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All sourcesNASA NTRSDOE OSTI
DOE OSTI2015

Temporal Changes in Rat Liver Gene Expression after Acute Cadmium and Chromium Exposure

U.S. Service Members and civilians are at risk of exposure to a variety of environmental health hazards throughout their normal duty activities and in industrial occupations. Metals are widely used in large quantities in a number of industrial processes and are a common environmental toxicant, which increases the possibility of being exposed at toxic levels. While metal toxicity has been widely studied, the exact mechanisms of toxicity remain unclear. In order to further elucidate these mechanisms and identify candidate biomarkers, rats were exposed via a single intraperitoneal injection to three concentrations of CdCl 2 and Na 2 Cr 2 O 7 , with livers harvested at 1, 3, or 7 days after exposure. Cd and Cr accumulated in the liver at 1 day post exposure. Cd levels remained elevated over the length of the experiment, while Cr levels declined. Metal exposures induced ROS, including hydroxyl radical (•OH), resulting in DNA strand breaks and lipid peroxidation. Interestingly, ROS and cellular damage appeared to increase with time post-exposure in both metals, despite declines in Cr levels. Differentially expressed genes were identified via microarray analysis. Both metals perturbed gene expression in pathways related to oxidative stress, metabolism, DNA damage, cell cycle, and inflammatory response. This work provides insight into the temporal effects and mechanistic pathways involved in acute metal intoxication, leading to the identification of candidate biomarkers.

59 BASIC BIOLOGICAL SCIENCES↗
NASA NTRS1973

Effect of low temperature on metabolism of rat liver slices and epididymal fat pads.

Study of low temperature effects on the metabolism of radioisotope-tagged glucose and palmitate in rat liver slices and epididymal fat pads. The obtained data suggest that the oxidative capacity of rat liver and adipose tissue is maintained at low temperatures to a greater degree than the synthetic capacity. It was concluded that sufficient energy can be produced at 17 C for maintenance of essential tissue functions by these two tissues but that the energy requirements may not be met at 7 C.

Hillyard, L. A.↗
NASA NTRS1980

Effect of graded physical load on the state of the liver from morphometric data and biochemical blood indices of rats against a background of hypokinesia

Tests were conducted on 100 sexually immature inbred August and Wistar male rats in order to determine the effects hypokinesia, physical load and phenamine on the liver. Weight and linear dimension fell in hypokinesia; total serum protein lowered and aldolase and cholesterol and beta-lipoprotein levels rose. Blood sugar content rose and liver glycogen fell. Interlinear differences of these indices are found. Rehabilitated physical loading against hypokinesia background diminished and at times completely prevented its negative effect. Extent of correction depended on animal species. Evidence of genotypical conditionality of organism adaptation to physical load in hypokinesia was found.

Nikityuk, B. A.↗
NASA NTRS1980

Content of total iron, copper and manganese in liver of animals during hypokinesia, muscle activity and process of recovery

It is shown that the content of total iron, copper and manganese in the liver of animals is altered depending on the intensity and duration of their swimming. Hypodynamia for 7 days does not alter the concentration of iron, but sufficiently increases the content of copper and manganese. The barometric factor effectively influences the maintenance of constancy in the content of microelements accumulated in the liver after intensive muscle activity.

Potapovich, G. M.↗
NASA NTRS1981

The nature of compensatory and restorative processes in the livers of animals irradiated during hypokinesia

The nature of postirradiation repair in the livers of rats irradiated during hypokinesia is investigated. Hepatocyte population counts, mitotic activity, binuclear cell content, and karyometric studies were done to ascertain the effects of combined hypokinesia and radiation. Hypokinesia is shown to change the nature and rate of post-irradiation changes in the liver, the effect varying with the timing of irradiation relative to the length of hypokinesia. It is concluded that the changes in the compensatory and restorative processes are caused by stress developed in response to isolation and restricted mobility. By changing neuroendocrine system activity, the stress stimulates cell and tissue repair mechanisms at a certain stage essential to the body's reaction of subsequent irradiation.

