A marriage of old and new: chemostats and microarrays identify a new model system for ammonium toxicity.
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Animals↗
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Structure-toxicity relationships for the effects to Tetrahymena pyriformis of aliphatic, carbonyl-containing, alpha,beta-unsaturated chemicals.
Toxicity data for 82 aliphatic chemicals with an alpha,beta-unsaturated substructure were compiled. Toxicity was assessed in the 2-day Tetrahymena pyriformis population growth impairment assay. Toxic potency [log(IGC50(-1))] for most of these chemicals was in excess of baseline narcosis as quantified by the 1-octanol/water partition coefficient (log K(ow)). The toxicity of the alpha,beta-unsaturated aldehydes was modeled well by log K(ow) in conjunction with the sum of partial charges on the vinylene carbon atoms (Q(C4) + Q(C3)) and the energy of the lowest unoccupied molecular orbital (E(lumo)). These electronic descriptors were also successful at modeling the toxicity of alpha,beta-unsaturated ketones. The toxicity of a range of acrylates was constant within about 0.2 of a log unit. Conversely, the toxicity of methacrylates and esters containing the vinylene group varied considerably and was explained by their hydrophobicity. The comparison of the quantitative structure-activity relationship (QSAR) for the methacrylates and esters with that for non-polar narcosis showed little significant difference and hence suggested that substitution on the carbon-carbon double bond in the methacrylates and vinylene unsaturated esters does not enhance toxicity over that of baseline. Substitution on the carbon-carbon double bond in the alpha,beta-unsaturated aldehydes resulted in toxicity that was similar to that for saturated derivatives. Although an excellent hydrophobicity-dependent QSAR was developed for the esters containing ethynylene group, these compounds are considered to act as Michael-type acceptors. Attempts to combine different groups of Michael-type acceptors into a single QSAR, based on mechanistically derived descriptors, were unsuccessful. Thus, the modeling of the toxicity of the alpha,beta-unsaturated carbonyl domain is currently limited to models for narrow subdomains.
Animals↗
The lipid peroxidation model for halogenated hydrocarbon toxicity. Kinetics of peroxyl radical processes involving fatty acids and Fe(III) porphyrins.
The toxicity of halogenated alkanes originates from their metabolism by cytochrome P-450 which leads to the formation of reactive intermediates. In particular, peroxyl radicals derived from the halogenated compounds are believed to induce peroxidative chain degradation of lipids. To examine this hypothesis, radical reactions in a system involving FeIII-deuteroporphyrin as a model of cytochrome P-450, fatty acids or cholesterol, and carbon tetrachloride or the anesthetic agent halothane are studied by means of pulse radiolysis. It is shown that haloperoxyl radicals react with the fatty acids in competition with their reaction with the ferriporphyrin. Moreover, the secondary fatty acid peroxyl radicals also react efficiently with the porphyrin. A model for halogenated alkane toxicity is discussed in terms of these new findings. The importance of local oxygen concentration and structural arrangement of fatty acids around cytochrome P-450 are emphasized.
Cytochrome P-450 Enzyme System↗
Reproducible rat model for comparing late rectal toxicity from different brachytherapy techniques.
PURPOSE: Newer brachytherapy techniques, such as pulse-simulated low dose rate (PDR) and high dose rate (HDR) offer clinical and technical advantages over the conventional continuous low dose rate (CLDR) irradiation. The impact of these techniques on late normal tissue toxicity has remained largely undefined, with mathematical modeling and limited clinical experience providing some guidelines. We sought to develop a reproducible rat model for quantifying and comparing late rectal toxicity from different brachytherapy techniques. METHODS AND MATERIALS: An intrarectal applicator has been designed and techniques have been developed to deliver clinically relevant doses of CLDR to allow comparison to PDR and HDR. Female Wistar rats are utilized. The endpoints assessed are rectal obstruction and a histological grading of late rectal injury. RESULTS: Analysis of 65 rats given either sham or single acute pulse irradiation has demonstrated the model to be reproducible and reliable in evaluating late rectal toxicity. CONCLUSIONS: The use of this rat model to compare late rectal injury from various doses, dose rates, and fractionation parameters utilized by CLDR, PDR, and HDR will provide another tool for safely implementing these techniques into the clinical setting.
