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Biomedical subjects

B A Fowler

Publications and source records attributed to B A Fowler.

At least 91 records · Page 5Linked to original sources
PubMed1981

Relationship between metal toxicity to subcellular systems and the carcinogenic response.

The effects of metals on subcellular organelle functions have been reviewed in relation to carcinogenesis. Perturbations of the normal uptake and metabolism of carcinogens can arise through changes in microsomal enzyme activities, membrane permeabilities, and cell turnover. Metal effects on heme-dependent oxidative functions are well documented and are primarily manifested by increased heme degradation rates (microsomal heme oxygenase activity), decreased heme production (mitochondrial and cytosolic heme biosynthetic enzymes) and, in the case of a few metals, through nuclear effects of metals on the induction of microsomal enzymes. Many metals are accumulated by lysosomes, but known effects of metals on the function of these organelles in sequestering and storing organic compounds are few. Studies of changes in plasma or mitochondrial membrane permeabilities by metals have centered mainly on the susceptibility of membrane ATPase activities to metal ion alteration and on the involvement of metals in lipid peroxidation and free radical formation. Knowledge of the effects of metals on subcellular organelle functions should aid in the understanding of the mechanisms by which metal ions may play a role in the carcinogenic response.

Animals↗
PubMed1981

Concurrent exposure to lead, cadmium, and arsenic. Effects on toxicity and tissue metal concentrations in the rat.

Male rats were exposed to dietary Pb (200 ppm), Cd (50 ppm), or As (50 ppm) as arsenate either alone or in combination for 10 weeks using a 2 x 2 x 2 factorial design. Cd and As reduced weight gain even when differences in food intake were taken into account, and administration of both Cd and As depressed weight gain more than did either metal alone. Pb did not adversely affect food consumption or weight gain. Increased RBCs were observed after administration of Pb, Cd, or As, and more cells were observed when two or three metals were concomitantly administered. Despite increased numbers of circulating RBCs, hemoglobin and hematocrit were reduced, especially with the Pb-Cd combination. Analysis of blood chemistries showed normal ranges for blood urea nitrogen, creatinine, cholesterol, calcium, albumin, total protein, and bilirubin. Uric acid was increased by Pb, but not by Cd or As. SGOT activity was reduced by As alone. Serum alkaline phosphatase was reduced by either As or Cd but not Pb. Combinations of As and Cd did not further reduce the activity of this enzyme. Kidney weight and kidney weight/body weight ratios were increased by Pb alone, but Cd or As alone or in combination had no effect. Liver weight/body weight ratios were reduced in animals fed Cd. Kidney histology showed predominantly Pb effects, i.e., intranuclear inclusion bodies and cloudy swelling. Ultrastructural evaluation of kidneys from Pb-treated animals disclosed nuclear inclusion bodies and mitochondrial swelling. Concurrent administration of Cd reduced total mean bone and kidney Pb levels by 50% and 60%, respectively, and this was associated with a decrease in kidney intranuclear inclusions. Cd exposure also reduced renal, femur, and liver concentrations of Fe by 33%, 43%, and 63%, respectively, decreased femur Zn by 27%, but increased renal Zn by 20%. Administration of As produced mild swelling of tubule cell mitochondria, increased mean total renal Cu to 200% of control, and increased liver Fe by 44%. Dietary Pb produced increased urinary excretion of ALA and coproporphyrin. Dietary exposure to As caused increased urinary excretion of uroporphyrin and to a lesser extent coproporphyrin, whereas dietary Cd caused no significant changes in urinary levels of any of the porphyrins measured. Pb plus As produced an additive effect on coproporphyrin excretion but not that of ALA or uroporphyrin. These studies indicate that interactions between common toxic elements do occur and are characterized by alterations in both tissue trace metal levels and toxicity.

Animals↗
PubMed1980

Occupational lead exposure, nephropathy, and renal cancer.

