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PubMed2003

Differential regulation of 5' splice variants of the glutamate transporter EAAT2 in an in vivo model of chemical hypoxia induced by 3-nitropropionic acid.

Defective glutamate uptake has been implicated as a pathogenic event of neuronal damage related to cerebral ischemia and hypoxia. In several models of ischemia-hypoxia, a reduced immunoreactivity and altered RNA expression of excitatory amino acid transporter 2 (EAAT2), the major excitatory amino acid transporter, have been reported. However, the gene regulation of EAAT2 under these conditions is incompletely understood. In this study, we investigated alternative splicing of EAAT2 in an in vivo mouse model of chemical hypoxia as induced by 3-nitropropionic acid (3-NP). The neurotoxin 3-NP is an inhibitor of mitochondrial energy production. Furthermore, it is known to inhibit glutamate reuptake directly, representing at least one of the mechanisms responsible for 3-NP-induced neurodegeneration. Here we report an expression analysis of five known (mEAAT2/5UT1-5) and two novel (mEAAT2/5UT6, -7) 5' splice variants of EAAT2 using semiquantitative PCR. The RNA expression was studied at 2, 12, 24, 48, and 72 hr and 7 days after 3-NP administration. mEAAT2/5UT4 and mEAAT2/5UT5 were up-regulated in the frontal cortex and down-regulated in the hippocampus 12-72 hr after chemical hypoxia. In the cerebellum, there was an increased expression of mEAAT2/5UT4 and a down-regulation of mEAAT2/5UT5. mEAAT2/5UT3 show a different regional expression pattern, being regulated in the cerebellum only. mEAAT2/5UT1-7 encoded distinct 5' regulatory sequences, including conserved elements of translational control. It is easily conceivable that expression alterations of 5' splice variants of EAAT2 are related to glutamate transporter malfunction after chemical hypoxia. Our findings contribute to the hypothesis that RNA splicing events can serve as a molecular mechanism of posthypoxic gene regulation.

Alternative Splicing↗

PubMed2000

Cellular automata models of chemical systems.

This paper describes the use of kinematic, asynchronous, stochastic cellular automata to model liquid properties, solution phenomena and kinetic phenomena encountered in complex biological systems. Cellular automata models of dynamic phenomena represent in silico experiments designed to assess the effects of competing factors on the physical and chemical properties of solutions and other complex systems. Specific applications include solution behavior, separation of immiscible liquids, micelle formation, diffusion, membrane passage, first- and second-order chemical kinetics, enzyme activity and acid dissociation. Cellular automata is thus considered as providing an exploratory method for the analysis of dynamic phenomena and the discovery and understanding of new, unexpected phenomena.

Animals↗

PubMed2002

Reactive intermediate formation from the 2-(Fluoromethoxy)-1,1,3,3,3-pentafluoro-1-propene (compound A)-derived cysteine S-conjugate S-[2-(Fluoromethoxy)-1,1,3,3,3-pentafluoropropyl]-L-cysteine in pyridoxal model systems.

