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Biomedical subjects

J A Dormans

Publications and source records attributed to J A Dormans.

At least 37 records · Page 2Linked to original sources
PubMed1990

The early effects of methylmercury on the developing rat brain.

The effects of organic mercury compounds on the development of the brain are well known since the exposure of people at a large scale to methylmercury in the Minamata Bay area and in Iraq. The neuropathological examination of the brains of children prenatally exposed revealed dysplasia of the cerebral and cerebellar cortex, neuronal ectopia and several other developmental disturbances. In this experimental study we examined developmental mechanisms involved in methylmercury-induced cerebral anomalies. By examining the fetuses soon after treatment we concentrated in the initial effects of the treatment. The pregnant rats were given 10 mg/kg methylmercury chloride i.p. on day 18. Already at 2 h after administration mitochondrial degeneration occurred in the endothelium of the cerebral capillaries. Subsequently hemorrhages developed interfering with the cellular arrangement in the ventricular zone, with neuronal migration in the intermediate zone and with the development of the cortical cytoarchitecture. Macrophages and cavities appeared in the hemorrhagic areas. It is suggested that the abnormalities seen in the experiments can be considered as the initial methylmercury-induced effects which, in combination with various other toxic effects, ultimately result in the anomalies that have been observed in the brains of children prenatally exposed to methylmercury.

Animals↗
PubMed1990

Surface morphology and morphometry of rat alveolar macrophages after ozone exposure.

As the ultrastructural data on the effects of ozone on pulmonary alveolar macrophages (PAM) are lacking, transmission (TEM) and scanning (SEM) electron microscopy were performed on rat PAM present in alveolar lavages following exposure to ozone. Rats were continuously exposed for 7 d to ozone concentrations ranging from 0.25 to 1.50 mg/m3 for 7 d followed by a 5-d recovery period. Additionally, morphometry on lung sections was performed to quantitate PAM. In a second experiment rats were continuously exposed to 1.50 mg O3/m3 for 1, 3, 5, or 7 d. To study the influence of concurrent ozone exposure and lung infection, due to Listeria monocytogenes, rats were exposed for 7 d to 1.50 mg O3/m3 after a Listeria infection. The surface area of lavaged control PAM was uniformly covered with ruffles as shown by SEM and TEM. Exposure to 0.5 mg ozone/m3 for 7 d resulted in cells partly covered with microvilli and blebs in addition to normal ruffles. The number of large size PAM increased with an increase in ozone concentration. After 1 d of exposure, normal-appearing as well as many small macrophages with ruffles and scattered lymphocytes were seen. Lavage samples taken after 5 or 7 d of exposure showed an identical cell composition to that taken after 3 d of exposure. After Listeria infection alone, lavage samples consisted of mainly lymphocytes and some macrophages. Small quantitative changes, such as an increase in the number of polymorphonuclear neutrophils and large-size PAM, occurred in lavages after ozone exposure and infection with L. monocytogenes. Morphometric examination of lung sections revealed a concentration-related increase in the number of PAM, even in animals exposed to 0.25 mg ozone/m3 for 7 d. Centriacinar regions were more severely affected than other regions of lung tissue. By 5 d after termination of exposure to ozone, the number of lysozyme-positive alveolar cells was still significantly increased in centriacinar areas of the lung. The results indicate that ozone exposure causes major changes in the number, size, and surface morphology of PAM in rat lung. Furthermore, the results presented here suggest that changes in alveolar macrophage function are reflected by morphological changes.

Animals↗
PubMed1989

Study of the effects of ozone in emphysematous rats.

The effects of short-term exposure to ozone on control and elastase-induced emphysematous rats were examined to investigate whether emphysema would change the pulmonary susceptibility to oxidant air pollution. Emphysema was induced in rats after a single intratracheal instillation of 0.2 IU elastase/g body weight. Histologically, panacinar emphysema was apparent at 2, 4, 8, and 16 wk, that is, the total duration of the experiment. The diagnosis was confirmed by morphometry: the mean linear intercepts (MLI) of elastase-treated rats were significantly increased at all observation times, whereas the internal surface areas (ISA) of the elastase-treated rats were significantly decreased. In addition, pulmonary function tests provided supportive evidence for the diagnosis of emphysema. Respiratory system compliance and functional residual capacity showed a significant increase in elastase-treated rats. No differences in inspiratory capacity or in forced vital capacity between control rats and elastase-treated rats were observed. The above data are indicative for a rat model for elastase-induced emphysema. Short-term exposure to ozone of elastase-treated rats revealed panacinar emphysema, including an inflammatory response in the centroacinar region. No differences in MLI as well as in ISA between ozone-exposed rats (with or without emphysema) and their respective controls were observed. Short-term exposure to ozone induced an identical, significant increase in protein content, lactate dehydrogenase, glucose-6-phosphate dehydrogenase, and glutathione peroxidase activities in lungs of normal and emphysematous rats. Moreover, these results strongly suggest that emphysematous rats are not more susceptible to ozone than nonemphysematous rats.

