Dental pulp infarction in female rats following inhalation exposure to 2-butoxyethanol

Female Fischer 344 (F344)/N rats (10 per exposure group) were exposed to 2-butoxyethanol (BE) vapors (0, 31, 62.5, 125, 250, or 500 ppm 6 h/d, 5 d/wk, for 13 weeks) to characterize its prechronic toxicity. Dental lesions consisting of bilateral multifocal dental pulp thrombosis, pulp infarction, and odontoblast infarction were noted in the maxillary incisors of 3 of 4 rats from the 500-ppm group that were sacrificed when moribund during the first week of exposure. In addition, 1 rat from the 500-ppm group that was sacrificed on day 32 had similar unilateral incisor lesions but with additional findings consistent with a unilateral maxillary incisor fracture. In contrast, rats sacrificed after 13 weeks of exposure lacked dental lesions. In conclusion, BE has the potential to cause pulp thrombosis and odontoblast infarction in female rats. The apparent variability in response to BE noted in moribund sacrificed vs terminally sacrificed rats was attributed to development of tolerance to BE-induced hemolysis and subsequent incisor regeneration.     

Hemolytic anemia, thrombosis, and infarction in male and female F344 rats following gavage exposure to 2-butoxyethanol.

2-butoxyethanol (BE; ethylene glycol monobutyl ether) is used extensively in the manufacture of a wide range of domestic and industrial products which may result in human exposure and toxicity. BE causes severe hemolytic anemia in male and female rats and mice. In a recent report, female F344 rats exposed to 500 ppm BE by inhalation and sacrificed moribund on day 4 of treatment exhibited disseminated thrombosis associated with infarction in several organs. In contrast, no such lesions were observed in male rats similarly exposed to BE. Additional studies were therefore undertaken to compare the effects of BE in rats of both sexes. Rats received 250 mg BE/kg/day by gavage for 1, 2 or 3 days and were sacrificed 24 or 48 hr after the last dose. Control rats received 5 ml/kg water. Progressive time-dependent hemolytic anemia--macrocytic, hypochromic, and regenerative--was observed in both sexes of rats exposed to BE. Additionally, BE caused significant morphological changes in erythrocytes, first observed 24 hr after a single dose, including stomatocytosis, macrocytosis with moderate rouleaux formation, and spherocytosis. These morphological changes became progressively more severe as BE dosing continued and included the occasional occurrence of schistocytes and ghost cells, rouleaux formation in rats of both sexes, and an increased number of red blood cells with micronuclei in female rats. Overall, the progression of hemolytic anemia and morphological changes as a function of the number of days of exposure varied with gender and suggested a faster onset of hemolysis in female rats. The range of BE-related histopathological changes noted in both sexes was comparable; however, while these lesions were observed in female rats following a single dose, similar effects were first observed in males after 3 consecutive days of exposure to BE. Pathological changes involved disseminated thrombosis in the lungs, nasal submucosa, eyes, liver, heart, bones and teeth, with evidence of infarction in the heart, eyes, teeth and bones. Hemoglobinuric nephrosis and splenic extramedullary hematopoiesis were also noted. An apparent correlation between the severity of hemolytic anemia and subsequent disseminated thrombosis in BE-treated rats is proposed. Thrombosis may be related to intravascular hemolysis, which could be triggered by procoagulant release and/or alterations in erythrocyte morphology, as well as increased rigidity.     

2-Butoxyethanol female-rat model of hemolysis and disseminated thrombosis: X-ray characterization of osteonecrosis and growth-plate suppression

We recently proposed a chemically induced rat model for human hemolytic disorders associated with thrombosis. The objective of the present investigation was to apply a noninvasive, high-magnification X-ray analysis, the Faxitron radiography system, to characterize the protracted bone damage associated with this 2-butoxyethanol model and to validate it by histopathology. Groups of female Fischer 344 rats were given 0, 250, or 300 mg of 2-butoxyethanol/kg body weight daily for 4 consecutive days. Groups were then sacrificed 2 hours or 26 days after the final treatment. The treated animals displayed a darkened purple-red discoloration on the distal tail. Histopathological evaluation, including phosphotungstic acid-hematoxylin staining of animals sacrificed 2 hours after the final treatment, revealed disseminated thrombosis and infarction in multiple organs, including bones. The Faxitron MX-20 specimen radiography system was used to image selected bones of rats sacrificed 26 days posttreatment. Premature thinning of the growth plate occurred in the calcaneus, lumbar and coccygeal vertebrae, femur, and ilium of the treated animals. Areas of decreased radiographic densities were seen in the diaphysis of the femur of all treated animals. The bones were then examined histologically and showed a range of changes, including loss or damage to growth plates and necrosis of cortical bone. No thrombi were seen in the animals sacrificed at 30 days, but bone and growth plate changes consistent with prior ischemia were noted. The Faxitron proved to be an excellent noninvasive tool that can be used in future studies with this animal model to examine treatment modalities for the chronic effects of human thrombotic disorders.     