2-(Fluoromethoxy)-1,1,3,3,3-pentafluoro-1-propene (compound A) is a degradation product of the anesthetic sevoflurane and undergoes cysteine conjugate beta-lyase-dependent bioactivation to nephrotoxic metabolites in rats. The present experiments were designed to identify reactive intermediates formed from S-[2-(fluoromethoxy)-1,1,3,3,3-pentafluoropropyl]-L-cysteine, a compound A-derived cysteine S-conjugate, in two pyridoxal model systems, namely Cu2+/pyridoxal and N-dodecylpyridoxal in cetyltrimethylammonium micelles. S-[2-(Fluoromethoxy)-1,1,3,3,3-pentafluoropropyl]-L-cysteine was incubated in the model systems with benzyl bromide, pentafluorobenzyl bromide, aniline, and o-phenylenediamine as trapping agents. The products were purified by TLC and identified by 19F and 1H NMR spectroscopy and by GC/MS. In the absence of trapping agents, 2-(fluoromethoxy)-3,3,3-trifluoropropanoic acid and 3,3,3-trifluorolactic acid, which have been identified previously in biotransformation studies, were formed. With the chemical models, 2-(fluoromethoxy)-1,1,3,3,3-pentafluoropropanethiolate, the expected first intermediate, was not trapped with benzyl bromide. Rather, the dehydrofluorination product 2-(fluoromethoxy)-1,3,3,3-tetrafluoro-1-propenylthiolate was trapped with benzyl bromide to give benzyl 2-(fluoromethoxy)-3,3,3-trifluoropropanethioate, which was formed in both chemical models. When pentafluorobenzyl bromide was used as a trapping agent, GC/MS analysis showed that the expected thiolate was trapped to give pentafluorobenzyl 2-(fluoromethoxy)-1,1,3,3,3-pentafluoropropyl sulfide in the N-dodecylpyridoxal model. In both chemical models, 2-(fluoromethoxy)-3,3,3-trifluorothioacyl fluoride was trapped with aniline to give N-phenyl 2-(fluoromethoxyl)-3,3,3-trifluoropropanethioamide, which cyclized to give 3-phenyl-4-thiono-5-(trifluoromethyl)-1,3-oxazolane. The results demonstrate that most of the reactive intermediates and products formed by the beta-lyase-catalyzed biotransformation of compound A-derived cysteine S-conjugates are also formed in the two chemical systems studied. Some products were, however, formed in chemical systems that have not been observed in previous in vivo and in vitro studies; it is not known whether these products are formed in biological systems and whether they contribute to the observed nephrotoxicity of cysteine S-conjugates.

Anesthetics, Inhalation↗

PubMed2002

The bladder acellular matrix graft in a rat chemical cystitis model: functional and histologic evaluation.

PURPOSE: We investigated the feasibility of augmentation in a diseased bladder with a bladder acellular matrix graft. MATERIALS AND METHODS: In 50 female Sprague-Dawley rats chemical cystitis was induced by intravesical instillation of HCl repeated monthly to maintain chronic inflammation. Urodynamic studies were performed in all rats 1 week after the induction of chemical cystitis and repeated at sacrifice. The 29 rats in the experimental group underwent partial cystectomy (50% or greater), followed by bladder acellular matrix graft augmentation, while the 21 controls underwent monthly HCl instillation only. The rats were sacrificed at 2 weeks, 1, 2 and 3 months, respectively. The bladder was removed and examined for histological changes. RESULTS: Urodynamic studies showed that bladder capacity and compliance were significantly higher in the grafted than in the control group (p = 0.008 and 0.006, respectively, at 3 months). Histological studies revealed urothelial and smooth muscle regeneration within the bladder acellular matrix graft at 1 month and nerve regeneration at 3. The number of mast cells was significantly lower in the grafted region than in the host bladder of all grafted rats (p <0.001). CONCLUSIONS: In this rat chemical cystitis model bladder augmentation with a bladder acellular matrix graft led to functional and histological improvement over diseased host bladder.

Animals↗

PubMed1998

Investigation of a Monte Carlo model for chemical reactions.

Monte Carlo computer simulations are in use at a number of laboratories for calculating time-dependent yields, which can be compared with experiments in the radiolysis of water. We report here on calculations to investigate the validity and consistency of the procedures used for simulating chemical reactions in our code, RADLYS. Model calculations were performed of the rate constants themselves. The rates thus determined showed an expected rapid decline over the first few hundred ps and a very gradual decline thereafter out to the termination of the calculations at 4.5 ns. Results are reported for different initial concentrations and numbers of reactive species. Generally, the calculated rate constants are smallest when the initial concentrations of the reactants are largest. It is found that inhomogeneities that quickly develop in the initial random spatial distribution of reactants persist in time as a result of subsequent chemical reactions, and thus conditions may poorly approximate those assumed from diffusion theory. We also investigated the reaction of a single species of one type placed among a large number of randomly distributed species of another type with which it could react. The distribution of survival times of the single species was calculated by using three different combinations of the diffusion constants for the two species, as is sometimes discussed in diffusion theory. The three methods gave virtually identical results.