Air Pollutants↗
PubMed1989

Application of the disector method in the light microscopic quantification of type II pneumocytes in control and ozone-exposed rats.

Alveolar type II cells in control and ozone-exposed rat lungs were counted at the light microscopical level with the 'disector method'. The type II cells were unequivocally marked by histochemical staining for alkaline phosphatase activity in 2 microns plastic sections. By this counting method, the mean number of type II cells per lung in control rats was of the same magnitude as those reported in the literature, using point counting methods. After exposure of rats to 1.6 mg ozone/m3 for 7 days, a 50% increase in the mean number of type II cells was observed. The use of the disector method at the light microscopical level offers some advantages above a quantification at the electron microscopical level. The procedure is less time-consuming, larger areas can be screened, two parallel countings can be performed in one set of sections and there is no need for an exact knowledge about the diameter of the measured particle.

Alkaline Phosphatase↗
PubMed1989

Continuous intravenous infusion of deferoxamine reduces mortality by paraquat in vitamin E-deficient rats.

Paraquat, an oxygen radical-generating agent, is a widely used agrochemical that is also toxic for humans, in whom it may cause respiratory failure. In the present study, we investigated the effect of deferoxamine (DF), an iron chelator with antioxidant capacity, on paraquat toxicity in vitamin E-deficient rats. After the administration of paraquat at a dose of 20 mg/kg the animals were treated with a continuous intravenous infusion of DF for 14 days. In a dose-response study, four of six animals receiving 100 mg DF/kg/24 h survived the study period of 14 days compared with none in the saline-treated control group (n = 6), and three and two animals in the groups receiving 50 (n = 6) and 200 mg DF/kg/24 h (n = 6), respectively. In another series of experiments, animals were monitored for a total period of 35 days, at which time any survivors were killed, and lung histologic examination was carried out. Deferoxamine treatment was started simultaneously (n = 21), 6 h (n = 18), and 16 h (n = 18) after paraquat poisoning. Percent survival in the various time-point groups was 47.7 (p less than 0.01), 38.9 (p less than 0.02), and 22.2 (not significant), respectively, compared with 7.1 (n = 14) in the control group. The presence of lung damage was seen only in those of the surviving rats where DF was started at the 16 h time point after paraquat administration. In ancillary in vitro studies, where Escherichia coli was used as a source of enzymic activity for the redox-cycling of paraquat, DF completely inhibited the formation of hydroxyl radical (.OH).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Qualitative and quantitative changes in cytochrome P-450-dependent xenobiotic metabolism in pulmonary microsomes and isolated Clara cell populations derived from ozone-exposed rats.

