Dinucleotide repeat polymorphism at the D11S527 locus.
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Base Sequence↗
Biomedical subjects
M B Thompson
Publications and source records attributed to M B Thompson.
Experimental studies of the hematologic and immune system toxicity of nucleoside derivatives used against HIV infection.
Adverse effects stemming from the therapeutic use of dideoxynucleoside derivatives continue to occur in patients with AIDS or AIDS-related complex. For example, the continued use of 3'-azido-3'-deoxythymidine (AZT) and 2',3'-didoxycytidine (ddC), both of which confer clinical benefits in AIDS patients, may be complicated by anemia, neutropenia and thrombocytopenia and ddC also causes peripheral neuropathy. Subsequently, the National Toxicology Program (NTP) has undertaken efforts to define and characterize the toxicities associated with currently employed and potential AIDS therapeutics in experimental animals, with particular emphasis on the hematopoietic and immune systems. In addition to AZT and ddC, 2',3'-dideoxyadenosine (ddA), 2',3'-dideoxyinosine (ddI) and 2',3'-didehydrodideoxythymidine (d4T) have been examined. The present studies describe: (1) the development of a poorly regenerative macrocytic anemia in mice exposed to AZT or ddC. This anemia demonstrates a rapid and progressive time course of toxicity and reversibility after cessation of treatment; (2) the selective suppression of erythroid progenitor cells in mice exposed to d4T without concomitant effects on myeloid stem cells. Myelotoxicity appears to show metabolism-dependent strain-specificity and is more evident following in vitro exposure than in vivo exposure; and (3) the immunosuppressive effects following subchronic (30-day) exposure. Of the nucleoside derivatives studied, only ddA and ddI altered immune function and these changes were confined to suppression of antibody responses. It can be concluded that the overall similarities in the hematopoietic and immune system effects between rodents and humans indicate that such animal toxicology studies provide important information relevant to the toxicity of these drugs.
Animals↗
Toxicity studies of acetone administered in the drinking water of rodents.
Two- and thirteen-week toxicity studies were conducted using male and female F344/N rats and B6C3F1 mice. Animals were exposed to the following concentrations of acetone in their drinking water: two-week studies 0; 5000; 10,000; 20,000; 50,000; or 100,000 ppm acetone. Thirteen-week rat and female mouse studies 0; 2500; 5000; 10,000; 20,000; or 50,000 ppm acetone. Thirteen week male mice were exposed to 0; 1250; 2500; 5000; 10,000; or 20,000 ppm acetone. Depressed body weight gain was restricted to the 50,000 and 100,000 ppm exposure groups. Male and female mice exposed respectively to 20,000 or 50,000 ppm acetone for 2 weeks developed hepatocellular hypertrophy. This change was not apparent after 13 weeks of exposure although relative and absolute liver weight was increased in high dose female mice. Bone marrow hypoplasia was observed in 5/5 high dose (100,000 ppm) male rats during the 2-week studies. Treatment of male rats for 13 weeks resulted in a variety of mild and subtle hematological changes that often occurred at relatively low levels of exposure (5000 ppm) and resembled those seen during the clinical condition of megaloblastic anemia. Changes characteristic of hypogonadism (depressed sperm motility and cauda epididymal and epididymal weight and elevated incidence of abnormal sperm) were observed in male rats receiving 50,000 ppm acetone for 13 weeks. The incidence and severity of a kidney lesion that is morphologically similar to the spontaneously occurring nephropathy among aging F-344 rats were increased at 20,000 and 50,000 ppm acetone, respectively, in 13-week male rats. In summary, the effects of acetone were either subtle in nature or occurred during very high levels of exposure confirming acetone's low level of toxicity. The daily levels of acetone exposure were often several-fold greater than possibly encountered by humans during the accidental consumption of contaminated groundwater (250 ppm; 5 mg/day) and frequently exceeded maximum levels reported following acute toxic exposures (2,500 mg/kg).
Acetone↗
Hematologic toxicity of AZT and ddC administered as single agents and in combination to rats and mice.