Computer Simulation↗

PubMed2005

Modeling NMR chemical shift: A survey of density functional theory approaches for calculating tensor properties.

The NMR chemical shift, a six-parameter tensor property, is highly sensitive to the position of the atoms in a molecule. To extract structural parameters from chemical shifts, one must rely on theoretical models. Therefore, a high quality group of shift tensors that serve as benchmarks to test the validity of these models is warranted and necessary to highlight existing computational limitations. Here, a set of 102 13C chemical-shift tensors measured in single crystals, from a series of aromatic and saccharide molecules for which neutron diffraction data are available, is used to survey models based on the density functional (DFT) and Hartree-Fock (HF) theories. The quality of the models is assessed by their least-squares linear regression parameters. It is observed that in general DFT outperforms restricted HF theory. For instance, Becke's three-parameter exchange method and mpw1pw91 generally provide the best predicted shieldings for this group of tensors. However, this performance is not universal, as none of the DFT functionals can predict the saccharide tensors better than HF theory. Both the orientations of the principal axis system and the magnitude of the shielding were compared using the chemical-shift distance to evaluate the quality of the calculated individual tensor components in units of ppm. Systematic shortcomings in the prediction of the principal components were observed, but the theory predicts the corresponding isotropic value more accurately. This is because these systematic errors cancel, thereby indicating that the theoretical assessment of shielding predictions based on the isotropic shift should be avoided.

Journal Article↗

PubMed2001

Chemical equilibria model of strontium-90 adsorption and transport in soil in response to dynamic alkaline conditions.

Strontium-90 is a major hazardous contaminant of radioactive wastewater and its processing sludges at many Department of Energy (DOE) facilities. In the past, such contaminated wastewater and sludge have been disposed in soil seepage pits, lagoons, or cribs often under highly perturbed alkaline conditions (pH > 12) where 90Sr solubility is low and its adsorption to surrounding soil is high. As natural weathering returns these soils to near-neutral or slightly acidic conditions, the adsorbed and precipitated calcium and magnesium phases, in which 90Sr is carried, change significantly in both nature and amounts. No comprehensive computational method has been formulated previously to quantitatively simulate the dynamics of 90Sr in the soil-groundwater environment under such dynamic and wide-ranging conditions. A computational code, the Hydrologic Utility Model for Demonstrating Integrated Nuclear Geochemical Environmental Responses (HUMDINGER), was composed to describe the changing equilibria of 90Sr in soil based on its causative chemical reactions including soil buffering, pH-dependent cation-exchange capacity, cation selectivity, and the precipitation/dissolution of calcium carbonate, calcium hydroxide, and magnesium hydroxide in response to leaching groundwater characteristics including pH, acid-neutralizing capacity, dissolved cations, and inorganic carbonate species. The code includes a simulation of one-dimensional transport of 90Sr through a soil column as a series of soil mixing cells where the equilibrium soluble output from one cell is applied to the next cell. Unamended soil leaching and highly alkaline soil treatments, including potassium hydroxide, sodium silicate, and sodium aluminate, were simulated and compared with experimental findings using large (10 kg) soil columns that were leached with 90Sr-contaminated groundwater after treatment. HUMDINGER's simulations were in good agreement with dynamic experimental observations of soil exchange capacity, exchangeable cations, total 90Sr, and pH values of layers within the soil columns and of column effluents.

Adsorption↗

PubMed2003

The platelet as a model for chemical genetics.

Chemical genetics is an emerging strategy in chemical biology that promises to bring the power of true genetics to mammalian systems and facilitate the transfer of biological discoveries to therapeutics. The platelet is an anucleate cell with several features that render it suitable for chemical genetic analysis. This review addresses the benefits and challenges of chemical genetics using platelets as a model system.

Animals↗

PubMed2004

BETR-World: a geographically explicit model of chemical fate: application to transport of alpha-HCH to the Arctic.