Ocular expression of vascular cell adhesion molecule (VCAM-1) in 2-butoxyethanol-induced hemolysis and thrombosis in female rats.

We demonstrated previously that exposure of rats to 2-butoxyethanol (BE) was associated with morphological changes in red blood cells, hemolytic anemia, and disseminated thrombosis and infarction in different organs including the eyes. In order to elucidate the mechanism of thrombosis formation, we examined in this study the histology and immunohistochemical expression of vascular cell adhesion molecule-1 (VCAM-1), endothelial intercellular adhesion molecule-1 (ICAM-1), and P-selectin in the eyes of the female F344 rat exposed to 2, 3, or 4 daily doses of BE/250 mg/kg body weight. In this BE hemolysis and thrombosis model, positive VCAM-1 expression occurred only in eyes of rats exposed to 3 and 4 doses and was localized in the iris (epithelium lining the posterior surface, anterior mesenchymal epithelium), ciliary processes (lining epithelium, stromal cells), and retina (hypertrophic retinal pigment epithelium). Only weak immunolabeling was seen in eyes exposed to 2 doses. The appearance of VCAM-1 immunostaining correlated with the development of thrombosis located in the same structures. No change in ICAM-1 or P-selectin expression was seen. This immunolabeling distribution suggests that VCAM-1 functions in the pathogenesis of BE-related thrombosis by promoting adhesion of erythrocytes to the endothelium.     

Ultrastructural studies of the hepatocytes after chronic exposure to low levels of halothane.

Adult rats were exposed to 10 ppm or 500 ppm halothane 8 hr/day and 5 days/wk for 8 wk or 4 wk, respectively. In the liver from animals which were exposed to 10 ppm of halothane, the rough endoplasmic reticulum in some hepatocytes accumulated a floccular, electron-dense material which gave the hepatocytes a dense and dark appearance. Increase in the matrical density and C-shaped transformation were observed in the mitochondria of some hepatocytes. In addition to these findings, areas of focal cytoplasmic degradation, dilatation of the bile canaliculi, peribiliary accumulation of lysosomes, and extensive dilatation of the smooth endoplasmic reticulum to form large cytoplasmic vacuoles were also observed in the hepatocytes of animals which had been exposed to 500 ppm halothane. Toxic potential of halothane upon chronic exposure is suggested.     

Glomerular thrombosis and cortical infarction in cyclosporin-treated rabbits with acute serum sickness.

Rabbits given acute serum sickness (ASS) and treated with cyclosporin A (CyA) developed glomerular capillary thrombosis and cortical infarction, lesions not seen in unmodified ASS. Thirty-three NZW rabbits received a single intravenous injection of 250 mg/kg bovine serum albumen (BSA) with or without endotoxin (5 micrograms/kg) on day 0. Groups of rabbits were given intramuscular CyA as follows: 15 mg/kg from day -2 to +8, or 25 mg/kg/day from day -20 to +3 or day 0 to 5. Signs of this renal injury were haematuria, transient proteinuria, glycosuria and oliguria and they occurred during the rapid phase of antigen elimination when immune complexes were being formed. Seventeen of the 33 rabbits developed glomerular capillary thrombi and 11 of 17 also had glomerular and tubular infarction. Electron microscopic examination showed that these lesions were associated with severe endothelial injury and platelet-fibrin-leucocyte thrombi. These changes were more severe in the groups given 25 mg/kg. The lesions were not seen in untreated rabbits and ASS, nor in normal rabbits given equivalent doses of CyA alone. A strikingly similar renal lesion has been seen in patients receiving CyA following bone marrow transplantation, and also in the haemolytic uraemic syndrome. The model we describe may be valuable for the study of the mechanisms of endothelial injury and thrombosis in the kidney.     

