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Biomedical subjects

C R Angle

Publications and source records attributed to C R Angle.

At least 19 recordsLinked to original sources
PubMed1992

Neuroendocrine effects of toxic and low blood lead levels in children.

From 3 million to 4 million children in America have lead poisoning. This environmental toxin affects 1 in every 6 children younger than 6 years of age in the United States. The marked effects of lead toxicity on the central nervous system are well known, ie, lowering IQ and impairing memory, reaction time, and the ability to concentrate. Children are at greatest risk for the central nervous system effects of lead because the central nervous system is at its peak in development during the first few years of life. The negative correlation of stature and blood lead level (bPb) found in the National Health and Nutrition Examination Survey directed the authors to evaluate the possible neuroendocrine effects of this toxin in children. Twelve children were studied during toxic (greater than or equal to 40 micrograms/dL) and low bPb (less than 40 micrograms/dL). Classic provocative stimuli, L-dopa (15 mg/kg by mouth) and insulin (0.1 U/kg given intravenously), were used to determine human growth hormone (hGH) responses during toxic bPb and after chelation therapy in six of the subjects. An additional four subjects were studied during low bPb. In two patients LGH levels were determined every 20 minutes for 24 hours during toxic bPb. Thyroid-stimulating hormone and prolactin responses to thyrotropin-releasing hormone were also determined. All children studied showed growth retardation during toxic bPb. Mean peak hGH responses to provocative stimuli were lower during toxic bPb, but the responses were all within normal limits.(ABSTRACT TRUNCATED AT 250 WORDS)

Body Height↗
PubMed1991

Effect of sodium butyrate on metallothionein induction and cadmium cytotoxicity in ROS 17/2.8 cells.

ROS 17/2.8 cells, a cloned rat osteosarcoma cell line, are exceptionally sensitive to the cytotoxic effects of cadmium. This sensitivity is associated with the inability of this metal to induce the synthesis of metallothionein, a transition metal-binding protein, which detoxifies this metal by its sequestration. Sodium butyrate induces the synthesis of metallothionein in these cells in a concentration-dependent manner. Treatment with this agent also significantly increases the resistance of these cells to the cytotoxic effects of cadmium and the protective effect of butyrate is reversed upon its removal from culture medium. Butyrate treatment did not significantly alter the accumulation of cadmium by these cells. Hence, the increased synthesis of metallothionein in butyrate-treated cells is not due to increased cellular uptake of cadmium. Inhibition of DNA synthesis due to butyrate was not a sufficient condition to alter metallothionein synthesis or to protect against Cd-induced cytotoxicity. Equivalent inhibition of DNA synthesis with hydroxyurea failed to increase metallothionein synthesis in cadmium-treated cells. These results indicate that modulation of metallothionein gene expression in this cell line is the critical factor in determining cellular sensitivity to the cytotoxic effects of cadmium.

Animals↗
PubMed1990

Effect of 5-azacytidine on metallothionein inducibility and sensitivity to lethality of cadmium in rat osteosarcoma (ROS 17/2.8) cells.

ROS 17/2.8 cells, a cloned rat osteoblastic osteosarcoma cell line, were found to be extremely sensitive to the lethal effects of cadmium and to synthesize little, if any, metallothionein in response to cadmium exposure. Culture of cells for 24 h in the presence of 1 microM 5-azacytidine, a cytidine analog, increased the inducibility of metallothionein by cadmium and significantly reduced (P less than 0.001) cytotoxicity. Anion exchange chromatographic analysis of cadmium binding to low molecular mass cytotoxicity. Anion exchange chromatographic analysis of cadmium binding to low molecular mass cytosolic proteins showed that cells treated with cadmium and 5-azacytidine expressed at least 2 isoforms of metallothionein. One isoform of metallothionein with a low affinity for cadmium was constitutively expressed by these cells. The association of poor inducibility of metallothionein by cadmium with extreme sensitivity of cells to cadmium emphasizes the role of this protein in the cellular response to this toxic metal. The modulation of metallothionein inducibility and sensitivity to cadmium by 5-azacytidine treatment suggest that metallothionein gene structure and regulation are altered in ROS 17/2.8 cells.

Animals↗
PubMed1990

Toxicity of cadmium to rat osteosarcoma cells (ROS 17/2.8): protective effect of 1 alpha,25-dihydroxyvitamin D3.

Inadequate vitamin D intake is an important cofactor in clinical and experimental bone disease induced by chronic cadmium exposure. The interaction was investigated by culture of rat osteoblastic osteosarcoma cells (ROS 17/2.8) in a serum-free medium with equimolar concentrations of cadmium chloride and 1 alpha,25-(OH)2 vitamin D3. After addition of cadmium alone to culture medium, the unstimulated secretion of osteocalcin and cellular alkaline phosphatase activity were inhibited at 10 pM, and of DNA synthesis and proline incorporation into collagen at 500 nM. In the presence of equimolar amounts of cadmium and 1 alpha,25-(OH)2 vitamin D3, all four responses paralleled those of 1 alpha,25-(OH)2 vitamin D3 alone up to the inhibitory concentration of 500 nM cadmium. Neither 10 nM 1 alpha,25-(OH)2 vitamin D3 nor 1 microM cadmium induced synthesis of metallothionein in these cells indicating that the protective effect of D3 was not related to the induction of a metallothionein-like protein in ROS 17/2.8 cells. In the presence or absence of D3, cadmium inhibited osteoblastic function at concentrations below the whole-organ concentration of cadmium in bone as reported in experimental and clinical cadmium-induced osteotoxicity. The extreme sensitivity of ROS 17/2.8 cells to cadmium may relate to the absence of metallothionein synthesis.

