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Biomedical subjects

B A Fowler

Publications and source records attributed to B A Fowler.

At least 37 records · Page 2Linked to original sources
PubMed1992

Lead inhibits secretion of osteonectin/SPARC without significantly altering collagen or Hsp47 production in osteoblast-like ROS 17/2.8 cells.

In an effort to better understand the consequences of lead (Pb2+) on skeletal growth, the effects of Pb2+ were investigated using ROS 17/2.8 bone-like cells in vitro. These studies revealed that Pb2+ (4.5 x 10(-6) M -4.5 x 10(-7) M) has little or no effect on cell shape except when added immediately following seeding of the cells. However, proliferation of ROS cells was inhibited, in the absence of serum, at concentrations of 4.5 x 10(-6) M Pb2+. Protein production was generally increased, however, the major structural protein of bone, type I collagen, production was only slightly altered. Following treatment of ROS cells with Pb2+, intracellular levels of the calcium-binding protein osteonectin/SPARC were increased. Osteonectin/SPARC secretion into the media was delayed or inhibited. Coincident with retention of osteonectin/SPARC there was a decrease in the levels of osteonectin/SPARC mRNA as determined by Northern analysis. These studies suggest that processes associated with osteonectin/SPARC translation and secretion are sensitive to Pb2+.

Animals↗
PubMed1992

In vivo X-ray fluorescence of lead in bone.

The in vivo measurement of lead in bone by K X-ray fluorescence (K XRF) is becoming an increasingly widely utilized technique for assessing long-term lead dosimetry. Several groups have already reported the development of in vivo measurement systems, the majority adopting the 109Cd/backscatter K XRF technique because of its substantial advantages in terms of a robust measurement, lower detection limit (compared with 57Co/90 degrees), absence of the need for sedation of younger subjects, and lower effective (radiation) dose when calculated according to the most recent guidelines. The advantages of the 109Cd system are primarily a consequence of the physics principles of the technique. The apparatus of each XRF technique is transportable, facilitating easy establishment of mobile laboratory facilities. More research is needed to substantiate claims made for particular XRF technologies, but both L and K XRF techniques provide the possibility of improved understanding of the body's handling of the ubiquitous toxin lead.

Animals↗
PubMed1992

The role of Ca2+ in cadmium-induced renal tubular cell injury.

Changes in rat renal proximal tubule cell gene expression were studied in vitro using a cadmium metallothionein (CdMT) exposure model. Increased expression of MT together with alterations in the expression of several other stress protein products were demonstrated by 35S-two-dimensional gel electrophoresis. Stress proteins with estimated molecular masses of 32, 70 and 90 kDa were observed to be increased after 4 h of exposure. These changes preceded the onset of cell injury. Internal stores of Ca2+ were not found to be measurably altered, as measured by the changes in fluorescence of the dye FURA-2. These data suggest that the observed alterations in gene expression are directly mediated by Cd2+ and not secondary to increased availability of Ca2+ within the target cell population, perhaps mediated by the transacting factor which regulates MT synthesis. The calcuria resulting from in vivo exposure to Cd2+ in workers or CdMT exposure in animal models may be secondary to alterations in renal proximal tubule cell gene expression.

Animals↗
PubMed1991

Alterations in protein synthesis in rat liver cells by in vitro and in vivo exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin.

Alterations in protein synthesis in rat liver cells were examined following in vitro and in vivo exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Primary cultured rat liver parenchymal cells were exposed to 1 nM TCDD for 23 and 47 hr. Synthesis of two proteins with molecular weights (Mr) of 26,000 and 39,000 (designated 26k-P and 39k-P, respectively), other than cytochrome P450, was increased markedly in the cells. These proteins did not have the same antigens as cytochromes P450IA1 and P450IA2. Synthesis of three proteins with Mrs of 24,000, 25,000 and 29,000, respectively, was decreased by TCDD. TCDD was administered to rats at a dose of 100 micrograms/kg body weight. The amount of five proteins (two proteins with Mr of 26,000, one of 36,000 and two of 39,000) was increased in TCDD-treated rat liver. However, the proteins increased in vivo by TCDD were distinguishable from 26k-P and 39k-P by two dimensional gel electrophoresis.

Animals↗
PubMed1991

Purification of invertebrate metallothioneins.

Purification procedures that appear to be generally applicable to invertebrate MTs have only recently been developed and are described here. Thus far, few invertebrate MTs have been purified and characterized, although proteins that exhibit similarities to MT have been identified in numerous invertebrate species. A greater understanding of MTs of this group, which comprises most of the animals in the animal kingdom, will provide the basis for increased understanding of the evolution of this ubiquitous protein. Additionally, specific invertebrate species may provide useful models for probing MT function and contribute to a greater understanding of the biological role of MT.

Animals↗
PubMed1991

Effects of lead on the kidney: roles of high-affinity lead-binding proteins.