Toxicity studies of 3'-azido-2',3'-dideoxythymidine (AZT) and 2',3'-dideoxycytidine (ddC) were conducted in F344/N rats and B6C3F1 mice. The drugs were administered as single agents and in combination. In all studies, animals were treated by oral gavage twice a day, 7 days a week. In studies of the individual compounds, each was administered for 13 weeks at the following concentrations: AZT in rats, 0, 125, 250, 500, 1000 mg/kg and in mice, 0, 25, 50, 100, 400, 1000 mg/kg; ddC in rats and mice, 0, 250, 1000, 2000 mg/kg. Additional male rats and female mice that were treated with 0, 250, 1000, or 2000 mg/kg ddC and male and female mice treated with 0, 50, 400, 1000 mg/kg AZT were maintained for 30 days after treatment was stopped (at 94 days) to evaluate the reversibility of toxic effects. Hematologic variables were measured on Days 5, 23, and 94 (last day of dosing), and on Day 123 (after a 30-day period without treatment). AZT and ddC produced dose-related, poorly regenerative, macrocytic anemias as evidenced by decreases in erythrocyte counts, hematocrits, and hemoglobin concentrations and increases in mean corpuscular hemoglobin and mean corpuscular volume. Bone marrow samples in rats treated with AZT were hyperplastic whereas those in mice treated with AZT and rats and mice treated with ddC were hypoplastic. The hematologic toxicity of AZT was more severe than that of ddC. Generally, toxic effects of either chemical were greater in mice than in rats and more pronounced in female than in male animals. After 30 days without dosing, hematologic effects either resolved or dramatically improved. In studies in which ddC and AZT were administered in combination for 4 weeks at concentrations of 0/0, 0/500, 500/0, 10/500, 100/500, 500/500, and 500/1000 mg/kg ddC/AZT, there was macrocytic anemia in animals in the lower doses and marked microcytic anemia in surviving male mice in higher dose groups. Most female mice died in the 500/500 and 500/1000 mg/kg ddC/AZT dose groups. At lower concentrations (100/500, 500/1000 mg/kg ddC/AZT), effects of the two drugs were similar to those in the single drug studies. At higher concentrations (500/500 and 500/1000 mg/kg ddC/AZT), the combination treatment produced enhanced hematopoietic toxicity. These studies demonstrated the early and progressive time course of toxicity of AZT and ddC, species differences in sensitivities and responses, and reversibility of effects after termination of treatment. Based on these findings, a chronic toxicity study is being conducted with AZT in mice.
Animals↗
Correlation of changes in serum analytes and hepatic histopathology in rats exposed to carbon tetrachloride.
Clinical pathology data can significantly contribute to the characterization of a disease process if suitable time points for sample collection are chosen and combined with the measurement of biochemical analytes that are sensitive and specific for damage to a potential target organ. Using a well-defined model for hepatotoxicity, we correlated histopathological lesions in the liver with changes in selected serum analytes. Groups of Fischer-344 rats were treated with carbon tetrachloride (280 mg/kg in corn oil) for 1, 2, 4, 6, 8 or 10 days. Subgroups were allowed to recover for 1, 5 or 8 days, at which time blood and liver specimens were collected. Histologically, necrosis was detected in livers from rats treated for 1 and 2 days and allowed to recover for 1 day. This was followed by generalized fatty change in animals treated for longer periods. The maximum severity of fatty change occurred 7-12 days (total experimental time). A sharp rise and fall (48 h) in cytosolic enzyme activities were seen in serum. This preceded gradual increases in all analytes measured which eventually peaked at 9-11 days (total experimental time). The pattern seen in biochemical analytes paralleled the development of marked fatty change. We discuss relationships between the histologic and biochemical findings and conclude that appropriate clinical biochemistry measurements in a toxicology experiment can provide valuable mechanistic information.
Alanine Transaminase↗
Promotion of hepatocellular foci in female rats by chenodeoxycholic acid.