Chernov, I. P.↗
NASA NTRS1981

Experiment K304: Studies of specific hepatic enzymes and liver constituents involved in the conversion of carbohydrates to lipids in rats exposed to prolonged space flight

The effects of space flight on the activities of 26 enzymes concerned with carbohydrate and lipid metabolism in hepatic tissue taken from male Wistar rats are investigated. These activities were measured in the various hepatic cell compartments, i.e., cytosol, mitochondria and microsomes. In addition, the levels of glycogen, total lipids, phospholipids, triglycerides, cholesterol, cholesterol esters, and the fatty acid composition of the rat livers were also examined and quantified. A similar group of ground-based rats treated in an identical manner served as controls. Both flight and synchronous control rats were sacrificed at three time intervals: R+0, 7-11 hours after recovery; R+6, after 6 days; R+6(S), after 6 days (having undergone 2-5 hour periods of fixed stress in a "backupward" position on days 0, 3, 4, 5 and 6) and R+29, after 29 days post-flight. Although most of the enzyme activities and the amounts of liver constituents studied were unaffected by the period of weightlessness, some significant differences were observed.

Abraham, S.↗
NASA NTRS1981

Polyploidization delay in rat hepatocytes under liver growth inhibition by hypokinesia

A study of young rats, weighing 55 to 59 g, after being for 10 days in conditions of limited mobility, shows a retardation of body growth as well as that of liver growth. The decrease in the rate of growth is accompanied by a reduction of cell proliferation and by delay polyploidization of hepatocytes in the liver of experimental rats. The materials, methods, and results of research are discussed.

Faktor, V. M.↗
NASA NTRS1983

Biochemical changes in rat liver after 18.5 days of spaceflight (41566)

The effect of weightlessness on liver metabolism was investigated using tissue from rats flown in earth orbit for 18.5 days on the Soviet Cosmos 936 biosatellite and the changes in the activities of 28 carbohydrate and lipid enzymes were determined. The activities of two enzymes, palmitoyl-CoA desaturase and lactate dehydrogenase, increased, while the activities of five, glycogen phosphorylase, 6-phosphogluconate dehydrogenase, both acyltransferases which act on alpha-glycerolphosphate and diglycerides, and and aconitate hydratase decreased. The other enzyme activities were found to be unchanged. In addition, increased levels of liver glycogen and palmitoleate were detected which probably resulted from the lowered glycogen phosphorylase and increased palmitoyl-CoA desaturase activities, respectively, in those animals that experienced weightlessness. All of the changes observed in the rats after 18.5 days of spaceflight disappear by 25 days after the flight.

Abraham, S.↗
NASA NTRS1978

The Effects of Space Flight on Some Liver Enzymes Concerned with Carbohydrate and Lipid Metabolism in Rats

The activities of about 30 enzymes concerned with carbohydrate and lipid metabolism and the levels of glycogen and of individual fatty acids were measured in livers of rats ex- posed to prolonged space flight (18.5 days) aboard COSMOS 986 Biosatellite. When flight stationary, (FS) and flight centrifuged (FC) rats were compared at recovery (R(sub 0)), decrceases in the activities of glycogen phosphorylase, alpha glycerphosphate, acyl transferase, diglyceride acyl transferase, acconitase and Epsilon-phosphogluconate dehydrogenase were noted in the weightless group (FS). The significance of these findings was strengthened since all activities, showing alterations at R(sub 0), returned to normal 25 days post-flight. Differences were also seen in levels of two liver constituents. When glycogen and total fatty acids of the two groups of flight animals were determined, differences that could be attributed to reduced gravity were observed, the FS group at R(sub 0) contained, on the average, more than twice the amount of glycogen than did controls ad a remarkable shift in the ratio of palmitate to palmitoleate were noted. These metabolic alterations appear to be unique to the weightless condition. Our data justify the conclusion that centrifugation during space flight is equivalent to terrestrial gravity.