Animals↗
Cross-phylum comparison of a chronic biotic ligand model to predict chronic toxicity of copper to a freshwater rotifer, Brachionus calyciflorus (Pallas).
Short chronic 48-h toxicity tests with the freshwater rotifer Brachionus calyciflorus (Pallas) were conducted to assess the modifying effects of pH and natural dissolved organic carbon (DOC) concentration on reproductive toxicity of Cu. Toxicity tests were carried out in four test waters according to a 2 x 2 design, in which pH (6 and 7.8) and DOC (5 and 15 mg C/L) were the test variables. Concentrations of dissolved Cu with no observed effect at 48 h (NOEC) varied 12-fold between 8.2 and 103 microg/L. Higher DOC and higher pH resulted in a reduction of toxicity, which is in line with the concepts of the biotic ligand model (BLM). A chronic Cu-BLM, originally developed for the cladoceran Daphnia magna, was calibrated to the rotifer dataset and was found to be able to predict all rotifer NOECs with an error factor of less than 1.6. This finding may be of great interest for risk assessment and the establishment of water quality criteria, as it suggests that chronic Cu-BLMs are comparable across phyla (i.e., arthropoda to rotifera).
Animals↗
Global analysis of endothelial cell line proliferation patterns based on nutrient-depletion models: implications for a standardization of cell proliferation assays.
It is known that cell populations growing in different environmental conditions may exhibit different proliferation patterns. However, it is not clear if, despite the diversity of the so-observed patterns, inherent cellular growth characteristics of the population can nevertheless be determined. This study quantifies the proliferative behaviour of the permanent endothelial human cell line, Eahy926, and establishes to which extent the estimation of the cell proliferation rate depends on variations of the experimental protocols. Cell proliferation curves were obtained for cells cultured over 16 days and the influences of cell seeding densities, foetal bovine serum content and frequency of culture medium changes were investigated. Quantitative dynamic modelling was conducted to evaluate the kinetic characteristics of this cell population. We proposed successive models and retained a nutrient-depletion toxicity dependant model, which takes into account the progressive depletion of nutrients, as well as the increase of toxicity in the cell culture medium. This model is shown to provide a very good and robust prediction of the experimental proliferation curves, whatever are the considered frequency of culture medium changes and serum concentrations. Thus, the model enables an intrinsic quantification of the parameters driving in vitro EAhy926 proliferation, including proliferation, nutrient consumption and toxicity increase rates, rather independently of the experiments design. We therefore propose that such models could provide a basis for a standardized quantification of intrinsic cell proliferation kinetics.
Cell Count↗
Evaluation of pH inhibition effect on activated sludge by the pseudo toxic concentration (CPT) concept model.
It is generally accepted that the inhibition effect of pH on activated sludge follows the non-competitive inhibition kinetics. But the non-competitive inhibition kinetic equation cannot be directly applied to pH inhibition, due to the difficulty in quantification of pH as a term of inhibitor concentration. So, many empirical equations were developed especially for acidic condition to describe pH inhibition effect. In this research, the pseudo toxic concentration (CPT) concept model to quantify pH inhibition effect on activated sludge was proposed and compared with other existed models. Prediction of performance, presented by Prediction Accuracy and Prediction Accuracy Index, showed that the CPT concept model can explain the reduction of the maximum specific growth rate (mu max) more accurately than any other models do at a wide range of pH. The CPT concept model was applicable not only to activated sludge but also to specific microorganism groups, such as nitrifier, less acidophilic species and nitrifying biofilm.
Bacteria↗
Precision-cut liver slices as a new model to study toxicity-induced hepatic stellate cell activation in a physiologic milieu.