The effect of a prolonged ozone exposure (1.6 mg ozone/m3; 7 d; 24 h/d) on pulmonary cytochrome P-450-dependent xenobiotic metabolism was studied both in whole rat lung as well as in isolated bronchiolar Clara cell preparations. Ozone exposure was demonstrated to result in significant quantitative but also qualitative changes. All components of the pulmonary microsomal electron transport system appeared to be significantly increased in the lungs of exposed animals both per lung and per gram lung, although increases were no longer observed when expressed per milligram microsomal lung protein. Remarkably, it was demonstrated that the increases in the components of the pulmonary cytochrome P-450 system were not accompanied by a concomitant increase in all cytochrome P-450-dependent substrate conversions. In whole-lung microsomes ethoxycoumarin O-deethylase and ethoxyresorufin O-deethylase activities were unchanged or even significantly reduced when expressed per lung, per gram lung, per milligram microsomal protein, or per picomole cytochrome P-450. In contrast to these observations, pentoxyresorufin O-dealkylation appeared to be significantly increased upon ozone exposure when expressed per lung, per gram lung, and even per picomole cytochrome P-450. Clara cell populations isolated from ozone exposed rats showed a comparable qualitative shift in cytochrome P-450-dependent substrate conversion characteristics. On a cellular basis, ozone exposure resulted in a significant reduction of ethoxycoumarin and ethoxyresorufin O-deethylation and did not affect pentoxyresorufin O-dealkylase activity. Additional experiments, in which ozone-mediated inactivation of microsomal cytochrome P-450-dependent substrate metabolism was studied in vitro, demonstrated that the qualitative changes observed after in vivo exposure cannot be ascribed to a disproportional inactivation of different cytochrome P-450 isoenzymes. Based on these results and on lung morphometrics and cell isolation data presented, the observed effects should rather be ascribed to (1) the proliferation of cytochrome P-450 containing cell populations and (2) intrinsic cellular biochemical changes. The quantitative and qualitative ozone-induced changes in pulmonary cytochrome P-450-linked enzyme characteristics in whole lung and within specific lung cells, as demonstrated in the present study, may be expected to have important implications for the toxicity of xenobiotics whose (de)toxification depends on pulmonary cytochrome P-450-dependent metabolism.

Animals↗
PubMed1986

Influence of exposure regimen on nitrogen dioxide-induced morphological changes in the rat lung.

Experiments were performed to study the influence of concentration, exposure pattern, and length of exposure on the degree and extent of morphological alterations in the NO2-exposed rat lung. Four weeks of continuous exposure to 20 mg NO2/m3 consecutively revealed damage and loss of cilia, replacement of desquamated type I pneumocytes by type II pneumocytes resulting in a cuboidal epithelial lining, an influx of alveolar macrophages, and hypertrophy and hyperplasia of the bronchiolar epithelium. The animals recovered almost completely from the induced lesions within 8 days. Continuous exposure to 1, 2.5, or 5 mg/m3 displayed minimal alterations in the 5 mg/m3 group. The effects increased with exposure time. Intermittent or continuous exposure to 20 mg NO2/m3 resulted in minor differences after 4 weeks. The onset of the lesions was delayed and the massive influx of alveolar macrophages in the continuously exposed animals failed to appear in the intermittently exposed animals. This work demonstrates that in subacute experiments: Concentration plays a more important role in inducing pulmonary lesions than exposure time when the product of concentration and time is kept constant. This effect is stronger during intermittent exposure than during continuous exposure. Continuous exposure seems to be a more important factor with regard to a macrophage response than intermittent exposure. The rat lung has a large capacity to repair almost completely from damage caused by short-term NO2 exposure.

Animals↗
PubMed1986

The subchronic oral toxicity of the beta-isomer of hexachlorocyclohexane in rats.

The 13-week oral toxicity of beta-HCH, a non-pesticidal isomer of hexachlorocyclohexane, was investigated in rats with doses of 0, 2, 10, 50, or 250 mg/kg feed. Parameters studied comprised clinical signs, growth and food intake, biochemistry, hematology, organ weights, and histopathology. In all dose groups liver effects comprising increase of organ weight, centrilobular hepatocytic hypertrophy, and proliferation of smooth endoplasmic reticulum or increased activity of microsomal enzymes, were observed. In the 50 mg/kg group the weights of thymus and testes were affected. In the highest dose group, progressive clinical signs leading to the unscheduled sacrifice of approximately 50% of the rats were observed. Moreover, in the males of this group atrophy of the testes, characterized by a reduced size of the seminiferous tubules and a decreased number of interstitial cells was observed in association with spermatogenic arrest. The females in this group showed atrophy of the ovaries with impaired oogenesis and focal hyperplasia and metaplastic changes of the endometrial epithelium. These effects are discussed with respect to a possible estrogenic action of beta-HCH.

Administration, Oral↗
PubMed1986

Time-course study on doxorubicin-induced nephropathy and cardiomyopathy in male and female LOU/M/Wsl rats: lack of evidence for a causal relationship.