Chenodeoxycholic acid (CDC), a dihydroxylated primary bile acid, was evaluated for promotional activity in the liver of rats using a two-stage initiation-promotion model. CDC is a primary bile acid that can attain high concentrations in serum and liver during induced or naturally occurring hepatocellular disorders. Female Sprague-Dawley rats were injected once (i.p.) with diethylnitrosamine (DEN, 150 mg/kg) or sterile physiologic saline (SAL, 0.85% NaCl). Two weeks later, rats in each group were placed into one of two subgroups and fed either NIH-31 mash (Control) or NIH-31 mash containing 0.5% CDC for a 10 week period. At the end of the feeding period, blood and liver samples were collected for determination of bile acid profiles and quantitation of hepatocellular foci respectively. Serum samples were analyzed for concentrations of individual bile acids using a HPLC method that utilizes a post-column enzymatic reaction and fluorescence detection. Liver slices from the left hepatic lobe were stained for foci positive for placental glutathione S-transferase. In serum, significant increases occurred in concentrations of all forms of CDC and were accompanied by mild, insignificant increases in lithocholic acid. Decreased serum concentrations occurred in all forms of cholic and deoxycholic acids. Analysis of liver sections revealed that rats treated with DEN-CDC had significant increases in numbers and volume of foci compared to those treated with DEN-Control. For rats in groups DEN-CDC and DEN-Control, the numbers of foci per square centimeter were 32 and 12; per cubic centimeter, 2221 and 937; and the per cent volume of foci, 1.487 and 0.385 respectively. In this study, CDC was a promoter of hepatocellular foci. Because concentrations of CDC in liver and serum increase in a variety of hepatobiliary disorders, the possibility that increases in endogenous concentrations can enhance the formation of hepatocellular foci is being explored.
Animals↗
Inhalation toxicity studies of cobalt sulfate in F344/N rats and B6C3F1 mice.
Groups of 10 F344/N rats and B6C3F1 mice of each sex were exposed to cobalt sulfate heptahydrate aerosols of 0, 0.3, 1.0, 3.0, 10, or 30 mg/m3, 6 hr per day, 5 days per week, for 13 weeks. All rats and female mice and all but 2/10 male mice exposed at the top concentration survived to the end of the studies. Polycythemia was observed in exposed rats but not in mice. Sperm motility was decreased in mice exposed at 3 mg/m3 (the lowest concentration evaluated) and at higher concentrations, and increased numbers of abnormal sperm and decreased testis and epididymal weights occurred in mice exposed to 30 mg/m3. Cobalt content in the urine of rats increased with increasing atmospheric cobalt exposure. Primary histopathologic effects were limited to the respiratory tract. Lesions in rats and mice included degeneration of the olfactory epithelium, squamous metaplasia of the respiratory epithelium, and inflammation in the nose; inflammation, necrosis, squamous metaplasia, ulcers (rats), and inflammatory polyps (rats) of the larynx; metaplasia of the trachea (mice); and fibrosis, histiocytic infiltrates, bronchiolar epithelial regeneration, and epithelial hyperplasia in the alveoli of the lung. The most sensitive tissue was the larynx, with squamous metaplasia observed in rats and mice at the lowest exposure concentration of 0.3 mg/m3. Thus, a no-observed-adverse-effect level was not reached in these studies.
Administration, Inhalation↗
Comparative toxicity of arsine gas in B6C3F1 mice, Fischer 344 rats, and Syrian golden hamsters: system organ studies and comparison of clinical indices of exposure.
