators) led to recommendations by the National Research Council to conduct studies into possibly replacing γ-ray irradiators used in research involving small rodent and other models with X-ray instruments. A limiting factor is suitability of the X-ray photon energy spectra. The objective of our research was to demonstrate the suitability of the radiation energy spectrum of 320-kV X rays after filtration (HVL = 4 mm Cu) for in-vivo cytotoxicity studies in immunodeficient C.B-17 SCID mice. By using a previously-published Hazard Function (HF) model to characterize dose-response relationships for in vivo bone marrow and spleen cell survival fractions and also to characterize the acute lethality risk (hematopoietic syndrome mode) we demonstrate that the filtered 320-kV X-ray beam appears suitable for such studies. A key finding for C.B-17 SCID mice when compared to results previously obtained for immunocompetent C.B-17 mice is that the immunodeficient mice appear to be more radioresistant, implicating a possible role of the immune system capacity in radiosensitivity of mammals.

Scott, Bobby R.↗

DOE OSTI2026

Cellular signaling within aged skeletal muscle reveals a dysregulated stress-induced remodeling response following volumetric muscle loss in female mice

Severe muscle trauma disrupts endogenous repair mechanisms, producing chronic functional deficits that are incompletely characterized in aged populations. This study investigated inflammatory, molecular, and physiological responses to volumetric muscle loss in young adult and aged female mice. Serum cytokine profiling revealed elevated baseline inflammation in aged animals and a blunted response to injury, with cytokines such as IL-6 increasing 4.4-fold in young versus 1.8-fold in aged mice at day 3 compared to baseline. By day 28 post-injury, histological analyses showed comparable reductions in muscle size and increases in fibrosis across ages. Despite these similar tissue-level outcomes, age-dependent differences emerged in downstream functional and molecular responses. Muscle functional testing demonstrated persistent force deficits independent of age but altered muscle relaxation kinetics in aged mouse muscles (p < 0.001), suggesting dysregulated excitation-contraction coupling. Additionally, mice displayed age-associated differences in post-injury limb loading. Global proteomic analyses further confirmed age-associated enrichment of complement and antigen-processing pathways alongside metabolic dysfunction (p < 0.05). Phosphoproteomic profiling revealed reduced basal kinase activity in the muscles of aged mice yet exaggerated injury-induced phosphorylation of Mapk1-associated phosphosites, indicating a dysregulated stress response. Collectively, these findings suggest that aged murine muscles function within a heightened inflammatory and perturbed kinase-signaling environment that may hinder the coordination of regenerative programs, underscoring the need for regenerative strategies that address age-specific molecular contexts to improve functional recovery across the lifespan.

Habing, Krista M.↗

DOE OSTI2023

Adenosine A2A Receptor Up-Regulation Pre-Dates Deficits of Synaptic Plasticity and of Memory in Mice Exposed to Aβ1–42 to Model Early Alzheimer’s Disease

The intracerebroventricular (icv) injection of amyloid peptides (Aβ) models Alzheimer’s disease (AD) in mice, as typified by the onset within 15 days of deficits of memory and of hippocampal long-term potentiation (LTP) that are prevented by the blockade of adenosine A2A receptors (A2AR). Since A2AR overfunction is sufficient to trigger memory deficits, we tested if A2AR were upregulated in hippocampal synapses before the onset of memory deficits to support the hypothesis that A2AR overfunction could be a trigger of AD. Six to eight days after Aβ-icv injection, mice displayed no alterations of hippocampal dependent memory; however, they presented an increased excitability of hippocampal synapses, a slight increase in LTP magnitude in Schaffer fiber-CA1 pyramid synapses and an increased density of A2AR in hippocampal synapses. A2AR blockade with SCH58261 (50 nM) normalized excitability and LTP in hippocampal slices from mice sacrificed 7–8 days after Aβ-icv injection. Fifteen days after Aβ-icv injection, mice displayed evident deficits of hippocampal-dependent memory deterioration, with reduced hippocampal CA1 LTP but no hyperexcitability and a sustained increase in synaptic A2AR, which blockade restored LTP magnitude. This shows that the upregulation of synaptic A2AR precedes the onset of deterioration of memory and of hippocampal synaptic plasticity, supporting the hypothesis that the overfunction of synaptic A2AR could be a trigger of memory deterioration in AD.