Changes in collagen metabolism and proteinolysis after repeated inhalation exposure to ozone

To study the changes in collagen metabolism that occur in the pathogenesis of pulmonary fibrosis, female rats were exposed to 0, 0.57, and 1.1 ppm ozone for 19 hr/day for 11 days and sacrificed 12 or 60 days after initiation of exposure. The lungs of rats sacrificed at 12 days after initiation of exposure to 1.1 ppm had interstitial pneumonia characterized by a mixed inflammatory cell infiltrate, type II cell hyperplasia, and fibroplasia, a proliferation of the collagen-producing cells; increased cathepsin D and macrophage elastase activity, indicating macrophage-induced proteinolysis; a reduced percentage of the increased collagen production that was ultrafilterable, indicating a decreased rate of intracellular degradation of newly produced collagen prior to its secretion; and increased lavage fluid hydroxyproline, indicating turnover of extracellular collagenous matrix. Reduced intracellular collagen degradation correlated directly with both increased net collagen production and fibroplasia in rats exposed to 1.1 ppm ozone for 11 days. These changes preceded an increased total lung collagen and the development of modest fibroplasia and fibrosis in the alveolar duct regions by 60 days after the 1.1 ppm ozone exposure was initiated.     

Hepatic effects in beagle dogs administered atorvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, for 2 years.

The chronic toxicity of atorvastatin (AT), an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, was evaluated in beagle dogs. Dogs were treated with 0, 10, 40, or 120 mg/kg of AT daily. Treatment lengths were 52 wk, 52 wk followed by 12 wk without drug, or 104 wk. Decreases in cholesterol levels were dose related and stable throughout the treatment period. Increases in alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase were transient and dose related in severity at > or = 40 mg/kg. Two dogs administered 120 mg/kg of AT daily were sacrificed moribund during the first 9 wk of treatment. Hepatic lesions were reversible with or without continued treatment and dose related in severity and distribution. Hepatic microgranulomas and hepatocellular degeneration were seen at the 120-mg/kg dose in dogs sacrificed before 53 wk. Before 53 wk, hepatocellular lipofuscin deposits were increased in dogs given > or = 40 mg/kg of AT daily but were similar to controls after 12 wk without drug and after 104 wk of continuous treatment. Bile stasis occurred in dogs given > or = 40 mg/kg of AT daily at all time points but was less severe after reversal and at week 104 compared with week 52.     

Long-lasting effects of chronic ozone exposure on rat nasal epithelium

Ozone, the principal oxidant pollutant in photochemical smog, causes airway epithelial injury in the upper and lower respiratory tract of laboratory animals. We have recently reported that long-term inhalation exposure to ozone causes mucous-cell metaplasia (MCM) in the surface epithelium lining the nasal airways of F344 rats. The principal objective of the present study was to determine the persistence of ozone-induced MCM in the nasal epithelium after the end of a chronic exposure. Male F344/N rats were exposed to 0, 0.25, or 0.5 ppm ozone, for 8 h/d, 7 d/wk for 13 wk. Animals were killed 8 h, 4 wk, or 13 wk after the end of the chronic exposure. Ozone-related alterations in the nasal epithelium were qualitatively and quantitatively characterized through histochemistry, image analysis, and morphometric techniques. Some rats were exposed for an additional 8 h to 0.5 ppm ozone at 13 wk after the end of the chronic exposure to determine whether previous ozone exposure results in persistent changes in the sensitivity of nasal epithelium to acute injury. At the end of the chronic exposure, hyperplasia was present in the nasal epithelium of rats exposed to 0.25 and 0.5 ppm ozone. By 13 wk postexposure, this proliferative alteration was still evident only in the rats exposed to 0.5 ppm ozone. Ozone-induced MCM with associated intraepithelial mucosubstances was evident only in the nasal tissues of rats exposed to 0.5 ppm ozone. Though attenuated, these alterations in the nasal mucous apparatus were still detectable at 13 wk after the end of the exposure. At this same time after the chronic exposure, an acute (8 h) exposure to 0.5 ppm ozone induced an additional increase of mucosubstances in the nasal epithelium of rats previously exposed to 0.5 ppm ozone, but not in rats chronically exposed to 0 or 2.5 ppm ozone. The persistent nature of the ozone-induced MCM in rats documented in this report suggests that ozone exposure may have the potential to induce similar long-lasting alterations in the airways of humans.     

Ureteral blockade sensitizes to the generalized Shwartzman reaction.