A 48-year-old lead worker was found to have a cystic renal carcinoma during an evaluation of his occupational lead poisoning. Clinical studies showed elevated blood lead levels, impaired urinary concentrating ability, and reduced creatinine clearance. Histologic and electron microscopic studies showed this cystic tumor to be similar to renal carcinomas observed in animals with prolonged lead exposure. Lead content of the tumor was elevated (2.49 micrograms/gm) in comparison with adjacent renal tissue and with normal adult levels. In light of previous animal studies, this case adds increased evidence to the concern over the carcinogenic potential of prolonged lead exposure.

Adenocarcinoma↗
PubMed1979

Isolation and partial characterization of a cadmium-binding protein from the American oyster (Crassostrea virginica).

American oysters (Crassostrea virginica) were exposed to 0.1 ppm cadmium for 0--15 days in a flowing seawater system and then placed into clean flowing seawater for 24 h prior to sacrifice. Whole oysters were homogenized and a cadmium-binding protein isolated and purified by a process of centrifugation, heat-treatment, Sephadex G-75 chromatography, DEAE cellulose chromatography and disc gel electrophoresis. A highly anionic protein which is not present in control oysters was found to be present in cadmium-exposed animals after 3 days of treatment and to increase in concentration at succeeding time points. The protein does not extensively bind zinc or copper. Amino acid analysis of the purified protein disclosed an amino acid composition characterized by a high percentage of dicarboxylic amino acids and relatively little cysteine.

Animals↗
PubMed1979

Early cellular effects of circulating cadmium-thionein on kidney proximal tubules.

Circulating cadmium-thionein (Cd-MT) is cleared from the mammalian circulatory system by filtration through the kidney glomerulus with subsequent reabsorption by kidney proximal tubules. Damage to the tubules results following uptake of Cd-MT, which is dependent upon time and the dose level of cadmium administered. Intravenous administration of 109Cd-MT at doses of 0.017 and 0.17 mg Cd/kg body weight with examination of total renal uptake of 109Cd at 0.5, 3, and 24 hr disclosed that the rate of clearance from the blood and uptake by the kidney was significantly more rapid at the 0.017 mg Cd/kg dose. Ultrastructural changes resulting from intravenous injection of either form A or B of Cd-MT were characterized by increased numbers of pinocytotic vesicles and small, dense lysosomal structures. There was no evidence of mitochondrial swelling or cell death at either 3 or 6 hr after injection. The subcellular distribution of cadmium in kidney tissue at various times after administration of Cd-MT was determined by using differential centrifugation techniques with 109Cd and in situ by using x-ray microanalysis. At 30 min after injection of Cd-MT, significant amounts of cadmium were present in lysosomal fractions indicating an interaction between the tubular lysosome system and Cd-MT prior to the onset of overt cellular toxicity. Results suggest that Cd-MT is reabsorbed and broken down by kidney tubule cells in a physiological manner with possible subsequent release of the toxic cadmium ion.

Animals↗
PubMed1979

Factors influencing cadmium accumulation and its toxicity to marine organisms.

The toxicity of dissolved cadmium to a variety of marine animals has been found to be related to salinity, with decreased toxicity observed at higher salinities. Recent data from our laboratory have demonstrated that the toxicity of cadmium to estuarine shrimp and larval fish is a function of free cadmium ion concentration, which in turn is controlled by the chloride concentration of the water. As the chloride concentration (i.e., salinity of the water) increases, the concentration of free cadmium ion decreases relative to total dissolved metal, due to its complexation with chloride ions. These observations have been given further support by measurements involving the uptake of (115m)Cd by shrimp which showed that accumulation of (115m)Cd and chloride concentration also are inversely related. Experiments also have been conducted on the physiological effects of cadmium on the respiration of excised oyster gill tissue. Although tissues from oysters exposed for 14 days to 0.1 ppm total dissolved cadmium accumulated significant quantities of metal, no measurable effects on respiration rates were detected. Higher doses (0.3 and 0.6 ppm) caused both mortalities of oysters and accelerated respiration of excised oyster gill. Exposure to 0.1 ppm cadmium also caused the induction of and/or increased binding of cadmium to a specific low molecular weight protein in oysters. This protein appeared to have a detoxification function at low cadmium exposure levels, but in animals exposed to 0.6 ppm cadmium the induction mechanism apparently became saturated, allowing the excess cadmium to bind critical sites with resultant damage.