The Berkeley-Trent (BETR)-World model, a 25 compartment, geographically explicit fugacity-based model is described and applied to evaluate the transport of chemicals from temperate source regions to receptor regions (such as the Arctic). The model was parameterized using GIS and an array of digital data on weather, oceans, freshwater, vegetation and geo-political boundaries. This version of the BETR model framework includes modification of atmospheric degradation rates by seasonally variable hydroxyl radical concentrations and temperature. Degradation rates in all other compartments vary with seasonally changing temperature. Deposition to the deep ocean has been included as a loss mechanism. A case study was undertaken for alpha-HCH. Dynamic emission scenarios were estimated for each of the 25 regions. Predicted environmental concentrations showed good agreement with measured values for the northern regions in air, and fresh and oceanic water and with the results from a previous model of global chemical fate. Potential for long-range transport and deposition to the Arctic region was assessed using a Transfer Efficiency combined with estimated emissions. European regions and the Orient including China have a high potential to contribute alpha-HCH contamination in the Arctic due to high rates of emission in these regions despite low Transfer Efficiencies. Sensitivity analyses reveal that the performance and reliability of the model is strongly influenced by parameters controlling degradation rates.

Air Pollutants↗

PubMed2006

Structure-activity models of chemical carcinogens: state of the art, and new directions.

Chemical carcinogenicity has been the target of numerous attempts to create predictive models alternative to the animal ones, ranging from short-term biological assays (e.g. mutagenicity tests) to theoretical models. Among the theoretical models, the application of the science of structure-activity relationships (SAR) has earned special prominence. The qualitative approach to SAR has lead to the identification of a large number of reactive chemical substructures that are both mutagenic and carcinogenic. More sophisticated developments are the quantitative structure-activity relationship (QSAR) models, that link the physical chemical or structural properties of the molecules to the toxicological endpoints. Both approaches provide strong support to the process of risk assessment of the chemicals, especially in the phase of priority setting. Among the areas potentially able to contribute to further developments of (Q)SAR, the novel chemical relational databases are presented and discussed. The freely downloadable ISSCAN database on chemical carcinogens is presented.

Animals↗

PubMed2002

Collaborative validation study of the in vivo micronucleus test using mouse colonic epithelial cells.

The in vivo micronucleus test using mouse colonic epithelial cells was evaluated as the 11th collaborative study organized by the Collaborative Study Group on the micronucleus test (CSGMT) with three model chemicals that were known to induce chromosome damage in mouse colonic cells. Five laboratories participated in this validation study. All three model chemicals, i.e. 1,2-dimethylhydrazine dihydrochloride (1,2-DMH), N-methyl-N-nitrosourea (MNU), and mitomycin C (MMC), induced micronucleated colonic epithelial cells in a 4-day exposure protocol in all participating laboratories. We confirmed that the present single cell suspension method could be used to detect the model chemicals as micronucleus inducers in mouse colonic epithelial cells. Advantages of this method are that experiments are easy to perform and that intact cells can be analyzed. The present study suggested that the colon micronucleus assay proposed here is useful for mechanistic studies of colon carcinogenesis.

1,2-Dimethylhydrazine↗

PubMed2006

PAMPA--a drug absorption in vitro model 13. Chemical selectivity due to membrane hydrogen bonding: in combo comparisons of HDM-, DOPC-, and DS-PAMPA models.

This study compares the intrinsic permeability coefficients of 40 drug molecules, obtained by three popular variants of the PAMPA assay, based on: (a) n-hexadecane, (b) 2% w/v dioleyoylphosphatidylcholine in n-dodecane, and (c) 20% w/v lecithin in n-dodecane, the HDM-, DOPC-, DS-PAMPA models, respectively. It was shown that PAMPA permeability values consistently rank in magnitude according to: DS>DOPC>HDM, with molecules like metoprolol showing 1000-fold greater permeability in DS than in HDM. Abraham descriptors were used to rationalize these observations. Water-solubilized polar molecules form very strong H-bonds with the solvent. Such molecules need to break these bonds in order to enter the pure alkane phase, which, in turn, offers no compensating H-bond solvation. Thus, more energy appears to be needed for a polar molecule to penetrate a pure alkane barrier, compared to a barrier possessing some H-bond interactions. The 20% phospholipid content of the DS-PAMPA lipid may be thought to ease the permeation process, by offering a compensating source of H-bonding within the membrane phase.