Renal cortical necrosis (RCN) has been reported in the normal kidney of patients with a contralateral ureteral occlusion (UO). So far, studies have examined the mechanisms protecting the affected kidney from glomerular thrombosis and cortical necrosis; but to the authors' knowledge, none has ever investigated the potential role of UO on the occurrence of the associated disseminated intravascular coagulation (DIC) episode leading to RCN. Female rats with a ligature of the right or left ureter were given injections, at different times after surgery, of 400 micrograms Salmonella typhosa 0901 endotoxin. Other experimental groups included normal and sham-operation rats and animals with a unilateral nephrectomy or with one kidney rendered ischemic by complete ligature of the renal vessels and of the ureter. All the animals were sacrificed 4 hours after endotoxin, and kidney sections stained with PTAH were examined for the presence of fibrin thrombi. Glomerular thrombosis was never observed in any hydronephrotic kidney, but occurred with a low incidence (16%) in the contralateral organ in the group given endotoxin the second day after UO. The incidence and severity of glomerular capillary thrombosis gradually increased in the normal kidney as the delay between surgery and endotoxin was prolonged; the incidences (P less than 0.01) were 45% and 83%, respectively, after 6 and 10 days. Endotoxin failed totally to initiate the lesion 1 day after UO as well as in normal, sham-operation and unilaterally nephrectomized rats, and in animals with combined UO and ligature of the renal circulation. We conclude that the perfused hydronephrotic kidney liberates a factor(s) that sensitizes to DIC and glomerular thrombosis, typical of the generalized Shwartzman reaction.     

Bronchial and bronchiolar fibrosis in rats exposed to 2,3-pentanedione vapors: implications for bronchiolitis obliterans in humans

2,3-Pentanedione (PD) is a component of artificial butter flavorings. The use of PD is increasing since diacetyl, a major butter flavorant, was associated with bronchiolitis obliterans (BO) in workers and has been removed from many products. Because the toxicity of inhaled PD is unknown, these studies were conducted to characterize the toxicity of inhaled PD across a range of concentrations in rodents. Male and female Wistar-Han rats and B6C3F1 mice were exposed to 0, 50, 100, or 200 ppm PD 6 h/d, 5 d/wk for up to 2 wk. Bronchoalveolar lavage fluid (BALF) was collected after 1, 3, 5, and 10 exposures, and histopathology was evaluated after 12 exposures. MCP-1, MCP-3, CRP, FGF-9, fibrinogen, and OSM were increased 2- to 9-fold in BALF of rats exposed for 5 and 10 days to 200 ppm. In mice, only fibrinogen was increased after 5 exposures to 200 ppm. The epithelium lining the respiratory tract was the site of toxicity in all mice and rats exposed to 200 ppm. Significantly, PD also caused both intraluminal and intramural fibrotic airway lesions in rats. The histopathological and biological changes observed in rats raise concerns that PD inhalation may cause BO in exposed humans.     

Liver tumor promoting effects of fenbendazole in rats.

In order to examine whether fenbendazole has tumor-promoting activity, a total of 70 male Fischer 344 rats were initiated with a single intraperitoneal injection of 100 mg/kg of diethylnitrosamine (DEN) or were given the saline vehicle alone; beginning 1 wk later, rats were given a diet containing 3,600; 1,800; 600; 200; 70; or 0 ppm of fenbendazole for 8 wk. Subgroups of 5 rats each from the DEN+ 1,800; DEN+0; 1,800; and 0 ppm groups were euthanatized after 1 wk of fenbendazole treatment, and the remaining animals were euthanatized at 8 wk. After 1 wk, relative liver weights (ratios to body weights) were significantly increased in the DEN+ 1,800 and 1,800 ppm groups, and based on light microscopy, periportal hepatocellular hypertrophy was evident in these groups. After 8 wk, relative liver weights were significantly increased in the groups given > or =600 ppm with or without DEN initiation. Periportal hepatocellular hypertrophy, characterized by a marked increase in smooth endoplasmic reticulum, was observed in the groups given > or =600 ppm with or without DEN initiation. Induction of cytochrome P-450 (CYP) 1A2, 2B1, or 4A1 was noted in the fenbendazole-treated groups with or without DEN initiation; that associated with CYP 1A2 was most marked. Positive immunostaining for anti-CYP 1A1/2 or CYP 2B1/2 was observed diffusely in the livers of animals in the DEN+1,800 and DEN+3,600 ppm groups. The numbers and areas of connexin 32 (Cx32)-positive spots per square centimeter in centrilobular hepatocytes were significantly decreased in an almost dose-dependent manner with fenbendazole treatment after DEN initiation. In situ hybridization for Cx32 mRNA revealed a remarkable decrease in its expression in the centrilobular hepatocytes in the DEN+70 ppm group. The numbers of glutathione S-transferase placental-form positive single cells (plus mini foci) were significantly increased in the DEN+ 1,800 and DEN+3,600 ppm groups. Since those agents that induce CYP 2B1/2 isozymes and reduce Cx32 in centrilobular hepatocytes have been suggested to be liver tumor promoters, the present results indicate that fenbendazole may be a liver tumor promoter.     