Abraham, S.↗
NASA NTRS2000

Effects of JP-8 Jet Fuel on Homeostasis of Clone 9 Rat Liver Cells

Chronic exposure to JP-8 and other kerosene-based petroleum distillates has been associated with hepatic, renal, neurologic, pulmonary, and immune toxicity. However, the effects of kerosene-type jet fuels on cellular homeostasis hitherto have not been reported. Fluorescence imaging using a Meridian Ultima laser scanning fluorescence microscope was used to evaluate the effect of JP-8 jet fuel on a communication competent rat liver cell line. Several endpoints of cellular function were measured including gap junctional intercellular communication (GJIC), mitochondrial and plasma membrane potential (MMP and PMP, respectively), intracellular glutathione (GSH) concentration, glutathione-S-transferase (GST) activity, and reactive oxygen species (ROS) generation. Cells were treated with JP-8 (0.01 to 2% in ethanol (EtOH)) for the following time points: 1 h, 24 h, 48 h, and analysis immediately after addition of jet fuel. GJIC analyzed directly after addition of 1% JP-8 was reduced 4.9-fold relative to EtOH-dosed control groups and further reduction (12.6-fold) was observed in cells treated for 1 h. Moreover, GJIC was not recoverable in cells treated with 1% JP-8 for 1 h and subsequently washed and incubated in fresh medium for 1 h. Significant changes in GSH content and GST activity were observed in cells analyzed directly after addition of 1% JP-8. GSH content increased in cells treated for 1 h with less than 2% JP-8 whereas treatment with 2% JP-8 for 1 h resulted in a 50% reduction in intracellular GSH relative to EtOH-dosed controls. Cells treated with 1% JP-8 for 48 h exhibited changes in GSH levels. However, higher JP-8 concentrations exhibited more pronounced changes in GSH and GST, which led to suppression of GSH synthesis. ROS increased in a dose-responsive fashion at JP-8 concentrations up to 1%, but decreased to 80% of control values at 2% and 3% JP-8. A 25% reduction in PMP was observed in cells treated for 1 h with 1% JP-8. In contrast, cells treated for 48 h with 2% JP-8 exhibited a 25% increase when compared to control. No significant changes were noted in the 0.01 and 1% treatment groups. Moreover, no significant changes were observed in MMP or intracellular calcium concentrations in cells treated with 0.01 to 2% JP-8 for up to 48 h. In summary, the most significant effects observed in the present study which may contribute to the toxicity of JP-8 jet fuel in cultured rat liver cells include effects on GJIC, ROS production, and GSH depletion at high (i.e., greater than 2%) JP-8 concentrations.

Wilson, C. L.↗
NASA NTRS1988

Age dependency of base modification in rabbit liver DNA

Age-related modifications of DNA bases have been observed in the liver of the New Zealand white (NZW) rabbit (Oryctolagus cuniculus), a lagomorph with a median life span in captivity of 5-7 yr. The ages of the animals studied ranged from 6 wk to 9 yr. After the DNA had been extracted from the liver cell nuclei and hydrolyzed with acid, the bases were analyzed by column chromatography with Cellulofine gels (GC-15-m). Two peaks in the chromatogram, which eluted before the four DNA bases, contained modified bases. Those materials, which were obtained in relatively large amounts from old animals, were highly fluorescent, and were shown to be crosslinked base products by mass spectrometry. The yield of crosslinked products versus rabbit age (greater than 0.5 yr) can be fitted by an exponential function (correlation coefficient: 0.76 +/- 0.09).

NASA Discipline Radiation Health↗
NASA NTRS1990

Altered carbohydrate, lipid, and xenobiotic metabolism by liver from rats flown on Cosmos 1887

To determine the possible biochemical effects of prolonged weightlessness on liver function, samples of liver from rats that had flown aboard Cosmos 1887 were analyzed for protein, glycogen, and lipids as well as the activities of a number of key enzymes involved in metabolism of these compounds and xenobiotics. Among the parameters measured, the major differences were elevations in the glycogen content and hydroxymethylglutaryl-CoA (HMG-CoA) reductase activities for the rats flown on Cosmos 1887 and decreases in the amount of microsomal cytochrome P-450 and the activities of aniline hydroxylase and ethylmorphine N-demethylase, cytochrome P-450-dependent enzymes. These results support the earlier finding of differences in these parameters and suggest that altered hepatic function could be important during spaceflight and/or the postflight recovery period.

