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Biomedical subjects

B A Fowler

Publications and source records attributed to B A Fowler.

At least 109 records · Page 6Linked to original sources
PubMed1978

General subcellular effects of lead, mercury, cadmium, and arsenic.

This working paper summarizes the known ultrastructural and biochemical effects of lead, mercury, cadmium, and arsenic on subcellular organelle systems following in vivo administration. Documented metal-induced alterations in nuclear, mitochondrial, microsomal, and lysosomal functions are discussed in relation to their potential impact on cellular responses to other environmental agents. Each of the above elements has been found to interfere with normal cellular replication and genetic processes. Mitochondrial swelling and depression of respiratory function are discussed in relation to known metal-specific perturbations of mitochondrial heme biosynthetic pathway enzymes. Inhibition of microsomal enzyme activities and protein synthesis by lead and mercury is compared to the apparent absence of such effects following arsenic or cadmium exposure. Lysosomal uptake of all the metals is documented, but biochemical alterations in these structures have been reported for only mercury and cadmium. It is concluded that these toxic metals are capable of interacting with, and biochemically altering major cellular systems at dose levels below those required to produce signs of overt metal toxicity. The impact of these effects on cellular response to other metals and xenobiotics in complex exposure situations is presently unknown, and further research is urgently needed in this area.

Animals↗
PubMed1978

Interactions among lead, cadmium, and arsenic in relation to porphyrin excretion patterns.

This paper reviews the effects of lead (Pb), cadmium (Cd), and arsenic (As) on the mitrochondrion with emphasis on alteration of mitochondrial heme biosynthetic pathway. The information was used to examine results of a Pb x Cd x As interaction study which employed urinary porphyrin excretion patterns as one assessment criterion. Data from the study showed that dietary Pb produced increased urinary excretion of aminolevulinic acid (ALA) and coproporphyrin. Dietary exposure to organic or inorganic As caused increased excretion of uroporphyrin and to a lesser extent coproporphyrin, while dietary Cd caused no significant changes in urinary levels of any of the porphyrins measured. The combination of Pb plus As produced an additive effect on coproporphyrin excretion but not that of either ALA or uroporphyrin. These data are discussed in relation to utilization of urinary porphyrins for assessing toxicity and elemental interactions.

Animals↗
PubMed1977

Effects of concurrent administration of lead, cadmium, and arsenic in the rat.

Humans are exposed to a number of toxic elements in the environment; however, most experiments with laboratory animals investigate only one toxic element. To determine if concomitant exposure to lead (Pb), cadmium (Cd), and/or arsenic (As) modified the changes produced by any one metal in various parameters of toxicity, 168 male, Sprague-Dawley, young adult rats were fed nutritionally adequate diets to which had been added 0 or 200 ppm Pb as Pb acetate, or 50 ppm Cd as Cd chloride, or 50 ppm As as sodium arsenate or arsanilic acid in a factorial design for a period of 10 weeks. At these concentrations, Cd and As reduced weight gain even when differences in food intake were taken into account; 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 numbers of red blood cells (RBCs) were observed following administration of Pb, Cd, or As; usually more cells were observed when two or three metals were administered, compared to individual metals. Despite increasing numbers of circulating RBCs, hemoglobin and hematocrit were reduced, especially with the Pb-Cd combination and the Cd-arsanilic acid combination. Specific effects of Pb on heme synthesis were observed, including increased urinary excretion of delta-aminolevulinic acid; this increase was reduced by the presence of dietary cadmium. Analyses of blood showed values for the laboratory rat within normal ranges for blood urea nitrogen, creatinine, cholesterol, calcium, albumin, total protein, and bilirubin. Uric acid was increased by Pb, with little modification by dietary Cd or As content. Serum glutamate-oxalate transaminase activity was reduced by As. Serum alkaline phosphatase was greatly 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, with no effects of Cd or As alone or as interactions. Liver weight/body weight ratios were reduced in animals fed 50 ppm dietary Cd. Kidney histology shows predominantly Pb effects, namely, intranuclear inclusion bodies and cloudy swelling. Ultrastructural evaluation of kidneys from Pb-treated animals disclosed nuclear inclusion bodies of the usual morphology and mitochondrial swelling. Concurrent administration of Cd greatly minimized Pb effects on the kidney under conditions of this experiment. Liver histology suggests an increased rate of cell turnover with either As compound, but few specific changes.

Administration, Oral↗
PubMed1977

Ultrastructural and biochemical effects of prolonged oral arsenic exposure on liver mitochondria of rats.

This investigation was undertaken to further delineate the subcellular manifestations of arsenic toxicity following chronic exposure using combined ultrastructural and biochemical techniques. Male rats were given access to deionized drinking water solutions containing 0, 20, 40, or 85 arsenic as arsenate (As(+5)) for 6 weeks. In situ swelling of liver mitochondria was the most prominent ultrastructural change observed. Mitochondrial respiration studies indicated decreased state 3 respiration and respiratory control ratios (RCR) for pyruvate/malate but not succinate mediated respiration. Specific activity of monoamine oxidase which is localized on the outer mitochondrial membrane showed increases of up to 150% of control and cytochrome-C oxidase which is localized on the inner mitochondrial membrane showed increases in specific activity of 150-200%. Activity of malate dehydrogenase which is localized in the mitochondrial matrix was unchanged at any dose level. These studies indicate that decreased mitochondrial respiration is only one aspect of arsenic toxicity to this organelle. Marked arsenic-mediated perturbation of important enzyme systems localized in mitochondria which participate in the control of respiration and other normal mitochondrial functions are also important manifestations of cellular dysfunction.