Hepatic stellate cell (HSC) activation is a key event in the natural process of wound healing as well as in fibrosis development in liver. Current in vitro models for HSC activation contribute significantly to the understanding of HSC biology and fibrogenesis but still fall far short of recapitulating in vivo intercellular functional and anatomic relationships. In addition, when cultured on uncoated plastic, HSC spontaneously activate, which makes HSC activation difficult to regulate or analyze. We have examined whether the use of precision-cut liver slices might overcome these limitations. Liver slices (8 mm diameter, 250 microm thickness) were generated from normal rat liver and incubated for 3 or 16 h with increasing doses of carbon tetrachloride (CCl4). Rat liver slices remained viable during incubation, as shown by minimal enzyme leakage. Expression of markers for HSC activation and the onset of fibrogenesis in the liver slices was studied using real-time PCR and Western blotting. In unstimulated liver slices, mRNA and protein levels of desmin, heat shock protein 47, and alpha B-crystallin remained constant, indicating quiescence of HSC, whereas Krüppel-like factor 6 expression was increased. In contrast, incubation with CCl4 led to a time- and dose-dependent increase in mRNA expression of all markers and an increased alpha B-crystallin protein expression. In conclusion, we have developed a technique to induce activation of quiescent HSC in rat liver slices. This model permits the study of toxicity-induced HSC activation within a physiological milieu, not only in animal but ultimately also in human tissue, and could contribute to the reduction of animal experiments.
Animals↗
Reversal of amyloid beta toxicity in Alzheimer's disease model Tg2576 by intraventricular antiamyloid beta antibody.
There are considerable data on synaptic dysfunction in Alzheimer's disease (AD). However, the precise molecular basis for synaptotoxicity in AD is not known. We tested the hypothesis that amyloid beta (Abeta), as produced in Tg2576 mice overexpressing a mutant form of amyloid precursor protein, leads to changes in SNAP-25, a molecule required for Ca-sensitive neurotransmitter vesicle exocytosis. Anti-Abeta antibody was injected into the third ventricle (icv) of 10-month-old Tg2576 mice, preceding formation of plaques. Immunodensity of glial fibrillary acidic protein (GFAP) and SNAP-25 were quantitated in the hippocampus 1 month later. SNAP-25 was reduced by 96% in the inner molecular layer (SMi) of dentate gyrus, by 95% in the hilum, and by 75-76% in stratum lucidum (SL), stratum oriens (SO), and stratum radiatum (SR) of CA1-CA3 of the Tg2576 mice. GFAP was increased by more than 50-fold, specifically within the neuropil of CA1-CA3, and by twofold in portions of fimbria. One injection of 10 microg of anti-Abeta antibody into the third ventricle at 10 months completely prevented or restored changes in GFAP at 11 months of age. The restoration of SNAP-25 by anti-Abeta antibody compared with wild type was 69% in CA1-SO, 93% in CA1-SR, 85% in CA3-SL, 77% in SMi, and 60-73% in hilum. In addition, whereas control injections of saline or IgG produced greatly increased GFAP diffusely in the hippocampus of Tg2576 animals, there was no increase in GFAP after anti-Abeta injection, suggesting a synergistic interaction of nonspecific trauma with Abeta in the transgenic mice. This is the first report of depleted SNAP-25 immunoreactivity in Tg models and the first report of icv injection of anti-Abeta antibody in this model of AD. The largest reductions of the SNAP-25 are in hilum and SMi, so either reduction in the septal-hilum-SMi path is primary or reduction in this path begins at an earlier age than in CA3-CA1 fields. A single icv injection of anti-Abeta antibody is potent in reversing Abeta effects and, therefore, represents a suitable model for investigating early Abeta toxicity. In addition, intrathecal or icv antibody may be an efficient means of treating or preventing toxicity in AD, particularly under conditions of immune hyporesponsivity.
Alzheimer Disease↗
Vasocystostomy: a model for studying male reproductive toxicity in the rat.
A nonsacrificial rat model has been developed which permits the easy collection and measurement of spermatozoa. The ductus deferens is anastomosed to the bladder (Vasocystostomy) and urinary sperm is collected daily. The correlation between testicular histology and sperm counts indicates that this model is reliable. Using this model we demonstrate inhibition of sperm production by fluoroacetate.
Anastomosis, Surgical↗
Endogenous glucocorticoids attenuate Shiga toxin-2-induced toxicity in a mouse model of haemolytic uraemic syndrome.
