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At least 757 records · Page 42Linked to original sources
PubMed2004

A freshwater food web model for the combined effects of nutrients and insecticide stress and subsequent recovery.

A microcosm experiment that addressed the interaction between eutrophication processes and contaminants was analyzed using a food web model. Both direct and indirect effects of nutrient additions and a single insecticide application (chlorpyrifos) on biomass dynamics and recovery of functional groups were modeled. Direct toxicant effects on sensitive arthropods could be predicted reasonably well using concentration-response relationships from the laboratory with representative species. Model predictions showed that nutrient additions alone caused only small effects on toxicant fate and effects probably due to the relatively high dissipation rate of chlorpyrifos. Enhancement of eutrophication effects by the insecticide was relatively small and seemed to be additive. The recovery of some affected functional groups was hampered in the indoor microcosms due to their isolation from outdoor seed populations. Introducing recolonization scenarios in the model simulated dose-dependent recovery. Recolonization increased the recovering rate after exposure to the pesticide. Modeling can extend the use of microcosms as a link between laboratory and field as this allows the prediction of effects and recovery of ecosystems for concentrations that have not been experimentally tested.

Animal Nutritional Physiological Phenomena↗
PubMed2006

Suppression of polyglutamine-induced toxicity in cell and animal models of Huntington's disease by ubiquilin.

Expanded polyglutamine (polyQ) tracts are associated with the induction of protein aggregation and cause cytotoxicity in nine different neurodegenerative disorders. Here, we report that ubiquilin suppresses polyQ-induced protein aggregation and toxicity in cells and in an animal model of Huntington's disease. Overexpression of ubiquilin in HeLa cells and primary neurons reduced aggregation of polyQ-containing proteins and cell death induced by overexpression of a green fluorescent protein (GFP)-huntingtin fusion protein containing 74 polyQ repeats [GFP-Htt(Q74)], in a dose-dependent manner. Moreover, overexpression of ubiquilin suppressed oxidative stress-induced cell death in HeLa cell lines stably expressing GFP-Htt(Q74). In contrast, knockdown of ubiquilin expression in these cell lines was associated with increases in DNA fragmentation, caspase activation, GFP-fusion protein aggregation, and cell death. Caenorhabditis elegans lines expressing GFP-Htt fusion proteins in body wall muscle displayed a polyQ repeat length-dependent decrease in body movement compared with wild-type animals. RNA interference of the C. elegans ubiquilin gene exacerbated the motility defect, whereas overexpression of ubiquilin prevented, and could rescue, loss of worm movement induced by overexpression of GFP-Htt(Q55). These results suggest that ubiquilin might be a novel therapeutic target for treating polyQ diseases.

Adaptor Proteins, Signal Transducing↗
PubMed2002

Quantitative structure-activity relationship for the photoinduced toxicity of polycyclic aromatic hydrocarbons to the luminescent bacteria Vibrio fischeri.

Sunlight can greatly enhance the toxicity of polycyclic aromatic hydrocarbons (PAHs). Photosensitization reactions (e.g., generation of singlet-state oxygen) and photomodification reactions (e.g., photooxidation of PAHs to more toxic species) are both pathways of photoinduced toxicity of PAHs. Previously, a quantitative structure-activity relationship (QSAR) was developed for PAHs showing that a photosensitization factor (PSF) and photomodification factor (PMF) can be additively combined to describe photoinduced toxicity. That QSAR model was developed for the photoinduced toxicity of 16 PAHs to the higher plant Lemna gibba. The objective of this study was to apply the QSAR model developed for L. gibba to another organism. The organism chosen was the luminescent marine bacteria Vibriofischeri. Toxicity data used for the QSAR model were inhibition of luminescence and inhibition of growth of V. fischeri. Both short-term (15 min) and long-term (18 h) assays of toxicity were used. Light did not impact on PAH toxicity in the short-term assay, and thus the QSAR model did not correlate well with these data. Conversely, light greatly enhanced toxicity when the long-term assay was employed. The PMFs for the PAHs from the L. gibba QSAR showed a moderate correlation to bacterial toxicity in the long-term assay, whereas the PSFs showed only a weak correlation to toxicity. As was the case for L gibba, summing the PMF and the PSF resulted in a strong correlation to toxicity that had predictive value. Thus, a QSAR model derived for plants accurately described the toxicity of PAHs to a bacterial species. This indicates that the bipartite mechanism of PAH-photoinduced toxicity may be applicable to other organisms.

