Biomedical subjects
Publications and source records attributed to M Marion.
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Cadmium (Cd) is a non-essential, highly toxic heavy metal and a ubiquitous environmental contaminant. Evidence exists that Cd can affect parameters which are of great importance in the response towards xenobiotics. However, there is a lack of information about the mechanisms that take place at the cellular and molecular levels upon dual exposure to Cd and other toxins. The purpose of the present work was therefore to examine the biochemical interactions between Cd and a well-known genotoxic hepatocarcinogen, 2-acetylaminofluorene (AAF) in isolated rat hepatocytes. The cells were incubated for 10 hr with a sub-cytotoxic concentration (0.22 microM) of 109Cd. This was followed by a 10 hr exposure to 1 microM [3H]AAF. Cellular distribution of Cd and 3H was determined. Sephadex G-75 elution profiles of the cytosol showed that Cd was almost entirely associated with the intermediate molecular weight (IMW) fractions containing metallothionein (MT) ( > 80%), and with high molecular weight proteins. In parallel, the highest proportion of 3H was found in the low molecular weight components. Further analysis of IMW fractions by DEAE A-25 anion-exchange chromatography revealed that, in addition to Cd, there was some 3H which coeluted along with MT-I and MT-II isoforms, but preferentially with MT-I. Moreover, Cd pretreatment caused a 1.6-fold increase in MT level, as measured by the silver-saturation assay. Under these conditions, there was a 17% lower binding of 3H to the DNA. This reduced binding was neither accompanied by diminished AAF uptake nor by inhibition of cytochrome P-450 activity. Taken together, these results suggest that Cd exposure has a protective effect against the genotoxicity of AAF. MT, whose synthesis is induced, could play a role in the Cd-AAF interaction through scavenging of reactive metabolites.
There is now growing evidence that asbestos fibers could act in association with genotoxic compounds, either as cocarcinogens or promoters, in the process of carcinogenesis. The hepatocyte/UDS assay system has been taken to advantage to investigate the capacity of fibers to modulate the effects of genotoxic compounds on the cell, as we previously demonstrated the hepatocytes can engage in phagocytosis of chrysotile fibers. Measurement of UDS was performed by a biochemical procedure involving liquid scintillation counting (LSC) of a purified DNA fraction as well as by radioautography. Both LSC and radioautography revealed that chrysotile asbestos fibers UICC B at concentrations up to 100 micrograms/ml do not elicit UDS, whereas 2-acetylaminofluorene (2-AAF) at low concentrations (0.05-0.625 micrograms/ml) significantly induces it in parallel positive controls. In an attempt to test the cocarcinogen hypothesis, cultures of hepatocytes were simultaneously exposed for 20 h to 2-AAF (0.05 and 0.25 micrograms/ml) and asbestos fibers (1 and 10 micrograms/ml) given as simple mixtures. It was found that the 2-AAF-induced UDS activity was the same whether fibers were present or not. This was observed with both UDS evaluation procedures at all concentration combinations selected. An analysis of variance applied to the data collected from several experiments confirmed that there was no significant 2-AAF-fiber interaction. Our data suggest the absence of intrinsic genotoxic properties for chrysotile fibers. They also indicate that the modulation of the cellular response to genotoxic agents by asbestos fibers is not detected under our test conditions and may require longer-term exposures to be expressed.
The effect of cadmium (Cd) on rat hepatocytes upon short term exposure was studied by focusing on the integrity of mitochondria and on the possible consequences of its disturbance, such as alterations in plasma membrane potential and loss of cell viability. Changes in the potential of mitochondrion and plasma membranes were monitored using [3H]triphenylmethylphosphonium (TPMP+) and [14C]SCN- probes, respectively. Isolated rat hepatocytes were exposed to increasing CdCl2 concentrations for short time periods (30-120 min). Cd measurement by atomic absorption showed that the cells efficiently accumulated Cd, as did mitochondria in situ. In CdCl2-treated cultures, it was observed that the release of TPMP+, which revealed a drop in the mitochondrial membrane potential, was time- and concentration-dependent, and that the first significant efflux was caused by a 30-min exposure to 89 microM CdCl2. No significant change in plasma membrane potential, as judged from the increase in the uptake of SCN-, was detected after 30 min, suggesting the greater precocity of the mitochondrial attack. Finally, the release of lactate dehydrogenase (LDH) occurred only after 2 h of exposure, reflecting ultimate stages of cell injury induced by Cd. These results suggest that Cd induces an alteration in mitochondrial function in hepatocytes which may lead to the loss of plasma membrane potential and cell viability. The study therefore adds further evidence of the role of mitochondria as primary targets in Cd-induced cytotoxicity.