Vascular intimal carcinomatosis: An autopsy case of unusual form of pulmonary metastasis of transitional cell carcinoma

A 44-year-old woman with an unusual form of pulmonary metastasis is described. She presented with pulmonary thrombosis and clinical signs of disseminated intravascular coagulation (DIC) and died of cerebral hemorrhage. The autopsy study revealed transitional cell carcinoma of the left renal peivils with pulmonary thrombosis In the large arteries. The intima of the vessels were intact on gross inspection except where the thrombi adhered to. The thrombi contained no tumor cells. However, microscopic examination identffied that the metastatic carcinoma diffusely replaced the endothelium and proliferated on to the intimal surface without invasion of the wall and metastatic nodules In the parenchyma. Other examined organs had neither primary nor metastatic tumors, except for microscopic metastasis to the inferior vena cava. To date, this pattern of metastasis has not been noted In previous literature. This condition was deslgnated as being vascular intimal carcinomatosis because of its characteristic manner of tumor proliferation on vascular intima.     

Effects of glucocorticoid on BMD, micro-architecture and biomechanics of cancellous and cortical bone mass in OVX rabbits

The incidence of osteoporosis continues to increase with progressively aging populations. The purpose of this study was to detect the effects of glucocorticoid (GC) treatment on bone mineral density (BMD), biomechanical strength and micro-architecture in cancellous and cortical bone in ovariectomized (OVX) rabbits. Twenty adult female New Zealand white rabbits were randomly divided into three groups. The OVX-GC group (n=8) received a bilateral ovariectomy first and then daily GC treatment (methylprednisolone sodium succinate, 1mg/kg/day) for 4 weeks beginning 2 weeks after ovariectomy treatment. The OVX group (n=4) received a bilateral ovariectomy without GC treatment. The sham group (n=8) only received the sham operation. BMD was determined prior to and 6 weeks after the operation in the spine. Six weeks after the operation, the animals were sacrificed, and cancellous bone specimens were harvested from the femoral condyle and lumbar vertebrae. Cortical bone specimens were obtained from the femoral midshaft. The femoral specimens were scanned for apparent BMD. All specimens were tested mechanically and analyzed by microcompute tomography (micro-CT). In cancellous bone, GC treatment resulted in significant decreases in BMD, bone biomechanical strength and micro-architecture parameters in lumbar vertebrae. Similar trends in BMD and micro-architectural changes were also observed in the femoral condyle in the OVX-GC group compared with the sham group. However, there was no significant decline in any parameter in either lumbar vertebrae or femoral condyle in the OVX group. Similarly, no significant difference was found in any parameter in cortical bone among the three groups. Thus, the 4-week GC treatment in OVX rabbits could result in a significant bone loss in cancellous bone but not in cortical bone. This model is comparable to the osteoporosis-related changes in humans. OVX alone was not sufficient to induce osteoporosis.     

Interaction of Angiotensin with Disseminated Intravascular Coagulation: A Possible Mechanism in the Genesis of Acute Renal Failure