In order to examine possible species differences in response to arsine exposure, multiple inhalation studies consisting of acute (1-day), subacute (14- and 28-day), and subchronic (90-day) exposures to this agent were conducted using three different species of rodents. Evaluations of hematopoietic organs and alterations in the heme biosynthetic pathway were the focus of these studies. Species used were B6C3F1 mice (exposed 1, 14, or 90 days), Fischer 344 rats (exposed 14, 28, or 90 days), and Syrian Golden hamsters (exposed 28 days). All arsine exposures were at concentrations of 0.5, 2.5, or 5.0 ppm except for 90-day studies, in which concentrations were lowered to 0.025, 0.5, or 2.5 ppm. No changes in body weight gain were observed in either sex of mice or hamsters. The only decrease in body weight gain occurred in male rats exposed to 5.0 ppm arsine for 28 days. Significant exposure-related increases in relative spleen weights occurred in both sexes of mice and rats in the 0.5 (except 14-day female rats), 2.5, and 5.0 ppm exposure groups from all studies and in hamsters in the 2.5 and 5.0 ppm exposure groups. Generally, increases in relative liver weight occurred in fewer exposure groups and were of a lesser magnitude than increases in spleen weight. Other parameters affected included decreased packed cell volumes (mice, rats, and hamsters), hematology profiles (rats), and an increase in delta-aminolevulinic acid dehydratase activity in all species. Arsenic content was measured in livers of rats after 90 days of exposure. Concentrations increased in relation to atmospheric concentrations of arsine. Histopathologic changes included increased hemosiderosis and extramedullary hematopoiesis in spleen and intracanalicular bile stasis (mice only) in liver. Additionally, bone marrow hyperplasia was observed in rats. Effects on other organs were not observed, suggesting that the hematopoietic system is the primary target for arsine. In conclusion, we have determined that the effects of arsine exposure upon mice, rats, and hamsters are similar. Most importantly, even though no effects on the hematopoietic system were observed following a single exposure to 0.5 ppm arsine which is 10 times the Threshold Limit Value (TLV) set by the American Conference of Governmental Industrial Hygienists, repeated exposure to 0.025 ppm (one-half the TLV) caused a significant anemia in rats.
Administration, Inhalation↗
Evidence for oxidative damage to red blood cells in mice induced by arsine gas.
In animals and human beings exposed to arsine gas (AsH3) a severe and fulminant lysis of erythrocytes occurs. Little is known about the effects of subchronic exposure on the hematopoietic system or about the mechanism of hemolysis produced by arsine gas. To examine these, we exposed male and female mice to 0.000, 0.025, 0.500 and 2.500 ppm arsine gas for 6 h a day, 5 days a week during a 90-day period. After 5, 15, and 90 days of exposure, blood was collected and routine hematologic profiles were performed to document the effects of arsine gas on peripheral blood. A moderate hemolytic anemia, indicated by decreases in erythrocyte counts, hematocrits, hemoglobin concentrations and increases in mean corpuscular hemoglobins and mean corpuscular hemoglobin concentrations, was seen in blood samples collected after 5 days of exposure. In blood collected after 15 and 90 days of exposure, the anemia was less severe but a greater increase in mean corpuscular volumes and absolute reticulocyte counts revealed an active regenerative response. Higher concentrations of methemoglobin in animals in the 2.500 ppm exposure group (measured after 90 days of exposure) indicated that the rate of oxidation of heme (ferrous to ferric) increased due to exposure to arsine gas. Additionally, the presence of Heinz bodies in blood smears stained with brilliant cresyl blue and decreases in reduced glutathione concentrations in red blood cells exposed to arsine gas in vitro provide evidence that the mechanism of hemolysis involves depletion of intracellular reduced glutathione resulting in an oxidation of sulfhydryl groups in hemoglobin and possibly red cell membranes.
Air Pollutants, Occupational↗
Patterns of metabolism in embryonic reptiles.
VO2 of eggs of the turtle Emydura macquarii, the crocodilian Alligator mississipiensis, and the tuatara Sphenodon punctatus, were measured throughout incubation. E. macquarii and A. mississipiensis, species in which hatching synchrony may be important, show a decline in VO2 prior to hatching ('peaked' pattern). This is similar to the pattern shown by ratite birds, where the decline period may be variable and facilitates hatching synchrony. The same interpretation is used here for reptiles. Hatching synchrony seems unimportant in S. punctatus, no decline in VO2 is observed, and the pattern of VO2 is similar to that shown by most precocial birds. Developmental asynchrony in reptilian nests, e.g., E. macquarii, probably results from temperature differences within the nest. Turtles with nests that are unlikely to experience developmental asynchrony, show truncation of the 'peaked' pattern, similar to the usual avian precocial pattern, or even extreme truncation approaching that of altricial birds. A pattern of ontogenetic VO2 in snakes (which have precocious young) similar to that in birds with altricial young may indicate a basic developmental difference in snakes.
Alligators and Crocodiles↗
Toxic responses in F344 rats and B6C3F1 mice given roxarsone in their diets for up to 13 weeks.
