Mammalian models

Dawson BV, Johnson PD, Goldberg SJ, et al. 1990. Cardiac teratogenesis of trichloroethylene and dichloroethylene in a mammalian model. J Am Coll Cardiol 16 1304-1309. 

No mortality was found in any embryo exposed to the controls. On the contrary, all the embryos exposed to the non-diluted samples of penta-, octa-, and deca-BDE commercial mixtures were dead after 24 h (Fig. 10). When the untreated PBDEs samples were diluted at 50%, a gradient of toxicity was observed penta > octa > deca. After dilution at 5%, no embryos exposed to untreated samples were dead. In agreement with our results, it has been demonstrated that the toxicity of deca-BDE is commonly lower than for octa- and penta-BDE commercial products exposures with mammalian models [64]. The different toxicity found in mammalian models and also in zebrafish should be related to the higher accumulation of lower brominated congeners in the body, because of their greater partitioning and retention in lipid-rich tissues and lower rates of metabolism and elimination in relation to deca-BDE. 

Pritsos, C.A. 1996. Mitochondrial dysfunction and energy depletion from subchronic peroral exposure to cyanide using the Wistar rat as a mammalian model. Toxic Subst. Meehan. 15 219-229. 

As observed in mammalian models, the immune system of fishes is a sensitive target organ system to evaluate toxicity. For a more thorough review of environmental immunotoxicology in fishes, with reference to specific classes of xenobiotics, readers are referred to several reviews that deal with the subject over a span of nearly three decades [45-47, 54-57], While fish in the environment may be exposed to a variety of xenobiotics, the most frequently investigated xenobiotics are the polycyclic aromatic hydrocarbons (PAHs) and halogenated aromatic hydrocarbons (HAHs) due to the presence and activation of the aryl hydrocarbon receptor (AhR) in fish, and heavy metals due to their ubiquitous environmental distribution. 

With the widespread availability of cell culture facilities, the reduced costs of media and reagents and above all, the commercialisation of a variety of transfection and expression kits, mammalian cells have now become probably the standard for functional studies of transmembrane transporters. Unsurpassed predictivity of the mammalian models may outweigh the higher costs and the lengthiness of the process, compared with bacterial cultures or Xenopus oocytes. Nevertheless, structural studies may require larger amounts than those easily produced in mammalian cells and the appeal of insect cell cultures for... 

To further evaluate the role of CRH in both neuroendocrine and behavioral functions, a mammalian model of CRH deficiency has been generated by targeted mutation in embryonic stem cells (Mugha et al. 1995). CRH-deficient mice reveal a fetal glucocorticoid requirement for lung maturation. Postnatally, they display marked glucocorticoid deficiency and an impaired endocrine response to stress (Jacobson et al. 2000 Mugha et al. 1995). 

In order to fully understand the antidiabetic effects of vanadium, or any other drug, cellular studies are extended to mammalian models of diabetes, frequently in rodents. Models exist and have been used for vanadium studies of both type 1 and type 2 diabetes. Below, general results observed with vanadium compounds in the various model systems are described. More detailed descriptions of the molecular signal transduction systems affected are given in references [12,13,100,133],... 

The development, validation, and application of TEFs have been reviewed regularly since 1984 by Safe [25,36,37]. The limitations of this approach have been identified [38]. To assess the relative potencies and to derive consensus on TEFs for PCDDs, PCDFs, and dioxin-like PCBs, the WHO-European Centre for Environmental and Health (WHO-ECEH) and the International Program on Chemical Safety (IPCS) have initiated a project and published their interim report [39]. The most important limitations, namely possible synergism or antagonism among dioxins and its stereo isomers and the lack of pharmacokinetic consideration, have been addressed in this report. USEPA researchers [40] showed that the relative potency of PCBs, PCDFs, and 2,3,7,8-TCDD is tissue specific and thus estimates of TEFs based on hepatic EROD activity is limited. Additionally, limitations of TEFs based on mammalian models to aquatic species have been demonstrated [41]. The international initiative on TEFs has recognized these pitfalls and recommended development of TEFs for fish and other wildlife. 

A quick comparison of QSAR 1.82-1.84 reveals the strong similarity between the avian and mammalian models. In fact because of its increased stability, chicken liver DHFR has often been used as a surrogate for human DHFR in enzyme-inhibition studies. The intercepts, coefficients with Tr g and optimum tt q for avian (6.33, 1.01, 1.9), human (6.07, 1.07, 2.0), and mouse leukemia (6.12, 0.98, 1.76) can be compared to the corresponding values for P. carinii (6.48, 0.73, 3.99) and Leishmania major (5.05, 0.65, 4.54). ( SAR 1.81 and 1.87 are not included in the comparison because crude pigeon enzyme was used in... 

In the present chapter we suggest the use of fish embryos as a powerful screening system that could be used to prioritize compounds for later testing using rodent or other mammalian models and clinical trials. We describe the peculiarities of the model, provide examples that show promising applications, and discuss potential limitations and future research perspectives. 

META [22,23] was developed by Gilles Klopman and coworkers. The mammalian model covers a wide range of reactions promoted by 26 types of enzymes. Metabolic products can be assessed automatically for potential carcinogenicity and the results reported to the user. Separate knowledge bases cover aerobic biodegradation, anaerobic biodegradation, and photodegradation. 

Mammals are attractive models to study ototoxicity, since the anatomical characteristics of the inner ear and drug-dependent inner ear pathologies are similar to humans. Experimental designs generally include the measurement of auditory potentials (mostly nonin-vasive ABRs) and postmortem evaluation of cochlear pathology. Overall, mammalian models are an essential step in translational research. 

Trout have thus become adopted and established as a model of carcinogenesis for a number of reasons. In summary, they (i) have low rearing costs compared to rodents, (ii) provide a highly sensitive early life-stage bioassay, (iii) are sensitive to a wide variety of carcinogens, (iv) are responsive to promoters and inhibitors, (v) have a well-defined tumor pathology, (vi) are mechanistically comparable to mammalian models and (vii) provide more tissues for analysis compared with smaller aquarium fish. 

Extensive evidence conclusively demonstrates that another important mechanism of action of adrenotoxicants is the generation of ROS and the imbalance between prooxidants and antioxidants in the cell. The resulting oxidative stress is a mechanism mediating the toxic effects of numerous chemicals in a wide array of cells and organs, in many if not all, animal and plant species. Numerous studies with mammalian models using either in vitro exposures of tissues and cells or whole animal studies,... 

Looking ahead, we hope that this review may stimulate scientists with an interest in endocannabinoid signalling to exploit not only the familiar mammalian model species (rats, mice) but also the rich diversity of non-mammalian animals where the existence of endocannabinoid receptors has been established. 

Mammalian model organisms are key systems for disease and disorder research, but the contribution of comparative analysis with nonmammalian organisms can be equally critical. The common fruit fly has orthologs to 177 human disease genes and provides the foundation for rapid analysis of some of the basic processes involved in human disease [16]. Conserved chromosomal regions associated with complex human... 

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