Administration, Oral↗
PubMed1977

Effects of arsenic on pyruvate dehydrogenase activation.

Our studies illuminate a particular site of altered pyruvate utilization by liver mitochondria isolated from arsenic-fed rats. Initially, pyruvate dehydrogenase (PDH) levels were measured before and after in vitro activation. The liver homogenates were prepared from male rats given access to deionized drinking water solutions containing 0, 20, 40, and 85 ppm arsenic as sodium arsenate (As+5) for 3 and 6 weeks. After 3 weeks, the effects of arsenic at the highest dose level were pronounced on the basal activity (before activation), with inhibition up to 48% of the control values. The total PDH (after activation) was inhibited by 14, 15, and 28% of the control values at 20, 40, and 85 ppm As+5, respectively. A similar pattern of inhibition of PDH was observed at 6 weeks, although the inhibition was lower at the highest dose. This effect is probably a reflection of mitochondrial regeneration at this time and dose. The inhibition of PDH both before and after activation suggests a direct arsenic effect on pyruvate utilization which does not involve a lipoic acid moiety. Evidence is also presented which indicates an arsenic effect on the regulating kinase and/or phosphatase. The metabolic effects of impaired mitochondrial utilization by pyruvate are also discussed.

Animals↗
PubMed1977

Effects of chronic arsenic exposure on hematopoietic function in adult mammalian liver.

In these studies the effects of ingested arsenic (As(+5)) on hepatic heme biosynthetic capability and hemoprotein function in adult male rats were investigated. Animals exposed for 6 weeks to 0, 20, 40, or 85 ppm sodium arsenate in the drinking water suffered depression of hepatic delta-aminolevulinic acid (ALA) synthetase and heme synthetase (ferrochelatase) activities, with maximal decreases to 67 and 55% of control levels, respectively, at 85 ppm. Concomitantly, urinary uroporphyrin levels were elevated by as much as 12 times, and coproporphyrin by as much as 9 times, control values. The rate of incorporation of (3)H-ALA into mitochondrial and microsomal hemes was depressed by 40-50% at 20 ppm but was increased with regard to controls by as much as 150% at the higher treatment levels. A similar biphasic pattern was observed in regard to (14)C-leucine incorporation into cellular membranal proteins. In contrast, the levels of ALA dehydratase, uroporphyrinogen I synthetase, aminopyrine demethylase, and cytochrome P-450 were not significantly changed in As(+5)-treated rats. These results support the hypothesis that chronic, low level, arsenic exposure results in selective inhibition of mitochondrial-bound heme biosynthetic pathway enzymes (ALA synthetase and heme synthetase) resulting in a substantial increase in urinary porphyrins, uniquely characterized by a greater increase in uroporphyrin than coproporphyrin levels. These changes occur independent of, or prior to, alterations in hepatic hemoprotein-dependent functions and may thus serve in the clinical analysis of pretoxic exposure to arsenic compounds in human populations.

5-Aminolevulinate Synthetase↗
PubMed1977

The transplacental toxicity of methyl mercury to fetal rat liver mitochondria. Morphometric and biochemical studies.

Ultrastructural morphometric and biochemical changes in liver mitochondria of fetal rats whose mothers were exposed to methyl mercury hydroxide in their drinking water at concentrations of 0, 3, 5, or 10 p.p.m. for 4 weeks prior to mating and through day 19 of pregnancy are described. A dose-related decrease in the volume density of mitochondria was observed in fetal hepatocytes of dams given the 5- and 10-p.p.m. dose levels. This finding was associated with decreased mitochondrial protein synthesis, which appeared to result primarily from decreased synthesis of mitochondrial structural proteins. Loss of respiratory control was observed in mitochondria from animals in the 3-p.p.m. dose group whereas state 3 respiration was abolished in animals exposed to the 5- and 10-p.p.m. dose levels. The specific activities of monoamine oxidase and cytochrome oxidase, outer and inner mitochondrial membrane marker enzymes respectively, showed dose-related decreases of up to 62 and 78 per cent of control, respectively. delta-Aminolevulinic acid synthetase, which is loosely bound to the inner mitochondrial membrane, also showed dose-related decreases of up to 68 per cent of control. Malate dehydrogenase, a mitochondrial matrix marker enzyme, showed no change in activity at any dose level tested. These observations were correlated with dose-related tissue concentrations of methyl and inormpaired mitochondrial biogenesis and functional development is one basis for explaining the sensitivity of fetal animals to methyl mercury toxicity.

5-Aminolevulinate Synthetase↗
PubMed1977

Tetrachlorodibenzo-p-dioxin induction of renal microsomal enzyme systems: ultrastructural effects on pars recta (S3) proximal tubule cells on the rat kidney.