NASA Experiment Number COS 1887-4↗
NASA NTRS2005

Kinetic Studies of Iron Deposition Catalyzed by Recombinant Human Liver Heavy, and Light Ferritins and Azotobacter Vinelandii Bacterioferritin Using O2 and H2O2 as Oxidants

The discrepancy between predicted and measured H2O2 formation during iron deposition with recombinant heavy human liver ferritin (rHF) was attributed to reaction with the iron protein complex [Biochemistry 40 (2001) 10832-10838]. This proposal was examined by stopped-flow kinetic studies and analysis for H2O2 production using (1) rHF, and Azotobacter vinelandii bacterial ferritin (AvBF), each containing 24 identical subunits with ferroxidase centers; (2) site-altered rHF mutants with functional and dysfunctional ferroxidase centers; and (3) rccombinant human liver light ferritin (rLF), containing 110 ferroxidase center. For rHF, nearly identical pseudo-first-order rate constants of 0.18 per second at pH 7.5 were measured for Fe(2+) oxidation by both O2 and H2O2, but for rLF, the rate with O2 was 200-fold slower than that for H2O2 (k-0.22 per second). A Fe(2+)/O2 stoichiometry near 2.4 was measured for rHF and its site altered forms, suggesting formation of H2O2. Direct measurements revealed no H2O2 free in solution 0.5-10 min after all Fe(2+) was oxidized at pH 6.5 or 7.5. These results are consistent with initial H2O2 formation, which rapidly reacts in a secondary reaction with unidentified solution components. Using measured rate constants for rHF, simulations showed that steady-state H2O2 concentrations peaked at 14 pM at approx. 600 ms and decreased to zero at 10-30 s. rLF did not produce measurable H2O2 but apparently conducted the secondary reaction with H2O2. Fe(2+)/O2 values of 4.0 were measured for AvBF. Stopped-flow measurements with AvBF showed that both H2O2 and O2 react at the same rate (k=0.34 per second), that is faster than the reactions with rHF. Simulations suggest that AvBF reduces O2 directly to H2O without intermediate H2O2 formation.

Bunker, Jared↗
NASA NTRS2012

High Dietary Iron and Radiation Exposure Increase Biomarkers of Oxidative Stress in Blood and Liver of Rats

Radiation exposure and increased iron (Fe) status independently cause oxidative damage that can result in protein, lipid, and DNA oxidation. During space flight astronauts are exposed to both increased radiation and increased Fe stores. Increased body Fe results from a decrease in red blood cell mass and the typically high Fe content of the food system. In this study we investigated the combined effects of radiation exposure (0.375 Gy of Cs-137 every other day for 16 days for a total of 3 Gy) and high dietary Fe (650 mg Fe/kg diet compared to 45 mg Fe/kg for controls) in Sprague-Dawley rats (n=8/group). Liver and serum Fe were significantly increased in the high dietary Fe groups. Likewise, radiation treatment increased serum ferritin and Fe concentrations. These data indicate that total body Fe stores increase with both radiation exposure and excess dietary Fe. Hematocrit decreased in the group exposed to radiation, providing a possible mechanism for the shift in Fe indices after radiation exposure. Markers of oxidative stress were also affected by both radiation and high dietary Fe, evidenced by increased liver glutathione peroxidase (GPX) and serum catalase as well as decreased serum GPX. We thus found preliminary indications of synergistic effects of radiation exposure and increased dietary Fe, warranting further study. This study was funded by the NASA Human Research Project.