Lopes, Cátia R.↗

DOE OSTI2023

Evaluation of an Image-Derived Input Function for Kinetic Modeling of Nicotinic Acetylcholine Receptor-Binding PET Ligands in Mice

Positron emission tomography (PET) radioligands that bind with high-affinity to α4β2-type nicotinic receptors (α4β2Rs) allow for in vivo investigations of the mechanisms underlying nicotine addiction and smoking cessation. Here, we investigate the use of an image-derived arterial input function and the cerebellum for kinetic analysis of radioligand binding in mice. Two radioligands were explored: 2-[ 18 F]FA85380 (2-FA), displaying similar pKa and binding affinity to the smoking cessation drug varenicline (Chantix), and [ 18 F]Nifene, displaying similar pKa and binding affinity to nicotine. Time–activity curves of the left ventricle of the heart displayed similar distribution across wild type mice, mice lacking the β2-subunit for ligand binding, and acute nicotine-treated mice, whereas reference tissue binding displayed high variation between groups. Binding potential estimated from a two-tissue compartment model fit of the data with the image-derived input function were higher than estimates from reference tissue-based estimations. Rate constants of radioligand dissociation were very slow for 2-FA and very fast for Nifene. We conclude that using an image-derived input function for kinetic modeling of nicotinic PET ligands provides suitable results compared to reference tissue-based methods and that the chemical properties of 2-FA and Nifene are suitable to study receptor response to nicotine addiction and smoking cessation therapies.

2-FA85380↗

DOE OSTI2020

The Gut Microbiome and Alcoholic Liver Disease: Ethanol Consumption Drives Consistent and Reproducible Alteration in Gut Microbiota in Mice

Phenotypic health effects, both positive and negative, have been well studied in association with the consumption of alcohol in humans as well as several other mammals including mice. Many studies have also associated these same health effects and phenotypes to specific members of gut microbiome communities. Here we utilized a chronic plus binge ethanol feed model (Gao-binge model) to explore microbiome community changes across three independent experiments performed in mice. We found significant and reproducible differences in microbiome community assemblies between ethanol-treated mice and control mice on the same diet absent of ethanol. We also identified significant differences in gut microbiota occurring temporally with ethanol treatment. Peak shift in communities was observed 4 days after the start of daily alcohol consumption. We quantitatively identified many of the bacterial genera indicative of these ethanol-induced shifts including 20 significant genera when comparing ethanol treatments with controls and 14 significant genera based on temporal investigation. Including overlap of treatment with temporal shifts, we identified 25 specific genera of interest in ethanol treatment microbiome shifts. Shifts coincide with observed presentation of fatty deposits in the liver tissue, i.e., Alcoholic Liver Disease-associated phenotype. The evidence presented herein, derived from three independent experiments, points to the existence of a common, reproducible, and characterizable “mouse ethanol gut microbiome”.

59 BASIC BIOLOGICAL SCIENCES↗

NASA NTRS1975

Hematologic changes in mice during and after exposure to severe hypobaric hypoxia

Exposing mice to an atmospheric pressure of 300 mm Hg for 16 d caused a variety of hematologic effects. Hematocrit increased rapidly in the first 8 d of exposure and slowly in the second 8 d. Reticulocyte counts rose above normal, peaked on day 8, and then fell rapidly toward the control level. Macrocytic erythrocytes, formed during exposure, remained macrocytic after the termination of exposure and after the loss of their reticulum. The posthypoxic mice proved sensitive for erythropoietin bioassay. Mice injected with normal dog serum showed a significantly higher incorporation of Fe-59 than control mice injected with physiologic saline. A reduction of the duration of exposure to 10 d resulted in only a slight decrease in the sensitivity of the mouse bioassay system. However, a 16-d exposure at a pressure of 360 mm Hg resulted in considerably less sensitive bioassay animals.

Huff, J. E.↗

NASA NTRS1977

Electrophoresis pattern of serum from mice exposed to different concentrations of sulfur dioxide

Three day old mice were continuously exposed to sulphur dioxide concentrations at 0ppm, 0.05ppm, 0.15ppm and 1ppm for eight weeks. At the end of the experiment, blood samples were collected and centrifuged for electrophoresis studies of the serum in 5 percent acrylamide gel. The length of bands of different serum proteins from the SO2 exposed mice was at a variance as compared with the length of bands from the control exposed mice and alpha-1 band seems to be missing from the serum of SO2 exposed mice.