Algorithms↗

PubMed1996

Mathematical model for chemically induced lipid peroxidation in precision-cut liver slices: computer simulation and experimental calibration.

A biologically based pharmacodynamic (BBPD) model was developed in order to describe and simulate chemically induced lipid peroxidation in precision cut mouse liver slices. The model was written in Advanced Continuous Simulation Language (ACSL) and simulations were performed using SIMUSOLV software on a VAX/VMS mainframe computer. The BBPD model simulated formation of lipid hydroperoxides and thiobarbituric acid reactive substances (TBARS) over time as a function of the amounts of cytochrome P450 (CYP)-activated chemical inducer and active antioxidants. The rate of peroxidation was controlled by lipid peroxidizability, destruction of CYP, autooxidation, and activity of glutathione peroxidase. The BBPD model was initially parameterized with the literature data for TBARS formation during lipid peroxidation, reported for rat liver slices induced with bromotrichloromethane and tert-butyl hydroperoxide (TBOOH). Then, the biochemical parameters were adjusted to reflect the physiology of the mouse liver, and the BBPD model was used to simulate TBARS formation during lipid peroxidation in precision cut mouse liver slices induced with TBOOH. The BBPD model predictions were in agreement with the experimental data.

Animals↗

PubMed2004

Regional differences in chemical fate model outcome.

The fate of anthropogenic substances in the environment is increasingly determined using multimedia mass balance models. It is, therefore, critical to fully understand how such models work and what their limitations are. The effects of uncertainty and variation in the chemical properties, discharges, and landscape parameters on model outcome have been examined by other researchers. Here, the role of landscape properties in controlling region-to-region differences in chemical fate is examined. Specifically, regions of Canada and the ChemCAN model are used to explore the region-to-region difference in fate for benzo[a]pyrene, hexachlorobenzene, tetrachloroethylene, alpha-hexachlorocyclohexane, 2,2',5,5'-tetrachlorobiphenyl (PCB 52), and atrazine emitted individually to air, water, and soil. To facilitate the same analysis in other places a description of the model and the methods for obtaining the landscape parameters used here are given. Differences in fate are the unique result of combining the input parameters of chemical properties, emission data, and landscape parameters. While region-to-region differences are small compared to the chemical-to-chemical differences that may span many orders of magnitude for physical-chemical or degradation properties, chemical fate is not the same for regions of differing landscape parameters. It is therefore concluded that the quality of results obtained from regional environmental fate models can be improved by the use of region-specific landscape parameters.

Atrazine↗

PubMed2003

Chemical fate of arsenic and other metals in groundwater of Bangladesh: experimental measurement and chemical equilibrium model.

The presence of toxic level of inorganic arsenic in groundwater used for drinking in Bangladesh and neighboring India is unfolding as one of the worst natural disaster in the region. The purpose of this work is to ascertain the chemical fate of arsenic and other metals in groundwater of Bangladesh. A combination of techniques was used to measure 24 metals, 6 anions, Eh, pH, dissolved oxygen, conductivity, and temperature to understand the distribution of components which were then used in computational chemical equilibrium model, MINEQL+, for detailed speciation. It was found that the fate of arsenic and its speciation were inextricably linked to the formation of hydrous ferric oxide (HFO) and its kinetic. The HFO induced natural attenuation removes 50-75% of total arsenic in first 24 h through a first order kinetics. Adsorption on HFO is the predominant mode of removal of arsenic, iron, manganese, and most trace metals. The equilibrium model points to the presence of excess active sites for the removal of arsenic. MINEQL+ shows that significantly higher concentration of HFO forming iron is required to remove arsenic below maximum contamination level (MCL) of 50 microg/L than predicted by stoichiometry. The practical implication of this work is the prediction of water quality based on models.

Arsenic↗

PubMed1990

Intrathecal injection of a specific enzyme in rats as a model for chemically induced spinal cord injury.