The concept that during an immune challenge the release of glucocorticoids (GC) provides feedback inhibition on evolving immune responses has been drawn primarily from studies of autoimmune and/or inflammatory processes in animal models. The epidemic form of haemolytic uraemic syndrome (HUS) occurs secondary to infection with Gram-negative bacteria that produce Shiga toxin (Stx). Although Stx binding to the specific receptors present on renal tissue is the primary pathogenic mechanism, inflammatory or immune interactions are necessary for the development of the complete form of HUS. The aim of this study was to investigate the influence of endogenous GC on Stx-toxicity in a mouse model. Stx2 was injected into GC-deprived mice and survival rate, renal damage and serum urea levels were evaluated. Plasma corticosterone and cytosolic GC receptor (GR) concentration were also determined at multiple intervals post-Stx2 treatment. Higher sensitivity to Stx2 was observed in mice lacking endogenous GC, evidenced by an increase in mortality rates, circulating urea levels and renal histological damage. Moreover, Stx2 injection was associated with a transient but significant rise in corticosterone secretion. Interestingly, 24 h after Stx inoculation significant increases in total GR were detected in circulating neutrophils. These results indicate that interactions between the neuroendocrine and immune systems can modulate the level of damage significantly during a bacterial infection.
Adrenal Glands↗
[Applications of a rat model of chronic bronchitis on toxicity of PM2.5].
OBJECTIVE: To study the acute toxicity of PM2.5 to the rats with chronic bronchitis and the control rats and the difference between the model rats and the control rats on PM2.5 toxicity. METHODS: With the use of an intratracheal instillation, both groups were exposed to suspensions of PM2.5. After three times, the levels of ALB, LDH, AKP, MDA and GSH in bronchoalveolar lavage fluid (BALF) were analyzed. RESULTS: PM2.5 could induce the acute toxicity to both model rats and control rats, and dose-response relationships were observed in all indexes. In model rats, the levels of ALB, LDH, AKP, and MDA were higher in control rats( P < 0.05), while the levels of GSH were lower in control rats (P < 0.05). CONCLUSION: PM2.5 could have acute toxic effects on both model rats and health rats, and the rats with chronic bronchitis are more susceptible to PM2.5 than health rats.
Air Pollutants↗
Animal models of chronic ethanol toxicity.
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Alcoholism↗
MBNL1 and CUGBP1 modify expanded CUG-induced toxicity in a Drosophila model of myotonic dystrophy type 1.
Myotonic dystrophy type 1 (DM1) is a neuromuscular disorder caused by a CTG expansion in the 3' UTR of the dystrophia myotonica protein kinase (DMPK) gene. It has been hypothesized that the pathogenesis in DM1 is triggered by a toxic gain of function of the expanded DMPK RNA. This expanded RNA is retained in nuclear foci where it sequesters and induces alterations in the levels of RNA-binding proteins (RNA-BP). To model DM1 and study the implication of RNA-BP in CUG-induced toxicity, we have generated a Drosophila DM1 model expressing a non-coding mRNA containing 480 interrupted CUG repeats; i.e. [(CUG)20CUCGA]24. This (iCUG)480 transcript accumulates in nuclear foci and its expression leads to muscle wasting and degeneration in Drosophila. We also report that altering the levels of two RNA-BP known to be involved in DM1 pathogenesis, MBNL1 and CUGBP1, modify the (iCUG)480 degenerative phenotypes. Expanded CUG-induced toxicity in Drosophila is suppressed when MBNL1 expression levels are increased, and enhanced when MBNL1 levels are reduced. In addition, (iCUG)480 also causes a decrease in the levels of soluble MBNL1 that is sequestered in the CUG-containing nuclear foci. In contrast, increasing the levels of CUGBP1 worsens (iCUG)480-induced degeneration even though CUGBP1 distribution is not altered by the expression of the expanded triplet repeat. Our data supports a mechanism for DM1 pathogenesis in which decreased levels of MBNL and increased levels of CUGBP mediate the RNA-induced toxicity observed in DM1. Perhaps more importantly, they also provide proof of the principle that CUG-induced muscle toxicity can be suppressed.
Animals↗
A mouse model for staphylococcal enterotoxins toxicity.
The study of staphylococcal enterotoxins (SE), which can adversely affect man and animals, is hindered by the absence of a practical animal model. Only humans and primates are sensitive to SE oral intake whereas other species such as cats and dogs require intravenous SE administration to induce biological effects. Rodents are very resistant even to relatively high doses of SE. Treatment of mice with D-galactosamine (20 mg/mouse) rendered them highly susceptible to micrograms of toxins leading to lethal shock. Differences in toxic potential have been observed between types of SE. Carboximethylated SE, which have been shown not to induce emesis in primates were also able to induce shock. Anti-tumour necrosis factor antiserum (anti-TNF-alpha) and, to a lesser extent anti-SE antisera, reduced the lethality to SE in D-galactosamine-treated mice. This proposed cost-effective animal model may be used to study the immunopathological properties of natural, recombinant or mutant SE.