Singh, J.↗

NASA NTRS1986

Treatment of trypanosome-infected mice with exogenous interferon, interferon inducers, or antibody to interferon

Earlier studies have demonstrated that mice resistant to Trypanosoma brucei rhodesiense (the B10.BR/SgSnJ strain) produces, upon infection by this parasite, two peaks of serum interferon (IFN), while the susceptible mice (C3HeB/FeJ) produces no IFN. In the present study, survival times were compared for B10.BR/SgSnJ, C3HeB/FeJ, and CBA/J (an intermediately resistant strain) mice that were injected, prior to infection with the parasite, with either of the following three preparations (1) IFN-gamma, (2) an antibody to IFN-gamma and (3) polyriboinosinic-polyribocytidylic acid (to induce IFN-alpha/beta). No effect on the survival times of mice by any of these preparations could be demonstrated, contrary to some previous reports.

Degee, Antonie L. W.↗

NASA NTRS1995

The Effects of Rm-CSF and Ril-6 Therapy on Immunosuppressed Antiorthostatically Suspended Mice

Antiorthostatically suspended mice had suppressed macrophage development in both unloaded and loaded bones, indicating a systemic effect. Bone marrow cells from those mice secreted less macrophage colony-stimulating factor (M-CSF) and interleukin-6 (IL-6) than did control mice. Because M-CSF and IL-6 are important to bone marrow macrophage maturation, we formulated the hypothesis that suppressed macrophage development occurred as a result of the depressed levels of either M-CSF or IL-6. To test the hypothesis, mice were administered recombinant M-CSF or IL-6 intraperitoneally. We showed that recombinant M-CSF therapy, but not recombinant IL-6 therapy, reversed the suppressive effects of orthostatic suspension on macrophage development. These data suggest that bone marrow cells that produce M-CSF are affected by antiorthostatic suspension and may contribute to the inhibited maturation of bone marrow macrophage progenitors.

Armstong, Jason W.↗

NASA NTRS2000

Pulmonary Toxicity Study of Lunar and Martian Dust Simulants Intratracheally Instilled in Mice

NASA is contemplating sending humans to Mars and the Moon for further exploration. The properties of Hawaiian and Californian volcanic ashes allow them to be used to simulate Martian and lunar dusts, respectively. NASA laboratories use these dust simulants to test performance of hardware destined for Martian or lunar environments. Workers in these test facilities are exposed to low levels of these dusts. The present study was conducted to investigate the toxicity of these dust simulants. Particles of respirable-size ranges of lunar simulant (LS), Martian simulant (MS), TiO2 (negative control) and quartz (positive control) were each intratracheally instilled (saline as vehicle) to groups of 4 mice (C57BL, male, 2-3 month old) at a single treatment of 1 (Hi dose) or 0.1 (Lo dose) mg/mouse. The lungs were harvested at the end of 7 days or 90 days for histopathological examination. Lungs of the LS-Lo groups had no evidence of inflammation, edema or fibrosis. The LS-Hi-7d group had mild to moderate acute inflammation, and neutrophilic and lymphocytic infiltration; the LS-Hi-90d group showed signs of chronic inflammation and some fibrosis. Lungs of the MS-Lo-7d group revealed mild inflammation and neutrophilic and lymphocytic infiltration; the MS-Lo-90d group showed mild fibrosis and particle-laden macrophages (PLM). Lungs of the MS-Hi-7d group demonstrated mild to moderate inflammation and large foci of PLM; the MS-Hi-90d group showed chronic mild to moderate inflammation and fibrosis. To mimic the effects of the oxidative and reactive properties of Martian soil surface, groups of mice were exposed to ozone (3 hour at 0.5 ppm) prior to MS dust instillation. Lung lesions in the MS group were more severe with the pretreatment. The results for the negative and positive controls were consistent with the known pulmonary toxicity of these compounds. The overall severity of toxic insults to the lungs were TiO2<LS<MS<Quartz. For the mice in the 90-d study, blood samples were taken for immunotoxicity study. Antinuclear antibodies (such as those against Golgi, kinetichore, and centromere) were detected in serum in a greater extent in mice treated with LS than those with quartz, suggesting that LS, like quartz, has the potential of inducing antoimmune disease.