Araceae↗
PubMed2005

Biological role of glutathione in nitric oxide-induced toxicity in cell culture and animal models.

Glutathione (GSH) plays an important role in cellular defense response in many in vitro and in vivo models. Here we investigated its role in NO()-induced toxicity in cell culture and mouse models. Wild-type (TK6) and p53-null (NH32) human lymphoblastoid cells were treated with NO(.) at a steady-state concentration of 0.6 muM, similar to the level estimated to occur in inflamed tissues. In both cell types, GSH was depleted by this exposure in a dose- and time-dependent manner. Contrary to expectations, prior depletion of GSH by treatment with l-buthionine-SR-sulfoximine did not potentiate NO(.)-induced cell killing or DNA deamination in TK6 cells. In activated RAW264.7 murine macrophages producing NO(.), intracellular GSH content did not change, although gamma-glutamate-cysteine ligase was upregulated. NO(.) overproduction in RcsX lymphoma-bearing SJL mice resulted in significantly elevated GSH levels in various organs. Administration of the NO(.) synthase inhibitor N-methylarginine abolished the increase in GSH in these animals. Collectively, these data indicate a multifaceted and complex involvement of GSH in responses of cells and tissues to toxic levels of NO(.). NO(.) treatment effectively depleted GSH levels in human lymphoblastoid cells, but this alteration was not a critical initiating factor for NO(.)-mediated toxicity. Murine macrophages maintained GSH homeostasis when exposed to endogenously produced NO(.). In RcsX lymphoma-bearing mice, upregulation of de novo synthesis of GSH appeared to be a response to the toxic effects of NO(.).

Animals↗
PubMed2005

Relating results of chronic toxicity responses to population-level effects: modeling effects on wild Chinook salmon populations.

Standard toxicity tests assess the physiological responses of individual organisms to exposure to toxic substances under controlled conditions. Time and space restrictions often prohibit the assessment of population-level responses to a toxic substance. Compounds affecting various toxicity endpoints, such as growth, fecundity, behavior, or immune function, alter different demographic traits and produce different impacts on the population. Chronic effects of immune suppression, reproductive impairment, and growth reduction were examined using life history models for Chinook salmon (Oncorhynchus tshawytscha). Modeled immune suppression acted through reductions in age-specific survival, with first- and second-year survival producing the greatest changes in the population growth rate (lamda). A 10% reduction in various reproductive parameters all produced a similar lamda, but different sensitivity and stable age distributions. Growth reduction models incorporated effects to both survival and reproduction and produced additive effects. Overall, model output indicated that for Chinook salmon, alteration of first-year survival has the greatest relative impact on lamda. Results support the importance of linking toxicity endpoints to the demographic traits that they influence and help generate toxicity tests that are more relevant for the species. Life history modeling provides a useful tool to develop testable hypotheses regarding specific and comparative population-level impacts.

Animals↗
PubMed2004

Early prediction of drug metabolism and toxicity: systems biology approach and modeling.

Many of the drug candidates that fail in clinical trials are withdrawn because of unforeseen effects of human metabolism, such as toxicity and unfavorable pharmacokinetic profiles. Early pre-clinical elimination of such compounds is important but not yet possible. An ideal system would enable researchers to make a confident elimination decision based purely on the structure of a new compound, and incorporate and use multiple pre-clinical experimental data to support such a decision. Currently available resources can be split into three categories: (i). structure-activity relationships (SAR) computational models based on compound structure; (ii). 'pattern' databases of tissue or organ response to drugs, compiled from high-throughput experiments; and (iii). 'systems biology' databases of metabolic pathways, genes and regulatory networks. In this review, we outline the advantages and drawbacks of each of these systems and suggest directions for their integration.

Animals↗
PubMed2004

Gut microflora & toxic metals: chromium as a model.