Because of the importance of the renin-angiotensin system in renal homeostatic mechanisms, the effect of angiotensin administration upon disseminated intravascular coagulation has been studied in rabbits. An infusion of angiotensin II (0.1 μg/kg/min for 2 hours) produced neither histologic abnormalities in the kidneys nor an elevation of creatinine. After an infusion of thrombin (2.0 units/kg/min for 2 hours) only 3 of 10 rabbits, when sacrified 24 hours later, showed histologic lesions comprised of occasional fibrin thrombi and foci of tubular necrosis. Creatinine levels did not rise. In contrast, the combination of angiotensin and thrombin resulted in renal lesions in 12 of 14 animals. Four had frank cortical necrosis, while combinations of tubular necrosis, glomerular thrombosis and segmental glomerular infarction occurred in the others, together with elevated creatinine levels. Blockade of α-adrenoreceptors with phenoxybenzamine in 12 animals did not prevent either these histologic changes or creatinine elevation, showing that the effect of angiotensin was independent of α-adrenoreceptor stimulation. The synergistic interaction between angiotensin and disseminated intravascular coagulation was not explained by differences in the consumption of plasma fibrinogen but apparently was due to localization of fibrin thrombi within glomerular capillaries by the vasomotor actions of angiotensin, as has previously been shown to occur with α-adrenoreceptor simulation. Such a mechanism might contribute to renal glomerular deposition of fibrin in acute ischemic renal failure.     

Dose-dependent renal tubular toxicity of harman and norharman in male F344 rats.

The renal toxicity of harman and norharman, administered for 2 or 4 weeks at dietary levels of 1,000, 500, or 0 parts per million (ppm), was investigated in 6-week-old male F344/DuCrj rats. Although rats fed 1,000 ppm harman or norharman, but not the 500 ppm level, demonstrated marked body weight retardation from 1 week to termination, no mortalities occurred. Marked elevation of water consumption was evident in rats given harman or norharman at 1,000 ppm, but not at 500 ppm, together with large increases in urine of low specific gravity. Urinary lysosomal enzymes (N-acetyl-beta-D-glucosaminidase, NAG, and lactate dehydrogenase, LDH) and sugar levels were increased, and the brush border enzymes (gamma-glutamyl transpeptidase, GGT, and alkaline phosphatase, ALP) decreased. Furthermore, serum biochemistry revealed clear elevation of parameters indicating renal toxicity in these rats. Histopathologically, rats fed 1,000 ppm harman or norharman, but not 500 ppm, demonstrated focal toxic renal degenerative/necrotic and regenerative lesions in proximal, distal, and collecting tubules. These changes were associated with a clearly increased labeling index (LI) of the nuclei of renal tubular epithelial cells on immunohistochemical staining for 5-bromo-2'-deoxyuridine (BrdU). Chemical specific crystal formation within tubular lumina was evident in rats fed 1,000 ppm, but not 500 ppm, this being considered the cause of the renal tubular lesions. It was concluded that harman and norharman exert renal toxicity at the dietary level of 1,000 ppm, but not 500 ppm, in male F344 rats.     

Enhancing effects of oltipraz on the development of spontaneous hepatic lesions in LEC rats

Oltipraz, developed as an antischistosomal agent, protects against the hepatotoxicity of many xenobiotics and is known to be an effective inhibitor of experimental carcinogenesis in rodents. In the present study, we investigated its effects on the development of lesions in LEC rats, established as a mutant strain characterized by a hereditary predisposition for hepatic damage with severe jaundice. A total of 35 male 6-week-old LEC rats were divided into 2 groups, one administered diet supplemented with oltipraz at a dose of 400 ppm, and the other fed basal diet alone. Animals in each group were sequentially sacrificed at 10, 15, and 25 weeks after commencement of the oltipraz administration. Eight animals died or became moribund in the oltipraz group during weeks 10 and 11 of the treatment, whereas only one rat in the nontreatment group died after 16 weeks. All dead or moribund animals showed severe or moderate jaundice. The treatment caused a decrease in body weight gain from 9 to 13 weeks, and an increase in relative liver weight at each sacrifice point. Serum biochemical assays performed at week 25 revealed elevated levels of serum AST, ALT, LDH, ALP, gamma-GTP, and Cu in the treated-animals. The glutathione level in the livers of oltipraz-treated animals was significantly higher than that in the control rats. Histopathologically, enlarged hepatocytes with large nuclei, focal necrosis, pigment granule-laden Kupffer cells and hypertrophy of renal tubule cells were observed in both groups, but the severity of these changes was greater in the oltipraz group. Our results thus indicate that spontaneous hepatic damage in LEC rats is enhanced by oltipraz, by a mechanism that remains to be elucidated.     