A spinal cord injury model is described using chymopapain as a neurotoxic agent in rats. The trauma was evaluated by neurophysiological and morphological methods. Electrically evoked compound action potentials were used to quantify the neurophysiological effects caused by the injection of chymopapain into the lumbar dural theca in rats. A branch of the sciatic nerve was stimulated with voltage impulses of constant amplitude (40 V) and duration (0.1 ms) at the right external malleolus. The responses were recorded at the dorsal root entry zone L1. We used different doses of the enzyme (1000 i.u./ml; 2500 i.u./ml; 5000 i.u./ml). A total amount of 0.1 ml was injected into the rats' lumbar spinal canal intrathecally (n = 18). The control rate (n = 8) were subjected to exactly the same stimulus and recording procedures but the test solution was a corresponding volume of isotonic saline. Two hours after injection the animals were examined clinically and then sacrificed for histology. The prolongation of the latency of the electrically evoked potentials caused by the enzyme was very clear at the doses of 2500 i.u. and 5000 i.u. being about 10-15% relative to the mean latency before administration of the drug. The histological evaluation showed hemorrhage, vascular damage and indirect signs of myelin edema of the lumbar nerve tissue. Our study indicates that chymopapain injections into the lumbar spinal canal can be used as a reproducible model for spinal cord injury research.

Animals↗

PubMed2000

The prediction of partitioning coefficients for chemicals causing environmental concern.

Various types of partition coefficients have been used to facilitate the prediction of the concentration of pollutants in different phases in the environment. Many thousands of chemicals may exist in our environment which makes prediction work difficult or impossible due to a deficiency of knowledge of those unfamiliar compounds. In this study, the correlation between an octanol-water partition coefficient (Kow), water solubility (S) and a normalized soil/sediment partition coefficient (Koc) was investigated though the examination of 148 model chemicals. These model chemicals were classified into five major categories for easier adoption in future use. They are aliphatic compounds, aromatic compounds, pesticides, herbicides and polyaromatic hydrocarbons (PAH). Linear models are developed to correlate these partition coefficients in each category. The prediction of unfamiliar chemicals in the same category becomes possible if the fundamental properties of these chemicals (such as solubility) are previously known.

1-Octanol↗

PubMed1996

A compartmental brain model for chemical transport and CO2 controlled blood flow.

A compartmental transport model is developed, capable of predicting the evolution of CO2, HCO-3 and H+ in the cerebrovascular system. In the model, the transport of these components is simulated at a subset of three compartments: cerebrospinal fluid (CSF), capillary-choroid plexus and brain tissue, belonging to a seven compartmental assembly representing the entire brain. The remaining ones are; artery, vein, venous sinus and jugular bulb. The model accounts for advection associated with non-steady perfusion fluxes across semi-previous boundaries. Pressures, associated with perfusion, are solved in the seven-compartment model. The three-compartment transport model also takes into account changes in compartmental volume due to displacement of its boundaries, diffusion through boundaries and rate of generation of substances by chemical reactions. A first-order reaction rate is assumed in the CSF compartment. A parameter estimation method is then developed to assess boundary diffusivities from time-averaged observed values of perfusion pressure, tension of carbon dioxide, pH values, and concentration of free hydrogen and bicarbonate ions. An equation of state describing the regulation of flow from arteries to capillaries, as a function of CO2 tension in the CSF, is then suggested. Upon solving all coupled mass balance equations, and for a pre-evaluated perfusion pressure in the artery and capillary compartments, one can estimate the change in arteries to capillaries conductance at every time step. Boundary diffusivities between the capillary, cerebrospinal fluid and brain tissue compartments, were estimated. A sensitivity analysis proves the consistency between model predictions and available clinical observations, this, in terms of the influence of the parameter associated with CO2 metabolic rate on CO2 tension. It was shown that decrease of this tension caused an abrupt pressure fall at the first instant which later increased to an asymptotic value. This, however, was not evident in the capillaries at which pressure slightly falls and then remains constant.

Bicarbonates↗