The gastrointestinal tract (GIT) is exposed to various environmental pollutants including metals, that contaminate food and water which may have toxic effects on body. GIT has large amount of microbes that live in symbiosis and help the host in different ways. The resident gut microflora have a significant role to play in detoxification and elimination of the harmful metals from the body. Chromium is a naturally occurring heavy metal found commonly in environment in trivalent (Cr III) and hexavalent (Cr VI) forms. Cr (VI) compounds have been shown to be potent occupational carcinogens. The reduction of Cr (VI) to Cr (III) results in the formation of reactive intermediates that together with oxidative stress and oxidative tissue damage, and a cascade of cellular events including modulation of apoptosis regulatory gene p53 contribute to the cytotoxicity, genotoxicity and carcinogenicity of Cr(VI)-containing compounds. The data discussed here with reference to chromium show that gut microflora have a marked capacity to cope with the increased load of ingested metals and may contribute significantly in the protection against metal toxicity.

Apoptosis↗
PubMed2004

Interaction between a rat model of cerebral ischemia and beta-amyloid toxicity: inflammatory responses.

BACKGROUND AND PURPOSE: Clinical data suggest that Alzheimer disease (AD) and stroke together potentiate cognitive impairment. Inflammatory mechanisms are involved in AD pathology and stroke and may be the mediator between AD and stroke toxicity. METHODS: AD was modeled by cerebroventricular injections of beta-amyloid (Abeta[25-35]) and subcortical lacunar infarcts by striatal endothelin injections. Inflammatory mechanisms were examined using immunohistochemical analysis. Memory and motor tasks were assessed using the Montoya staircase test. RESULTS: Abeta injections elicited increases in pathological and inflammatory correlates of AD in multiple forebrain sites. Increases in astrocytosis and reactive microglia in the hippocampus were enhanced with the combination of endothelin and Abeta(25-35). Abeta(25-35) treatment decreased performance in the Montoya staircase behavioral test. CONCLUSIONS: The enhanced inflammatory response with Abeta toxicity and ischemia may mediate the inability to improve behavioral performance caused by the stroke. Anti-inflammatory treatment may ameliorate the pathological and behavioral deficits associated with the combination of AD and stroke.

Alzheimer Disease↗
PubMed1988

A Gompertz age-specific mortality rate model of aging, hormesis, and toxicity: fixed-dose studies.

Based on the proposition that the logarithm of age-specific mortality rate (Gompertzian) is a linear measure of the mean intensity of injury for a homogeneous mammalian population in a uniform environment, a model was developed which characterizes mortality experience resulting from both toxic and hormetic actions. The mortality-reducing component (longevity hormesis) was assumed to be reversible; toxic effects, on the other hand, were assumed to accumulate irreversibly. Following chronic low-dose administration of selected toxic substances, it was demonstrated (in certain cases) that longevity hormesis could enhance lifespan, even in the presence of concomitant toxicity. Even when toxicity was evident, hormesis could ameliorate some of the mortality. The assumption that high-dose chronic toxicity studies can generate realistic estimates of risk at low doses is challenged.

Aging↗
PubMed1991

Epidermis generated in vitro: practical considerations and applications.

The technology for culture of epidermis is one of the most advanced to date for generation of a tissue in vitro. Cultured epidermis is already used for a number of applications ranging from use as a permanent skin replacement to use as an organotypic culture model for toxicity testing and basic research. While simple epidermal sheets have been grafted successfully, more advanced models for skin replacement consisting of both dermal and epidermal components are in development and being tested in a number of laboratories. One of the most advanced in vitro models is the living skin equivalent, an organotypic model consisting of a collagen lattice contracted and nourished by dermal fibroblasts overlaid with a fully formed epidermis.

Culture Techniques↗
PubMed2003

Bradykinin B2 receptor activates extracellular signal-regulated protein kinase in mIMCD-3 cells via epidermal growth factor receptor transactivation.