Animals↗
Cryoprotectant toxicity and cryoprotectant toxicity reduction: in search of molecular mechanisms.
Cryoprotectant toxicity is a fundamental obstacle to the full potential of artificial cryoprotection, yet it remains in general a poorly understood phenomenon. Unfortunately, most relevant biochemical studies to date have not met the basic criteria required for demonstrating mechanisms of toxicity. A model biochemical study of cryoprotectant toxicity was that of Baxter and Lathe, which demonstrated that alteration of a specific enzyme (fructose diphosphatase, or FDPase) was the cause of impaired glycolysis after treatment with and removal of dimethyl sulfoxide (D). FDPase alteration by D was reported to be preventable by the simultaneous presence of amides. This protection could be due to a "counteracting solute" effect similar to that employed by nature, but we find no meaningful correlation between the general protein stabilizing or destabilizing tendency of the cryoprotectant medium and its toxicity. Baxter and Lathe postulated that the effect of D arises from hydrogen bonding between D and the epsilon amino groups of surface lysine residues on FDPase, and it was found that molecules which resembled this group could block the alteration induced by D, presumably by competing with lysine residues for association with D. However, we find that the interaction between D and lysine in the presence of water is actually thermochemically repulsive, and that the presence of formamide does not affect the interaction between D and lysine, implying no useful complex formation between formamide and D. We were also unable to demonstrate that the blocking compounds consistently reduce toxicity when added to D rather than substituting for D, contrary to predictions based on complex formation between blocking compounds and D. In summary, it seems that present concepts of cryoprotectant toxicity are in need of serious revision.
Amides↗
Effects of whole-body VX vapor exposure on lethality in rats.
Male and female rats were whole-body exposed to VX vapor in a 1000-L single-pass exposure chamber. Estimated exposure dosages producing lethal (LCT50) effects in 50% of exposed male and female rats were established for 10, 60, and 240 min exposure durations. A potency comparison with GB and GF shows that VX becomes increasingly more potent than these G agents with increasing exposure duration. VX is approximately 4-30 times more potent than GB and 5-15 times more potent than GF. Gender differences in the estimated median dosages were not significant at the 10, 60, and 240 min exposure durations. An empirical toxic load model was developed and the toxic load exponent for lethality (n) in the equation Cn x T = k was determined to be n = 0.92. The VX-G regeneration assay was successfully used as a biomarker for the presence of VX in the blood plasma and RBC fractions of the blood 24 h postexposure.
Animals↗
Actin-containing sera from patients with adult respiratory distress syndrome are toxic to sheep pulmonary endothelial cells.
Actin released from damaged cells after a variety of tissue injuries appears to be involved in multiple organ dysfunction syndrome. Under experimental conditions, when the quantity of actin present in plasma is made to exceed the protective capacity of the actin-scavenging mechanism, microembolism and pulmonary vascular angiopathy have been noted in rats. It remains to be determined whether this injury is a result of a direct toxic effect or occurs indirectly via platelet activation or fibrin interactions. We examined the effect of sera from patients with adult respiratory distress syndrome (ARDS), as well as G-actin added to normal serum, on the viability, morphology, and function of cultured sheep pulmonary artery endothelial cells (SPAEC). Both patient sera and normal sera to which actin was added were toxic in the cell culture model; this toxicity could be abrogated, at least partially, by preincubation with gelsolin, which is known to complex with actin. A significant portion of the toxicity of sera from patients with ARDS was sensitive to heat (56 degrees C), suggesting an important role of complement. Sera from patients with ARDS were shown to contain filaments of F-actin by immunoblot and rhodamine phalloidin staining after ultracentrifugation. Thus, saturation of the actin-scavenging system by addition of exogenous G-actin to plasma produces direct pulmonary endothelial cell injury. Furthermore, plasma from patients with ARDS secondary to bacterial pneumonia is toxic to SPAEC, and a small but significant contributory role of actin is apparent in these studies.
Actins↗