Lead-induced nephropathy produces both tubular and interstitial manifestations of cell injury, but the pathophysiology of these lesions is not completely understood. Delineation of the molecular factors underlying renal handling of lead is one of central importance in understanding the mechanisms of renal cell injury from this agent. Recent studies from this laboratory have identified several distinct high-affinity lead-binding proteins (PbBP) from rat kidney and brain that appear to play critical roles in the intracellular bioavailability of lead to several essential cellular processes in these target tissues at low dose levels. The PbBP from rat kidney has been shown to be a specific cleavage product of alpha 2-microglobulin, which is a member of the retinol-binding protein superfamily. Recent preliminary Western blot and immunohistochemical studies have shown that a polyclonal antibody to the renal PbBP does not recognize the brain PbBP, which appears to be a chemically similar, but distinct molecule. These studies have also shown that the renal PbBP is selectively localized in only certain nephrons and only specific segments of the renal proximal tubule. The striking nephror and cell-type specificity of the localization reaction could result from physiological differences in nephron functional activity or selective molecular uptake mechanisms/metabolism differences that act to define target cell populations in the kidney. In addition, other preliminary studies have shown that short-term, high-dose lead exposure produces increased excretion of this protein into the urine with concomitant decreases in renal concentrations.

Alpha-Globulins↗
PubMed1990

Alteration in protein synthesis in primary cultures of rat kidney proximal tubule epithelial cells by exposure to gallium, indium, and arsenite.

Patterns of protein synthesis in primary cultures of rat kidney proximal epithelial tubule cells were examined following exposure to gallium (Ga) chloride, indium (In) chloride, and sodium arsenite. After incubation with these chemicals for 20 hr, newly synthesized proteins were labeled with [35S]methionine. 35S-labeled proteins in the cells were separated by SDS/polyacrylamide gel and two-dimensional gel electrophoresis and detected by fluorography. A protein with molecular weight (Mr) of 30,000 was markedly induced by exposure to 300 microM Ga or 10 microM arsenite, and synthesis of proteins with Mr of 85,000, 71,000, 65,000, 51,000, 38,000, and 28,000 was also increased by Ga or arsenite. Arsenite exposure increased synthesis of eight different proteins, which were not induced by Ga. No significant changes in protein synthesis were observed with 300 microM In exposure. Release of lactate dehydrogenase from the cells was not significantly increased by exposure to concentrations of 300 microM Ga and 3 microM arsenite or less. In the absence of overt cell injury, the induction of these proteins may be useful as an early indicator for assessing exposure to Ga.

Animals↗
PubMed1990

Arsine: absence of developmental toxicity in rats and mice.

Arsine gas is a potent hemolytic agent but the effects of exposure to tolerated concentrations on pregnancy and prenatal development have not been reported. In the present evaluation, groups of bred mice and rats were exposed to arsine at concentrations of 0.025, 0.5, or 2.5 ppm on Gestation Days (gd) 6 through 15. Animals were killed on gd 17 (mice) or on gd 20 (rats) and endpoints of maternal and developmental toxicity were evaluated. In rats, maternal spleens were enlarged in the 2.5 ppm group and there was a decrease in packed red cell volume in pregnant rats. Fetuses weighed more than in the control group but other endpoints of developmental toxicity were not affected by arsine exposure. In another experiment involving separate groups of rats, the arsenic content of maternal blood and fetal livers increased with increasing atmospheric arsine concentrations, as assessed on gd 20. In mice, maternal spleen size was significantly increased in the 2.5 ppm group. The number of live fetuses, mean fetal body weight, and percentages of resorptions or malformations per litter were not affected by arsine exposure. In conclusion, arsine at atmospheric concentrations that caused increases in maternal spleen size and measurable levels of arsenic in maternal blood and fetal livers did not adversely affect endpoints of developmental toxicity.

Air Pollutants, Occupational↗
PubMed1990

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↗
PubMed1990

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↗
PubMed1989

Preliminary purification and characterization studies of a low molecular weight, high affinity cytosolic lead-binding protein in rat brain.

Carrier-free 203Pb has been used to label high affinity lead-binding proteins in rat brain cytosol to allow their initial characterization. The low molecular weight 203Pb-protein complex collected from a Sephadex G-75 column eluate has been further purified by Sephadex DEAE chromatography and then partially characterized. The protein has a molecular weight of 23,000 daltons as determined by SDS polyacrylamide gel electrophoresis and significant levels of glutamic acid (9.3%), aspartic acid (10.8%) and cysteine (9.4%). Western blot studies conducted using the polyclonal antibody to the renal lead-binding proteins showed a lack of reactivity, indicating that the brain protein is immunologically distinct from that found in the kidney.

Animals↗
PubMed1989

Hematopoietic effects in mice exposed to arsine gas.