Bradykinin (BK) has been implicated in the regulation of renal function. Activation of extracellular signal-regulated protein kinase (ERK1/2) has been demonstrated in several models of toxic or proliferative renal injury. We studied activation of ERK1/2 by BK in a cell model of the most distal part of the nephron, inner medullary collecting duct (mIMCD-3) cells. Exposure of mIMCD-3 cells to BK (10(-10)-10(-5) M) resulted in a concentration-dependent increase in tyrosine phosphorylation of ERK1/2, with maximal effect at 10(-8) M BK. ERK1/2 activation by BK was observed as early as 1 min, peaked at 5 min, and was sustained at least for 1 h. The effect of BK was mediated by the B(2) receptor and was pertussis toxin-independent. Inhibition of phospholipase C, protein kinase C, or phosphatidylinositol 3-kinase did not alter ERK1/2 activation by BK. BK-induced ERK1/2 activation was Ca(2+)-calmodulin-independent but was sensitive to genistein, an inhibitor of tyrosine kinase(s). AG1478, a specific inhibitor of epidermal growth factor receptor (EGFR) kinase, completely blocked the effect of BK, suggesting an essential role of EGFR in ERK1/2 activation by BK. Immunoprecipitation/Western blot studies revealed that BK stimulated tyrosine phosphorylation of EGFR, its association with an adapter molecule Grb2, and complex formation between Grb2 and the adapter protein Shc. Activation studies of monomeric G protein Ras showed that BK-induced stimulation of Ras was dependent on EGFR tyrosine kinase activity. These studies demonstrate that BK stimulates Ras-dependent activation of ERK1/2 in mIMCD-3 cells via transactivation of EGFR through a novel mechanism.

Adaptor Proteins, Signal Transducing↗
PubMed2004

A comparative study of an accelerated life-test model and a toxicokinetics-based model for the analysis of Porcellio scaber survival data.

Statistical models have long been used for reliability analysis and risk assessment. In the present study, an accelerated life-test model was used to analyze a set of dose-time-response data obtained with the terrestrial isopod Porcellio scaber. Survival data were experimentally obtained by exposing P. scaber to diazinon (a nonpersistent insecticide) at six concentrations between 2 and 11.31 microg/g (toxicant/soil). Survival data are presented on a weekly basis. The accelerated life-test model assumed a log-normal distribution and constant variance across all diazinon concentrations. Model parameters were obtained by maximum likelihood estimation. The accelerated life-test model was compared to a toxicokinetics-based model reported in the literature. Survival predictions made by both models were compared with the observed data. Both the accelerated life-test model and the toxicokinetics-based model underestimated toxicity at a diazinon concentration of 8 microg/g. Overall, however, the accelerated life-test model outperformed the toxicokinetics-based model, with survival predictions closer to the observed data in most cases and a stronger correlation between predicted and observed survivals. However, as a statistical model, the accelerated life-test model did not reveal mechanistic information, and only statistical and distributional interpretations of its model parameters could be made.

Animals↗
PubMedDate not supplied

A hairless mouse model for assessing the chronic toxicity of topically applied chemicals.

An enormous number of synthetic chemicals are incorporated in topical drugs, cosmetics and toiletries. These have the potential to cause irritant reactions when chronically applied to human skin. In predictive tests for assessing the irritancy potential of these chemicals, haired species, especially rabbits, guinea pigs and mice, have figured prominently. Customarily these tests, including the renowned Draize rabbit test, have entailed a single acute exposure or at most daily exposures over a few weeks. Estimation of inflammation and tissue injury in these models have relied on visual assessment. We submit that this approach is no longer acceptable. Visual assessments are unreliable. Reactions which are scored equivalently by the naked eye may differ strikingly when examined histologically. Moreover, tissue injury may be present in clinically normal skin. Short-term results. even when abetted by routine histological evaluations, cannot predict the degree of injury from long-term exposures. Cosmetics and toiletries, for example, are used daily for decades, often over most of the lifespan of persons who are well groomed. We present the hairless mouse as a convenient, reliable model for assessing the chronic toxicity of diverse chemicals. Histological examination enables a detailed description of the different tissue components which participate in the complex cascade of changes that comprise the inflammatory response.

Administration, Topical↗
PubMedDate not supplied

A human single-chain Fv intrabody preferentially targets amino-terminal Huntingtin's fragments in striatal models of Huntington's disease.