A single oral administration of 2,3,7,8-tetrachlorodibenzo-p-dioxin to rats at a dose level of 25 microgram/kg produced marked proliferation of smooth endoplasmic reticulum in renal proximal tubule cells of the straight (S3) segments. This ultrastructural effect was associated with a pronounced induction of the microsomal enzymes glucuronyl transferase and benzopyrene hydroxylase which persisted for at least 16 days after treatment. Renal dissection studies disclosed that the activities of these enzymes in 2,3,7,8-tetrachlorodibenzo-p-dioxin-treated animals were not uniformly distributed within the kidney but followed the general known distribution of S3 cells. Enzyme activities were highest in the outer stripe of the medulla and cortex and lowest in the medulla. These studies demonstrate that the kidney does possess inducible microsomal enzyme systems, capabilities of which have not been appreciated previously due to the lack of a suitable inducing agent and their apparent concentration in a relatively small population of proximal tubule cells.

Animals↗
PubMed1977

Renal porphyrinuria during chronic methyl mercury exposure.

These studies demonstrate altered activities of renal heme biosynthetic pathway enzymes and elevated levels of urinary uroporphyrin and coproporphyrin in rats during chronic exposure to 3, 5, or 10 ppm methyl mercury hydroxide (MMH). Porphyrinuria appears to occur as a result of inhibition of renal ferrochelatase and uroporphyrinogen I synthetase, with secondary induction of delta-aminolevulinic acid (ALA) synthetase in kidneys but not livers of mercury-exposed rats. Since the renal heme biosynthetic system appears to be highly sensitive to MMH during continuous exposure to levels below those which elicit overt general organ damage, these results may have clinical utility in diagnosing pre-toxic biological responses to mercury in human populations.

5-Aminolevulinate Synthetase↗
PubMed1975

Bismuth localization within nuclear inclusions by x-ray microanalysis. Effects of accelerating voltage.

This report details the localization of bismuth by energy-dispersive x-ray microanalysis within characteristic nuclear inclusion bodies of renal tubular lining cells of rats following excessive exposure to this element. Peak to background ratios and analytical detection sensitivities for bismuth were found to vary for 04, 60 or 80 keV electron accelerating voltages. Optimum peak to background ratios were observed at 40 keV due to lower background generation, while greater detection sensitivities were recorded at 80 keV due to enhanced generation of bismuth characteristic x-rays.

Animals↗
PubMed1975

Levels of toxic metals in marine organisms collected from Southern California coastal waters.

Emission of toxic trace metals into southern California coastal waters has resulted in the extensive accumulation of the elements within marine sediments. The current study was undertaken to evaluate concentrations of trace metals in bottom-dwelling marine fauna collected from two sampling areas. Analyses carried out on muscle samples of the dover sole (Microstomus pacificus) and the crab (Cancer anthonyi) by proton-induced x-ray emission analysis showed considerable concentrations of arsenic and selenium. Samples of gonads, digestive gland, and muscle from the crab Mursia gaudichaudii analyzed by atomic absorption spectroscopy showed elemental concentrations in muscle similar to the crab Cancer anthonyi and much higher metal levels in gonad and digestive gland. These findings suggest the need for further studies concerning the relationship between emission of metals into the marine environment and their abundance in marine fauna.

Animals↗
PubMed1975

Phenobarbital protection against methyl mercury neophrotoxicity.

Phenobarbital injections to rats given a low oral dose level of methl mercury for 2 or 4 wk decreased methyl mercury-induced ultrastructural alterations in kidney proximal tubule cells, increased urinaryexcretion of inorganic mercury and increased blood concentrations of methylmercury. These effects were not seen after 2 wk of treatment but were highly significant after 4 wk.

Animals↗
PubMed1975

The effects of chronic oral methyl mercury exposure on the lysosome system of rat kidney. Morphometric and biochemical studies.

This report describes morphometric and biochemical changes in the renal lysosome system of rats exposed to 3, 5, or 10 p.p.m. concentrations of methyl mercury hydroxide in their drinking water for 4 weeks. Increased numbers of dense, granular lysosomes, previously found to contain mercury, were observed in tubule cells of rats receiving the 3 and 5 p.p.m. dose levels but not those of the 10 p.p.m. group. Tubule cells from animals given the 10 p.p;m. dose level displayed proteinaceous vacuoles with dense crystalloid structures, apical cytoplasmic extrusion, and cellular degeneration; Mitochondrial swelling within tubule cells of treated animals showed a marked dose-response relationship. Renal microsomal activity levels of ss-glucuronidase were strongly inhibited by methyl mercury hydroxide exposure at all dose levels, whereas the activity levels of acid phosphatase were unchanged. Lysosomal beta-glucuronidase was also inhibited by methyl mercury hydroxide exposure, whereas lysosomal acid phosphatase showed approximately a 2-fold increase in activity. The results are discussed in relation to the role of lysosomes in mediating the nephrotoxic effects of methyl mercury and other toxic trace metals.

Acid Phosphatase↗