Age Factors↗
PubMed1979

Studies of hepatic mitochondrial structure and function: morphometric and biochemical evaluation of in vivo perturbation by arsenate.

Ultrastructural morphometric and biochemical studies were conducted on hepatic mitochondria from control rats and rats treated in vivo with arsenate to examine changes in interrelationships between mitochondrial structure and biochemical functions. Morphometric analysis disclosed an over-all 1.2-fold increase in the relative mitochondrial volume density and 1.4-fold increase in the surface density of the inner mitochondrial membrane of arsenate-exposed rats. These structural changes were associated with a 1.5-fold increase in 14C-leucine incorporation into all mitochondrial proteins, which was primarily associated with the acid-insoluble membranous fraction. Mitochondria from arsenate-treated rats showed a marked disruption of normal conformational behavior with depression of nicotinamide adenine dinucleotide (NAD)-linked substrate oxidation and a resulting in vivo increase in the mitochondrial [NAD] to [NADH] ratio. Observed changes in mitochondrial membranes from arsenate exposure also resulted in 1.5- to 2-fold increases in the specific activities of the membrane marker enzymes monoamine oxidase, cytochrome oxidase, and Mg2+-ATPase. Activity of malate dehydrogenase, which is localized in the mitochondrial matrix, was unchanged. The results of this study demonstrate a positive quantitative in vivo correlation between mitochondrial structure and function and indicate a marked dependency upon membrane integrity for normal maintenance of the specific biologic activities performed by this organelle in vivo.

Animals↗
PubMed1979

Effects of separate and combined chronic mercuric chloride and sodium selenate administration in rats: histological, ultrastructural, and x-ray microanalytical studies of liver and kidney.

The separate administration of mercuric chloride (HgCl2) and sodium selenate (Na2SeO4) to male rats in drinking water or a combined administration of both (50 ppm Hg, 15 ppm Se) caused different signs of toxicity over a 22 week period. The HgCl2 group showed histopathological and ultrastructural lesions as evidenced by periportal fatty degeneration and cell necrosis in the liver and tubular necrosis with proteinaceous casts in the kidney. The Na2SeO4 group showed the most severe depression of growth and food and water consumption, but no pathological changes were seen in the liver or kidney. Simultaneous administration of both toxicants produced a protective effect on weight loss and histopathology. These effects were associated with the formation of electron dense nuclear inclusions in kidney proximal tubule cells and similar electron dense formations in the reticuloendothelial cell cytoplasm and in the extracellular space of Disse in the liver. These formations were shown to contain both Se and Hg by energy dispersive X-ray microanalysis. The basis of the protective interaction of these two elements appears to result from an alteration of the chemical form or association of the mercury and selenium.

Animals↗
PubMed1978

Pyruvate metabolism after in vivo exposure to oral arsenic.

This study investigated altered pyruvate metabolism after prolonged oral arsenic exposure. Male rats were given access to deionized drinking water containing 0, 40 or 85 ppm sodium arsenate (As5+) for 3 weeks. Respiration studies with mitochondria isolated from treated animals indicated decreased state 3 respiration (with ADP) and decreased respiratory control ratios (RCR) for pyruvate/malate-mediated respiration, but not for succinate-mediated respiration, as compared to control respiration values. In addition, pyruvate dehydrogenase activity was measured, in both liver and intestine, before and after Mg-activation in vitro. After 3 weeks, the effects of arsenic at the highest dose level were pronounced on the basal pyruvate dehydrogenase activity (before activation) as well as the total pyruvate dehydrogenase (after activation). The inhibition of pyruvate dehydrogenase activity both before and after Mg-activation suggests an arsenic effect on mitochondrial pyruvate metabolism which, in part, involves inhibition of pyruvate decarboxylase. Evidence is also presented which may indicate an arsenic effect on the kinase and/or phosphatase which regulate pyruvate dehydrogenase activity.

Animals↗