Amino-terminal fragments of huntingtin (htt) appear to result from proteolytic processing of the full-length protein in Huntington's disease (HD), and fragments containing pathological expansions of polyglutamine elicit toxicity in model systems. Such fragments are sequestered into insoluble aggregates, which may initially serve a cellular protective mechanism, while soluble fragments and/or oligomers may be a more acute toxic species. Agents which enhance mutant htt clearance have shown therapeutic potential in animal models of HD. Here, we present the first evidence of an htt-specific single-chain Fv intrabody (C4) that selectively targets the soluble fraction of amino-terminal htt fragments. Our findings suggest that the C4 intrabody binds weakly, but does not alter the levels of endogenous, full-length htt. C4 appears to decrease the steady-state levels of amino-terminal htt fragments by binding to non-aggregated, but not aggregated, htt species. Intrabodies may be used as potential curative agents, and as drug discovery tools, for HD and other misfolded protein disorders.

Animals↗
PubMed2003

Viscoanesthesia. Part II: toxicity to intraocular structures after phacoemulsification in a rabbit model.

PURPOSE: To investigate the toxicity of a solution that combines sodium hyaluronate 1.5% with lidocaine (0.5%, 1.0%, or 1.65%) to intraocular structures. SETTING: Center for Research on Ocular Therapeutics and Biodevices, Storm Eye Institute, Medical University of South Carolina, Charleston, South Carolina, USA. METHODS: Phacoemulsification was performed in both eyes of 29 rabbits. They were divided into 3 groups; in each group (n = 7), 1 viscoanesthetic solution was used before capsulorhexis. After irrigation/aspiration, 0.2 mL of the solution was purposely left in the capsular bag. In 1 rabbit in each group, the solution was injected into the vitreous cavity through a posterior capsulorhexis. In 8 rabbits used as controls, balanced salt solution (BSS(R)) (n = 4) or sodium hyaluronate 1.5% (n = 4) was injected into the vitreous cavity. Enucleations were performed 15, 30, and 60 days postoperatively. Histological sections were cut and stained with hematoxylin-eosin, periodic acid-Schiff, and Masson trichrome stains. RESULTS: Light microscopic evaluation of the eyes enucleated after 15, 30, and 60 days in the study and control groups showed similar findings in intraocular structures such as the ciliary body and retina. No evidence of an inflammatory reaction, cell necrosis, or cell degeneration was observed in the histological sections. CONCLUSIONS: The use of viscoanesthesia during phacoemulsification appeared to be safe, with no histologic abnormalities observed with the 3 lidocaine concentrations. The efficacy of the anesthetic effects of these solutions will be addressed in clinical trials.

Anesthetics, Local↗
PubMed2006

Protective effect of thiazolo[5,4-b]indole in toxic pulmonary edema.

Antiedematous activity of new thiazolo[5,4-b]indole derivatives containing a fragment of isothiourea and characterized by higher antihypoxic activity compared to known antihypoxants was studied on a model of toxic edema of the lungs in mice. Compounds exhibiting high activity on two models of hypoxia (hypobaric and hemic) better protected from lung edema than compounds active only in hypobaric hypoxia.

Animals↗
PubMed2005

Modeling the effects of chronic toxicity on fish populations: the influence of life-history strategies.

Five life-history scenarios were composed to simulate fish population adaptations for survival under various environmental conditions. The scenarios encompassed differences in stage-specific survival, fecundity and hatch success, number of spawning events, and life-span effect response to chronic toxic impacts. The strategies represent a good survivor/generalist (GS), a species exhibiting high young-of-the-year survival, a species exhibiting high adult survival, a species with no parental care or guarding behavior, and an anadromous salmonid strategy. Although the modeled scenarios were similar in population growth rate and imposed toxic effects, differences concerning the influence of various traits were found. Scenarios characterized by a short life span, short time to reproductive maturity, moderate to high survival to reproductive maturity, large number of spawning events, and parental guarding behaviors experienced less perturbation from the imposed chronic stresses. The GS scenario, modeled after the round goby (Neogobius melanostomus), exemplified these characteristics. Scenarios exhibiting little difference between reproductive effort for younger and older adults recovered quickly from stressors on fecundity and adult survival rates. Greater population decline in response to commensurate impacts was seen for life-history strategies with long life span, no parental guarding behaviors, semelparity and annual iteroparity, high adult survival rates, and moderate to low fecundity.

Adaptation, Physiological↗