Morgan, Jennifer L. L.↗
NASA NTRSDate not supplied

Transcriptomics-based Machine Learning (ML) Analysis Predicts Space-Exposed Murine Livers

NASA has employed high-throughput molecular assays to identify sub-cellular changes impacting human physiology during spaceflight. Machine learning (ML) methods hold the promise to improve our ability to identify important signals within highly dimensional molecular data. However, the inherent limitation of study subject numbers within a spaceflight mission minimizes the utility of ML approaches. To overcome the sample power limitations, data from multiple spaceflight missions must be aggregated while appropriately addressing intra- and inter-study variabilities. Here we describe an approach to log transform, scale and normalize data from six heterogeneous, mouse liver derived transcriptomics datasets (ntotal=137) which enabled ML-methods to perform well (AUC ≥ 0.87) in classifying spaceflown vs ground control animals rather than mission-of-origin. Concordance was found between liver-specific biological processes identified from harmonized ML-based analysis and study-by-study classical omics analysis. This work demonstrates the feasibility of applying ML methods on integrated, heterogeneous datasets of small sample size.

Machine Learning↗
DOE OSTI2014

Case Study: Polycystic Livers in a Transgenic Mouse Line

Three mice (2 male, 1 female; age, 5 to 16 mo) from a mouse line transgenic for keratin 14 (K14)-driven LacZ expression and on an outbred Crl:CD1(ICR) background, were identified as having distended abdomens and livers that were diffusely enlarged by numerous cysts (diameter, 0.1 to 2.0 cm). Histopathology revealed hepatic cysts lined by biliary type epithelium and mild chronic inflammation, and confirmed the absence of parasites. Among 21 related mice, 5 additional affected mice were identified via laparotomy. Breeding of these 5 mice (after 5 mo of age) did not result in any offspring; the K14 mice with olycystic livers failed to reproduce. Affected male mice had degenerative testicular lesions, and their sperm was immotile. Nonpolycystic K14 control male mice bred well, had no testicular lesions, and had appropriate sperm motility. Genetic analysis did not identify an association of this phenotype with the transgene or insertion site.

Lovaglio, Jamie A.↗
DOE OSTI2016

Transcriptional regulation of the human Liver X Receptor α gene by Hepatocyte Nuclear Factor 4α

Liver X Receptors (LXRs) are sterol-activated transcription factors that play major roles in cellular cholesterol homeostasis, HDL biogenesis and reverse cholesterol transport. The aim of the present study was to investigate the mechanisms that control the expression of the human LXRα gene in hepatic cells. A series of reporter plasmids containing consecutive 5′ deletions of the hLXRα promoter upstream of the luciferase gene were constructed and the activity of each construct was measured in HepG2 cells. This analysis showed that the activity of the human LXRα promoter was significantly reduced by deleting the −111 to −42 region suggesting the presence of positive regulatory elements in this short proximal fragment. Bioinformatics data including motif search and ChIP-Seq revealed the presence of a potential binding motif for Hepatocyte Nuclear Factor 4 α (HNF-4α) in this area. Overexpression of HNF-4α in HEK 293T cells increased the expression of all LXRα promoter constructs except −42/+384. In line, silencing the expression of endogenous HNF-4α in HepG2 cells was associated with reduced LXRα protein levels and reduced activity of the −111/+384 LXRα promoter but not of the −42/+384 promoter. Using ChiP assays in HepG2 cells combined with DNAP assays we mapped the novel HNF-4α specific binding motif (H4-SBM) in the −50 to −40 region of the human LXRα promoter. A triple mutation in this H4-SBM abolished HNF-4α binding and reduced the activity of the promoter to 65% relative to the wild type. Furthermore, the mutant promoter could not be transactivated by HNF-4α. In conclusion, our data indicate that HNF-4α may have a wider role in cell and plasma cholesterol homeostasis by controlling the expression of LXRα in hepatic cells. - Highlights: • The human LXRα promoter contains a HNF-4α specific binding motif in the proximal −50/−40 region. • Mutations in this motif abolished HNF4α binding and transactivation of the hLXRα promoter. • Silencing of HNF-4α was associated with reduced LXRα protein levels and promoter activity. • The HNF-4α/LXRα axis may have a wide role in cell and plasma cholesterol homeostasis.

60 APPLIED LIFE SCIENCES↗