In a previous study on doxorubicin-induced cardiotoxicity in LOU/M/Wsl rats, severe nephropathy has been observed; therefore, the question was raised whether nephropathy adds to or even might be responsible for doxorubicin-induced cardiomyopathy in rats. For elucidation of this question, the temporal relationship between the onset of doxorubicin-induced cardiomyopathy and nephropathy was studied. In addition, examination was made of whether modifications of the treatment schedule could circumvent nephrotoxicity. Because preliminary studies had shown that female LOU/M/Wsl rats developed less doxorubicin-induced albuminuria, both male and female LOU/M/Wsl rats were treated with an iv dose of 1 mg doxorubicin/kg (body wt)/rat on five consecutive days and then weekly. Saline-treated animals served as controls. Albuminuria, serum albumin, and serum creatine levels were assessed weekly. For histologic examination, 5 male and 5 female rats were killed weekly. At day 14 and thereafter, doxorubicin-treated male rats showed albuminuria greater than or equal to 10 g/liter. Albuminuria of greater than or equal to 10 g/liter was not avoided by modifications of the treatment schedule. Female rats had on day 14 a urinary albumin level of 1.0-3.0 g/liter, yet reaching the level of greater than or equal to 10 g/liter at day 49. In male rats serum albumin levels decreased to levels below 10 g/liter (p less than .001 vs. finding for day 0); in contrast female rats maintained constant serum albumin levels till day 49. Serum creatine levels showed a tendency to rise, the values of male rats not being measured after day 28 due to hyperlipidemia; the levels of female rats increased from 37.8 +/- 3.0 mumol/liter to 53.7 +/- 2.5 mumol/liter on day 49 (P less than .001). At day 10 in male and female rats a grade 1-1.5 cardiomyopathy score, assessed according to the modified Billingham scoring system, was found, gradually increasing to grade 2.5-3 cardiomyopathy, both in males and females, on day 49. In male LOU/M rats the nephropathy developed steadily from day 14 and thereafter, whereas in females the rate of development of kidney damage was slower and at the end point of the study the severity of kidney lesions was less in comparison to that of the males. The onset of cardiomyopathy and nephropathy was simultaneous. It was concluded that cardiomyopathy observed in LOU/M rats is a phenomenon independent of nephropathy.

Albuminuria↗
PubMed1985

Comparative pathology of the canine model of glycogen storage disease type II (Pompe's disease).

The pathology of canine glycogen storage disease type II (acid alpha-glucosidase deficiency, GSD II) was studied in three genetically related Lapland dogs and compared to the pathology of human GSD II (McKusick 23230). Canine GSD II closely parallels the infantile form of the human disease, except for the presence of oesophageal dilatation. Generalized glycogen storage particularly affected muscular tissues (skeletal, oesophageal, cardiac and smooth muscle). The altered cells showed glycogen accumulation in the cytosol and in autophagic membrane-bound vacuoles (glycogenosomes). They also showed increased acid phosphatase activity consistent with the lysosomal nature of this storage disorder. The cytopathology in canine and human GSD II appears to evolve from segregation of glycogen during regular cellular autophagy, phagolysosomal accumulation of the undigested glycogen, and eventually rupture of distended glycogenosomes. This study indicates that the usefulness of canine GSD II as an animal model of human disease, extends to the area of pathogenesis.

Acid Phosphatase↗
PubMed1984

Antitumor effect, cardiotoxicity, and nephrotoxicity of doxorubicin in the IgM solid immunocytoma-bearing LOU/M/WSL rat.

Antitumor activity, cardiotoxicity, and nephrotoxicity induced by doxorubicin were studied in LOU/M/WSL inbred rats each bearing a transplantable solid IgM immunocytoma. Animals with a tumor (diameter, 15.8 +/- 3.3 mm) were treated with iv injections of doxorubicin on 5 consecutive days, followed by 1 weekly injection for 7 weeks (dose range, 0.015-4.0 mg/kg body wt). Tumor regression was observed with 0.5 mg doxorubicin/kg. Complete disappearance of the tumor was induced with 1.0 mg doxorubicin/kg. Histologic evidence of cardiotoxicity scored as grade III was only observed at a dose of 1.0 mg doxorubicin/kg. Light microscopic evidence of renal damage was seen above a dose of 0.5 mg doxorubicin/kg, which resulted in albuminuria and very low serum albumin levels. In the group that received 1.0 mg doxorubicin/kg, the serum albumin level decreased from 33.6 +/- 4.1 to 1.5 +/- 0.5 g/liter. Ascites and hydrothorax were observed simultaneously. The same experiments were performed with non-tumor-bearing rats, in which no major differences were observed. In conclusion, antitumor activity, cardiotoxicity, and nephrotoxicity were studied simultaneously in the same LOU/M/WSL rat. Albuminuria due to renal damage led to extremely low serum albumin levels, so ascites and hydrothorax were not necessarily a consequence of the observed cardiomyopathy.