Lam, Chiu-Wing↗

NASA NTRS2017

Genetic Correlation with the DNA Repair Assay in Mice Exposed to High-LET

We hypothesize that DNA damage induced by high local energy deposition, occurring when cells are traversed by high-LET (Linear Energy Transfer) particles, can be experimentally modeled by exposing cells to high doses of low-LET. In this work, we validate such hypothesis by characterizing and correlating the time dependence of 53BP1 radiation-induced foci (RIF) for various doses and LET across 72 primary skin fibroblast from mice. This genetically diverse population allows us to understand how genetic may modulate the dose and LET relationship. The cohort was made on average from 3 males and 3 females belonging to 15 different strains of mice with various genetic backgrounds, including the collaborative cross (CC) genetic model (10 strains) and 5 reference mice strains. Cells were exposed to two fluences of three HZE (High Atomic Energy) particles (Si 350 megaelectronvolts per nucleon, Ar 350 megaelectronvolts per nucleon and Fe 600 megaelectronvolts per nucleon) and to 0.1, 1 and 4 grays from a 160 kilovolt X-ray. Individual radiation sensitivity was investigated by high throughput measurements of DNA repair kinetics for different doses of each radiation type. The 53BP1 RIF dose response to high-LET particles showed a linear dependency that matched the expected number of tracks per cell, clearly illustrating the fact that close-by DNA double strand breaks along tracks cluster within one single RIF. By comparing the slope of the high-LET dose curve to the expected number of tracks per cell we computed the number of remaining unrepaired tracks as a function of time post-irradiation. Results show that the percentage of unrepaired track over a 48 hours follow-up is higher as the LET increases across all strains. We also observe a strong correlation between the high dose repair kinetics following exposure to 160 kilovolts X-ray and the repair kinetics of high-LET tracks, with higher correlation with higher LET. At the in-vivo level for the 10-CC strains, we observe that drops in the number of T-cells and B-cells found in the blood of mice 24 hours after exposure to 0.1 gray of 320 kilovolts X-ray correlate well with slower DNA repair kinetics in skin cells exposed to X-ray. Overall, our results suggest that repair kinetics found in skin is a surrogate marker for in-vivo radiation sensitivity in other tissue, such as blood cells, and that such response is modulated by genetic variability.

cosmic radiation↗

NASA NTRSDate not supplied

Guanine Oxidation in the Genome, not RNA Editing, Accounts for Single Nucleotide Variation in the Exome of Mice Flown on Board the ISS

We have conducted a further analysis of single nucleotide variation (somatic mutation) in mice flown aboard the ISS. We used data archived in GeneLab from a cohort of 18-week-old mice were flown to the ISS, housed in the Rodent Habitat and therefore subjected to microgravity for 37 days. Mice of similar age, sex and the same strain were used for ground controls housed in identical hardware and simulating, but not matching ISS environmental conditions (temperature, humidity and gas atmosphere). Primary data consists of next generation RNA sequencing for the tissues examined: eye, liver, skeletal muscle and kidney. We used novel software, developed at NASA Ames Research Center and deployed on the NASA Ames Supercomputer, to perform variant calling for single point mutations. Unexpectedly, we discovered a high degree of somatic mutation in ISS-flown mice, compared to controls. We found that the extent of somatic mutation correlated with the degree of gene expression in the four tissue types, with the highest degree of somatic mutation observed in genes with the highest degree of expression. Careful analysis that included measurement of specific nucleotide changes that occurred demonstrated that guanine substitutions were the most frequent, consistent with the hypothesis that reactive oxygen species-mediated guanine oxidation was responsible for the hypermutation events. By contrast, adenine substitutions would be expected if gene editing were responsible for the somatic mutation. These types of substitutions were much less frequent. The implication of these findings for astronaut health in a variety of mission scenarios will be discussed.