Cultures of rat hepatocytes have been used to study the interaction of chrysotile asbestos fibers with epithelial cells. The hepatocytes were incubated for 20 h with chrysotile asbestos (UICC B and a preparation of short fibers: 90% less than 2 micron) at concentrations of 1 or 10 micrograms/ml. Morphologic studies were then performed by means of transmission electron microscopy. Fibers were incorporated into plasma membrane invaginations, cytoplasmic vacuoles and phagolysosomes. These observations demonstrate that rat hepatocytes can engage in phagocytosis of chrysotile fibers. The results are compared to those previously obtained with mesothelial cells and tracheobronchial epithelium, exposed to asbestos in vitro. The advantages of the hepatocyte model to investigate the effects on cells of the association of asbestos fibers with genotoxic agents in relation to carcinogenesis are discussed.
The precise role and mechanism whereby otosclerosis is associated with sensorineural hearing loss remains unclear. Previous histopathologic reports are inconsistent with regard to the location of the otosclerotic focus, invasion of the otic capsule, and the number of remaining peripheral sensorineural elements. From the combined temporal bone collections of the University of Chicago and the Mayo Clinic, we identified a group of 125 ears from 80 patients, all with confirmed otosclerosis. Six of these ears were associated clinically with sensorineural hearing loss without stapes fixation. The histopathology of the otosclerotic focus was reviewed in terms of its location and depth of invasion. The cochlea and spiral ganglion were reconstructed, and the state of the organ of Corti and the presence or absence of peripheral cochlear nerve fibers were noted. Correlations with ganglion cell counts were made. The present study showed that the pattern of degeneration of peripheral sensory and neural elements in the cases presented is very similar to that found in cases of age-related processes such as presbycusis.
Hepatocytes in culture represent a useful model for investigating the effects of toxic agents on liver cells. However, further development of this model is hampered by the difficulty in promoting cell proliferation over prolonged periods and the lack of knowledge about the biochemical status of the cells relevant to the toxic response under proliferation conditions. In an effort to overcome these limitations, this work focused on the establishment of conditions to ameliorate the promotion of hepatocyte proliferation in vitro. It also examined the effects of growth stimuli on the levels of glutathione (GSH), a highly significant parameter influencing the resistance against toxic agents. In addition, albumin secretion was monitored as an indicator of liver-specific functions. Two modified L-15 media were developed: medium A for supporting cell differentiation, and medium B for promotion of proliferation. Collagen and Matrigel were used as substrata. In medium A, the time course of GSH levels was comparable for both substrata, with an initial increase followed by a plateau and then by a progressive decrease from the second to the fourth week. Hepatocytes cultured on collagen and sequentially exposed to medium B (containing epidermal growth factor +/- norepinephrine) and medium A, showed repeated responsiveness to stimulation of DNA synthesis. Moreover, for cultures on collagen, a higher GSH content was observed in parallel with DNA synthesis stimulation, while albumin secretion was diminished. Although cells on Matrigel were refractory to DNA synthesis stimulation, GSH levels were still increased upon exposure to the growth factors, while under these conditions, albumin synthesis remained unaltered.(ABSTRACT TRUNCATED AT 250 WORDS)
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Bacteriological, viral and serological investigators were carried out in a community with 100 prescholar children (Kindergarden), 34 of whom presented a clinical syndrome of whooping cough, in order to establish the bacteriologic or viral etiology of the syndrome. The etiologic role of organisms of the Bordetella, B. pertussis and B. parapertussis was invalidated by the bacteriologic and serological tests. Viral and serological tests, performed to demonstrate the participation of viral agents in the causation of this clinical syndrome, established an adenoviral diagnosis in 13 (43.3%) of the 30 children. Adenovirus type 6 was isolated and there was a significant increase in the titers of antibodies to adenoviruses.
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