Thirteen-week toxicity studies were conducted in groups of 10 F344 rats and B6C3F1 mice of each sex fed roxarsone at 0, 50, 100, 200, 400, or 800 ppm in the diet. Arsenic levels in blood, urine, kidneys, and liver of rats were measured in additional animals of each sex dosed with 100 or 400 ppm roxarsone. Compound-related mortality occurred in both sexes of rats at 800 ppm and mice at 800 and 400 ppm. Significant body weight gain depression occurred in both sexes of rats at 200, 400, and 800 ppm and mice at 800 ppm. Clinical signs of toxicity (trembling, ataxia, and pale skin) were seen primarily in rats and mice at 800 ppm. Lesions associated with roxarsone administration were noted only in the kidney of rats and were characterized by tubular necrosis and mineralization at the corticomedullary junction. Arsenic levels in urine, blood, liver, and kidneys increased over time and were directly proportional to the level of roxarsone in feed. These levels were greater than 6 times higher in rats than in mice and were about 2 time higher in males than in females. The no-observable-effect level for roxarsone toxicity was estimated at 100 ppm for rats and 200 ppm for mice. No hematology or clinical chemistry effects were found in rats or mice of either sex.
Animals↗
Thermal sensitivity of reptilian melatonin rhythms: "cold" tuatara vs. "warm" skink.
Daily rhythms in plasma melatonin levels were compared in two ecologically diverse reptilian species under natural environmental conditions in autumn. The nocturnal, cold temperature-adapted tuatara (Sphenodon punctatus) had a melatonin rhythm of much lower amplitude than did the diurnal desert-adapted sleepy lizard (Tiliqua rugosa). Experiments in controlled laboratory environments showed that, although both species are capable of attaining a comparable melatonin peak (approximately 750 pmol/l), the threshold temperature at which a significant daily rhythm occurs is approximately 15 degrees C in S. punctatus compared with approximately 25 degrees C in T. rugosa. This difference probably reflects the disparate thermoregulatory adaptations of the two species, S. punctatus favoring mean activity temperatures of 11.5 degrees C and T. rugosa, 32.5 degrees C. In ectotherms such as reptiles, therefore, species-typical thermoregulatory behavior may provide thermal cues that interact with photoperiod to provide the appropriate melatonin signal for the regulation of annual physiological cycles.
Animals↗
Bile acid profile in a dog with cholangiocarcinoma.
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Adenoma, Bile Duct↗
Magnetic resonance imaging of hepatic neoplasms in the rat.
Magnetic resonance imaging (MRI) at microscopic resolution was done on a live rat that had chemically induced hepatic neoplasms. Beginning at the anterior aspect of the liver, 16 contiguous transaxial slices (each 1.25 mm thick) were produced using three-dimensional Fourier transform sequences. The rat had been treated with diethylnitrosamine (200 mg/kg) at 70 days of age, and, subsequently, received periodic implants of 17a-ethynylestradiol for 60 weeks. Carr-Purcell-Meiboom-Gill (CPMG) sequences (repetition time = 2,000 and echo time = 20, 40, 60, 80 ms) were done to give quantitative measures of spin-spin relaxation times (T2). Pixel-by-pixel curve fitting from these multiple images yielded calculated T2 images. Histologic evaluation of three abnormal areas in the liver revealed solid and cystic hepatocellular adenomas. Although lesions were evident in early-echo images of the CPMG sequence, they were more apparent in the late-echo images. This was consistent with longer T2 relaxation times for the lesions. The voxels of dimensions (230 x 230 x 1,250 microns) permitted resolution of volume elements less than 0.07 mm3. This in turn permitted clear delineation of focal lesions less than 3 mm in diameter. The potential for MRI at microscopic resolution in toxicologic research is clearly demonstrated.
Animals↗
Three-dimensional MRI microscopy of the normal rat brain.