International Space Station↗

NASA NTRSDate not supplied

Comparison of Radiation-induced Damage Between Livers from Control and Chimeric Mice

Assessment of human health risks associated with space radiation exposure is based largely on the knowledge learned from studies in which animals, mostly rodents, are exposed to high-LET radiation on the ground. It has been recognized that translation of animal results to meaningful implications for human disease can be challenging, particularly for certain risk categories such as the high-LET radiation effects in the central nervous system (CNS). Considering limitations in utilizing non-human primates and clinical studies in humans, chimeric animals can potentially bridge the knowledge gap between rodents and humans. In a chimeric animal, a specific organ or a cell type is replaced with respective human cells that are functional. In this pilot study, we use PXB mice whose livers contain >90% human cells. These mice are exposed to gamma rays for investigations of DNA damage and transcriptomics changes in the humanized livers. Results obtained from PXB mice were compared non-engrafted control animals from the same background strain that are exposed to identical conditions. Staining of the liver tissues with H&E indicated that the human liver tissue in chimeric mice responds differently than the mouse liver tissue to gamma radiation on the cellular level, as evidenced by differences in inflammation and cellular damage seen on histopathology. The gene expression data collected from the liver samples will also be presented, which potentially offers an explanation for the differential responses.

Honglu Wu↗

NASA NTRSDate not supplied

Comparison of Radiation-Induced Damage Between Livers From Control and Chimeric Mice

Assessment of human health risks associated with space radiation exposure is based largely on the knowledge gained from studies in which animals, mostly rodents, are exposed to high-LET radiation on the ground. It has been recognized that translation of animal results to meaningful implications for human disease can be challenging, particularly for certain risk categories such as the high-LET radiation effects in the central nervous system (CNS). Considering limitations in utilizing non-human primates and clinical studies in humans, chimeric animals can potentially bridge the knowledge gap between rodents and humans. In a chimeric animal, a specific organ or a cell type is replaced with respective human cells that are functional. In this pilot study, we used PXB mice whose livers contain >90% human cells. These mice were exposed to gamma rays to investigate DNA damage and transcriptomics changes in the chimeric livers. Results obtained from PXB mice were compared to non-engrafted control animals from the same background strain that were exposed to identical conditions. Staining of the liver tissues with H&E indicated that the human liver tissue in chimeric mice responded differently than the mouse liver tissue to gamma radiation on the cellular level, as evidenced by differences in inflammation and cellular damage seen on histopathology. The gene expression data collected from the liver samples will also be presented, which potentially offers an explanation for the differential responses.

Honglu Wu↗

NASA NTRSDate not supplied

37-Day Microgravity Exposure in 16-Week Female C57BL/6J Mice is Associated with Weight Bearing Site-Specific Bone Loss

Exposure to space environment factors, including microgravity unloading and space radiation, is well-known to be associated with rapid bone loss in mammals, but significant questions remain about mechanistic aspects of this process. Specifically, bone loss may vary depending on many interacting factors including age and skeletal maturity, physical activity, social versus individual housing, and habitat configuration. Likewise cellular tissue loss mechanisms in space may include changes to mineral homeostasis by activation of bone degradation by osteoclasts, or inhibition of bone formation by osteoblasts, and be caused by microgravity mechanical unloading or increased space radiation. In this study we used microcomputed tomography to quantify bone loss in multiple skeletal sites of group housed mice either exposed to 37 days in space on ISS during the Rodent Research 1, (RR1), experiments using the NASA Rodent Habitat, (RH), versus ground controls in the same habitats or standard vivarium cages. Our results in space versus matched RH ground controls show significant cancellous and cortical bone loss in the femur and tibia, but not in vertebrae, indicating that only weight-bearing bones experience significant bone loss during spaceflight. This finding suggests that space radiation at the low levels found in low Earth Orbit may not be a significant contributing factor to bone loss in space. Interestingly while mice maintained in the RH maintained or gained bone relative to Basal controls, mice kept in standard vivarium cages for 37 days showed significant loss in weight bearing bones, not as acute, but comparable in magnitude to spaceflight effects. These results suggest the RH configuration versus vivarium cages, may allow for greater mechanical loading of weight bearing bones as mice climb internal habitat surfaces, promoting maintenance of bone regenerative health.

mouse↗

NASA NTRSDate not supplied

Comparison of Radiation-Induced Damage Between Livers From Control and Chimeric Mice

Honglu Wu↗