Induction of sister chromatid exchange in spleen and bone marrow cells of rats exposed by inhalation to different dose rates of ethylene oxide

We investigated the effects of dose rate on the frequency of sister chromatid exchange (SCE) in bone marrow and spleen cells of rats exposed to ethylene oxide (EtO). Four groups (18/group) of male Fischer 344 rats were exposed to EtO by inhalation. The exposures consisted of 100 ppm for 6 hr/day, 300 ppm for 2 hr/day, 600 ppm for 1 hr/day, and clean air control. All EtO treated rats were given a total exposure dose of 600 ppm-hr daily, 5 days/week for 3, 6, or 9 months. Six rats per group were sacrificed at each time point, and SCEs were measured in cultured spleen and bone marrow cells. A statistically significant increase was found in SCEs in both bone marrow and spleen cells for all treated groups and at each time point when compared to the control, except at the 3-month exposure for the middle and high dose-rate groups in bone marrow cells. In the spleen, the increases in SCEs were similar among the three experimental groups. In bone marrow, the lowest dose rate (100 ppm) resulted in higher SCE frequencies than the medium and high dose-rate group after 3 and 6 month exposures. The overall frequencies of SCEs in the spleen cells were higher than in the bone marrow cells. The increase in SCE frequencies and decrease in the replicative index in spleen cells were also dependent on the duration of exposure. These results indicate that (1) EtO, by inhalation, can cause SCEs both in spleen and bone marrow cells of Fischer 344 rats, (2) spleen cells are more sensitive to EtO than bone marrow cells, and (3) in bone marrow cells the lowest dose-rate (longest) exposure causes more SCEs than the highest dose-rate (shortest) exposures. © 1993 Wiley-Liss, Inc.     

Multisite carcinogenicity and respiratory toxicity of inhaled 1-bromopropane in rats and mice

Two-year 1-bromopropane (1-BP) inhalation studies were conducted because of the potential for widespread exposure, the lack of chronic toxicity and carcinogenicity data, and the known carcinogenicity of structurally related compounds. Male and female F344/N rats and B6C3F1/N mice were exposed by inhalation to 0, 62.5 (mice only), 125, 250, or 500 (rats only) ppm 1-BP for 6 hr/day, 5 days/week for 105 weeks. Exposure of male and female rats to 1-BP resulted in significantly increased incidences of adenomas of the large intestine and skin neoplasms. In male rats, the incidence of malignant mesothelioma of the epididymis was statistically significantly increased at 500 ppm, but the biological significance of this common lesion is unclear. Incidences of pancreatic islet adenoma in male rats were significantly increased at all concentrations relative to concurrent controls but were within the historical control range for inhalation studies. There was no evidence of carcinogenic activity of 1-BP in male B6C3F1 mice; however, significantly increased incidences of alveolar/bronchiolar neoplasms of the lung were present in female mice. Exposure to 1-BP also resulted in increased incidences of nonneoplastic lesions in the nose of rats and mice, the larynx of rats and male mice, the trachea of female rats and male and female mice, and the lungs of mice. Inflammatory lesions with Splendore Hoeppli (S-H) material were present primarily in the nose and skin of exposed male and female rats, indicating that 1-BP caused immunosuppression.     

内源骨髓间充质干细胞在心肌梗死后的迁移、归巢与分化

背景：目前的大多数研究主要集中在移植外源干细胞来源的心肌细胞对受损心肌进行修复与再生,而有关内源干细胞迁移、归巢及分化的研究比较少。 目的：观察内源骨髓间充质干细胞在心肌梗死后迁移、归巢以及分化情况。 方法：成年雌性C57BL/6小鼠随机分为2组：心肌梗死组(n=4)小鼠建立骨髓重建模型,于骨髓重建4周后行冠状动脉左前降支结扎术建立急性心肌梗死模型,1周后处死;对照组(n=3)小鼠进行单纯骨髓重建,于骨髓重建4周后处死。取心脏组织,采用免疫荧光染色检测心肌特异性蛋白Troponin Ⅰ的表达,观察心肌梗死后表达绿色荧光蛋白的骨髓间充质干细胞在心肌组织中的分布、分化情况。 结果与结论：骨髓重建小鼠心肌梗死组与对照组均可见到发绿色荧光的骨髓间充质干细胞,心肌梗死组骨髓间充质干细胞数量比对照组明显增多。两组切片均可见部分骨髓间充质干细胞呈GFP、Troponin Ⅰ和PI三阳性,心肌梗死组三阳性的细胞比对照组明显增多,表明心肌梗死后内源骨髓间充质干细胞能迁移、归巢到受损的心肌组织并获得心肌分化表型。