Arsine gas is a potent hemolytic agent. Concern about semiconductor workers prompted an in-depth study of arsine at the National Institute of Environmental Health Sciences to determine the hematopoietic effects of prolonged exposure to this gas. Female B6C3F1 mice were exposed by inhalation to 0, 0.5, 2.5, and 5 ppm arsine, 6 hr/day for 14 days. Body weights of exposed mice were comparable to those of controls, but a marked, concentration-related splenomegaly was observed. Higher level arsine exposure produced statistically significant decreases in red blood cells, hematocrit and hemoglobin, with increases in white blood cell counts and mean corpuscular volume of red blood cells. Erythropoiesis as measured by quantitation of erythroid precursors in culture revealed a marrow reduction of colony-forming unit erythroids/femur cells for all treated groups on Day 3 postexposure and only at the 5 ppm dose group on 24 days postexposure, while splenic erythropoiesis increased at higher concentrations of arsine. There was no alteration in bone marrow cellularity and a less significant effect on granulocyte-macrophage progenitors. A 12-week study of arsine at 0, 0.025, 0.5, and 2.5 ppm (6 hr/day) by inhalation showed similar effects on hematopoiesis in mice. In conclusion, arsine exposure at low concentrations produces a stress on the hematopoietic system characterized by hemolysis, which persists for a prolonged period following exposure.

Animals↗
PubMed1989

The relationship of body image perception and weight status to recent change in weight status of the adolescent female.

This descriptive correlational study investigated the relationship of body image perception and weight status to recent change in weight status of the adolescent female. Based on earlier research findings supporting the position that obese adolescent females demonstrate a negative body image perception as compared to the nonobese, this investigation identified the need to study body image perception as it applies to all adolescent females and to include a recent change in weight status as it may affect that perception. A convenience sample of 90 adolescent females between the ages of 13 and 17 years was selected from health and gym classes at a large midwestern metropolitan high school. Subjects were grouped into three categories: nonobese, overweight, and obese based on height, weight, and skinfold measurement. They were administered two questionnaires: the Body-Cathexis Scale and a self-report recent change in weight status and demographic questionnaire. Results indicated a significant positive correlation for the overall association of body image perception and weight status. When the analysis was partialled according to defined weight groups, the relationship held only for the overweight group. Differences in body image scores were obtained in association with each of the recent change-in-weight-status questions. Findings confirmed the need to study the association between body image perception and weight status to recent change in weight status with a more heterogeneous group of adolescent females.

Adolescent↗
PubMed1988

Effect of intratracheal gallium arsenide administration on delta-aminolevulinic acid dehydratase in rats: relationship to urinary excretion of aminolevulinic acid.

Exposure to gallium arsenide (GaAs) is a potential hazard in the semiconductor industry and there is a need for specific biological indicators of exposure/toxicity for this compound. These studies examined effects of GaAs exposure on the heme biosynthetic pathway enzyme delta-aminolevulinic acid dehydratase (ALAD). Male CD rats received GaAs suspensions at doses of 50, 100, or 200 mg/kg via a single intratracheal instillation. Six days after treatment a dose-dependent inhibition of blood ALAD was observed with activity decreasing to 5% of controls at the highest dose, with a concomitant marked increase in the urinary excretion of aminolevulinic acid (ALA). Inhibition of blood ALAD following administration of GaAs was maximal (30% of control) 3 to 6 days postexposure and returned to approximately control values on day 18. Urinary excretion of ALA was maximal 3 to 6 days postexposure and recovered toward control values at 18 days. Inhibition of kidney and liver ALAD following GaAs exposure was also evident. Intratracheal instillation of silica did not alter the activity of ALAD in blood, liver, or kidney. Marked increases in lung wet weight/body weight ratios were evident in lungs of silica- and GaAs-treated rats. Histopathological changes in the lungs were characterized by multifocal granulomas following silica treatment and Type II pneumocyte hyperplasia following GaAs treatment; mild necrosis was evident in both groups. Rats treated with 100 mg/kg GaAs exhibited swelling of kidney proximal tubule mitochondria 6 days following exposure. Silica and GaAs exposure produced marked decreases in cumulative weight gain. The concentration of gallium required to achieve half-maximal inhibition of ALAD in vitro was 200-fold less in blood and 40-fold less in kidney and liver than that required for arsenite and the inhibition was partially prevented by excess zinc. These data suggest that gallium is the primary inhibitor of ALAD following dissolution of GaAs in vivo and that competition for or displacement of zinc from the enzyme active site may be involved in the mechanism of inhibition. The data also demonstrated the utility of including a particulate control group when assessing the chemical-induced toxicity of compounds administered intratracheally as particulate suspensions. Finally, measurement of heme precursors, e.g., ALA, in urine coupled with assay of red blood cell ALAD activity may be of value as an early biological indicator of GaAs exposure and/or toxicity.

Aminolevulinic Acid↗