Magnetic resonance imaging techniques have been developed to enable imaging of the live rat brain with thin (1.2-mm) slices and microscopic pixels (115 X 115 microns). Signal-to-noise ratios high enough to realize the microscopic resolution are obtained with rf coils designed for the subject and through the use of three-dimensional Fourier spin warp imaging. The technique yields 16 contiguous slices. Correlation with fixed pathologic specimens enables unequivocal identification of gray and white matter structures in the brain of a live 200-g rat. Structures clearly visible in the MR images include Ammon's horn, the hypothalamus, corpus callosum and substantia nigra, as well as a number of brainstem nuclei.
Animals↗
Effect of age on the toxicity and metabolism of ethylene glycol monobutyl ether (2-butoxyethanol) in rats.
Heavy production as well as the diversity of 2-butoxyethanol (BE) uses, which include preparation of products intended for household uses, pose a high risk of human exposure to BE. The current studies were designed to investigate the acute toxicity of BE and to evaluate the effect of age on BE-induced toxicity in F344 male rats. Data presented in this report show that BE causes severe acute hemolytic anemia resulting in significant increases in the concentration of free plasma hemoglobin. Secondary to the hemolytic effects, BE also caused hemoglobinuria as well as histopathologic changes in the liver and kidney. These effects of BE were dose- and time-dependent. Further, both the hemolytic effects and the secondary effects of BE were age dependent with older rats being more sensitive than younger rats. The metabolic basis of the greater susceptibility of older rats to BE-induced toxicity was investigated by comparing BE metabolism in adult (9- to 13-week-old) and young (4- to 5-week-old) rats. These studies revealed that there was a significantly higher portion of the administered dose eliminated by young rats as CO2 as compared to that eliminated by older rats. Similarly, a significantly higher portion of the administered dose was excreted in the urine of young rats. HPLC analysis of the urinary metabolites of BE in adult and young rats showed that the ratio of butoxyacetic acid (BAA)/BE-glucuronide + BE - sulfate (previously thought to reflect an activation/detoxification index of BE; see text) was significantly higher in older rats. We currently believe that the increase in the activation/detoxification index in older rats is caused by decreased degradation of BAA to CO2 (as evident by the lower percentage of the dose excreted as CO2 by older rats) and by depressed urinary excretion of BAA (as evident from the lower percentage of the dose excreted in the urine of older rats.
Administration, Oral↗
Validation and application of a liquid-chromatographic/enzymatic assay for individual bile acids in the serum of rats.
A liquid-chromatographic technique with a post-column enzymatic reaction and fluorescence detection was validated for analysis of individual bile acids in the serum of rats. Extraction recoveries averaged 91.1% (SD 6.9%) for all bile acids. The assay was sensitive (minimum detection of 16.8 pmol per 100-microL injection), linear (r greater than 0.999 for concentrations ranging between 45 and 112,500 pmol per 100-microL injection), and reproducible (mean CVs for three different concentrations of standards and a serum pool ranged from 4.4% to 12.2%). In rats treated for three days with either neomycin, carbon tetrachloride, alpha-naphthylisothiocyanate, or total bile-duct ligation (five animals per group), total concentrations of bile acids were significantly increased (P less than 0.004). Concentrations of 16 of 17 individual bile acids differed significantly between groups (P less than 0.04). Examination of the relative concentrations (percent of total) of individual bile acids by canonical discriminant analysis placed each animal into the appropriate treatment or control group. Use of this technique in toxicological studies can help detect and identify specific types of disruptions in the enterohepatic circulation of bile acids.
1-Naphthylisothiocyanate↗
Three-dimensional magnetic resonance microscopy of the developing chick embryo.
Magnetic resonance imaging microscopy was performed on live chick embryos. A combination of high gradient strength (0.47 mT/cm), special purpose radiofrequency coils and 3-dimensional Fourier imaging was used to obtain images with effective thickness of 1.25 mm and pixel dimensions as small as 200 mu in the live chick embryo. The signal-to-noise ratio was sufficient to allow unequivocal identification of the individual chambers of the heart, spinal cord, ventricles in the brain, and vascular structures in the liver of a live 11-day embryo. Anatomical assignment was accomplished with the aid of correlated histologic sections. Because there are no external landmarks, the plane of imaging is frequently oblique, making the 3-dimensional acquisition particularly useful.
Animals↗