Albuminuria↗
PubMed1981

Short-term induction of neoplastic nodules in the rat liver. II. Study of their development and the effects of withdrawal of 2-acetylaminofluorene.

Neoplastic liver nodules were induced by a single administration of N-nitrosodiethylamine (NDEA) and selectively stimulated to growth by 2-acetylaminofluorene (2-AAF) and partial hepatectomy to provide morphological data on very early and late stages of preneoplastic development. Presumptive preneoplastic liver cells were recognizable by light and electron microscopy by 2 days after partial hepatectomy, and they developed within 2 weeks into large, solid nodules consisting of plates of 2 or 3 cell layers thick, that compressed the surrounding non-nodular tissue. The cells showed nuclei with an enlarged nucleolus, tortuously dispersed rough endoplasmic reticulum (RER) and an electron lucent cytoplasm. These features remained present throughout the first 2 weeks of growth. During this period the initially small, distinct smooth endoplasmic reticulum areas proliferated gradually. They were associated with an increasing incidence of cytoplasmic membranes whorl formation and incidentally with annulate lamellae. After withdrawal of 2-AAF the majority of the nodules regressed resulting in slowly disappearing foci of glycogen rich cells. A relatively small number of solid nodules persisted. They were characterized by large cells with a homogeneous eosinophilic cytoplasm, enlarged cells with a homogeneous eosinophilic cytoplasm, enlarged nucleoli and dispersed RER. Because these characteristics were absent in nodular cells that had reverted to normal liver cells, it is not appropriate to consider these characteristics to represent neoplastic transformation per se.

2-Acetylaminofluorene↗
PubMed1981

An experimental study on the morphogenesis of spina bifida.

This investigation was performed to study the morphogenesis of caudal meningomyeloschisis or spina bifida aperta during neurulation. Pregnant rats were treated wih trypan blue to induce these defects in the closure of the neural walls. Maternal serum was studied to determine trypan blue levels. Both control and treated embryos were examined grossly, at cellular and subcellular level on days 10 through 13 of gestation. Trypan blue was distributed throughout the maternal tissues. There existed a maternal blood-brain barrier and a barrier at the level of the visceral yolk sac and embryonic gut preventing passage of the dye through these entodermal structures. The interstitial space in the paraxial mesenchyme was considerably increased in day 10 treated embryos (6--7 somites) but cellular and ultrastructural changes were not seen. This accumulation of intercellular fluid was only seen in the restricted area of the mesoderm above the invaginating intra-embryonic entoderm. On day 11 the closure of the neural walls was completed in control embryos. In the treated embryos of the similar stages a blister which contained embryonic blood cells had replaced the interstitial mesenchymal fluid. This structural disturbance in the non-segmented mesenchyme interfered primarily with the neurulation and resulted in caudal meningomyeloschisis (spina bifida aperta). Trypan blue was thought to interfere with the function of the extra-embryonic membranes and the primitive gut. The results of this study supported the hypothesis of indirect teratogenic effect upon the embryo.

Abnormalities, Drug-Induced↗
PubMed1980

Failure of the antioxidant vitamin E to protect against adriamycin-induced cardiotoxicity in the rabbit.

Recently, vitamin E has been proposed to protect against Adriamycin-induced cardiotoxicity. We studied contractile decline and ultramicroscopic alterations of the heart of rabbits chronically treated with Adriamycin up to a cumulative dose of 400 mg/sq m. High doses of vitamin E did not protect against the Adriamycin-induced development of severe contractile decline as evaluated by means of measurement of the interval-force relationship curve. Light and electron microscopic analysis did not show any signs of protection against Adriamycin-induced morphological alterations. Biochemical and hematological alterations. Biochemical and hematological alterations caused by the antineoplastic agent were similar in both Adriamycin-treated animal groups. Coadministration of vitamin E did result in an increased life span. This study indicates that vitamin E does not protect against the development of cardiomyopathy and contractile decline after chronic exposure to Adriamycin.

Animals↗