Animals↗
PubMed1990

Lead inhibits the basal and stimulated responses of a rat osteoblast-like cell line ROS 17/2.8 to 1 alpha,25-dihydroxyvitamin D3 and IGF-I.

Low-level exposure to lead impairs longitudinal growth in children and in experimental animals. The proposed mechanisms include decreased osteocalcin secretion in response to 1 alpha,25-(OH)2 vitamin D3 and decreased response to insulin-like growth factor-I. The interaction of lead, 1 alpha,25-(OH)2 vitamin D3, and insulin-like growth factor-I was investigated in an osteoblast-like cell line from rat osteosarcoma, ROS 17/2.8. Cells were cultured 24 hr in a serum-free medium with lead, 1 alpha,25-(OH)2 vitamin D3, and insulin-like growth factor-I. 1 alpha,25-(OH)2 vitamin D3 (10 nM) evoked a 4-5 X increase in osteocalcin secretion and a 100% increase in cellular alkaline phosphatase activity but no increase in DNA/cell layer. Insulin-like growth factor-I (92.5 ng/ml) evoked a 100% increase of osteocalcin secretion and a 20% increase in cellular DNA contents but no change in cellular alkaline phosphatase activity. Basal and stimulated cellular osteocalcin secretion, cellular alkaline phosphatase activity, and DNA contents were significantly inhibited by addition of 1-10 microM lead. The data are consistent with a toxic effect of lead on osteoblastic function and the cellular responses to 1 alpha,25-(OH)2 vitamin D3 and insulin-like growth factor-I. This interaction may be relevant to impaired childhood growth at low levels of lead exposure.

Alkaline Phosphatase↗
PubMed1989

Increased erythrocyte protoporphyrins and blood lead--a pilot study of childhood growth patterns.

The National Health and Nutrition Survey 1976-1980 demonstrated the inverse association of blood lead 8-35 micrograms/dl (0.4-1.7 microM) with height and weight in 2680 children 1-7 yr old. Growth has not been examined. A retrospective pilot study was made of growth, 0-42 mo, for 54 children found to have erythrocyte protoporphyrins greater than 35 micrograms/dl (0.6 mM) at 12-23 mo. For 24/54, all blood leads were less than 30 micrograms/dl (1.2 microM), with a peak annual mean of 18.5 micrograms/dl (0.9 microM); for 30/54, mean blood lead was 46.7 micrograms/dl (2.2 microM) at 12-23 mo with all subsequent blood leads greater than or equal to 30 micrograms/dl (1.2 microM). In both groups the mean height and weight at birth were at the 25th percentile. The high-lead children had increased weight velocity at 15 mo of age and were heavier at 24 mo. Weight gain related to total caloric intake, supporting food consumption, and hand-to-mouth behavior as significant factors in an increased blood lead ages 9-24 mo. The monthly directional change of height and weight percentiles after 24 mo, however, showed a decreased frequency of upward shifts when blood lead was greater than or equal to 30 micrograms/dl. Although an early high food intake appears to contribute to high blood lead by increasing the intake of lead from food and mouthing, persistent increases in the high blood lead and erythrocyte protoporphyrins were associated with subsequent growth retardation.

Black People↗
PubMed1988

Indoor air pollutants.

A major contribution of the pediatrician is to help families rank the multitude of pollutants according to their known risk for child health. Elimination of household smoking and completely effective venting of indoor heating devices are beneficial to all and mandatory in homes of allergic children. Acute releases of NO2 by gas ranges and ovens may be a significant factor in an increased incidence of respiratory infection, especially in children under two years. Despite intensive investigation, immunosuppressive and other health effects have not been defined for indoor levels of PBBs, PCBs, and related halogenated hydrocarbons. The analytic ability to determine nanomolar concentrations of numerous toxic chemicals opens a Pandora's box of inquiry. New methods, particularly immunologic, are urgently needed to quantitate the dose response to multiple combinations of chemicals and determine their significance for the health of the "tight-box" generation of children.

Air Pollutants↗
PubMed1987

Childhood lead toxicity and impaired release of thyrotropin-stimulating hormone.

Decreased stature of children is epidemiologically associated with increased blood lead independent of multiple socioeconomic and nutritional variables. Since endocrine dysfunction occurs in adult lead workers, we studied two girls, 2 years of age, before and after calcium disodium edetate chelation for blood leads (PbB) of 19-72 micrograms/dl. The height of both children had crossed from the 50th to below the 10th percentile during the course of chronic lead toxicity. Basal free T4, T4, T3, cortisol, somatomedin C, and sex steroids were normal. A decrease in the growth hormone response and elevation of basal prolactin and gonadotropins were noted in one. Both children demonstrated blunted thyrotropin-stimulating hormone (TSH) responses to thyrotropin-releasing hormone (TRH) in six of seven challenges. This prompted in vitro studies of cultured cells from rat pituitaries. After incubation of pituitary cells with 0.1-10 microM Pb2+ for 2 hr, followed by the addition of TRH, there was a dose-dependent inhibition of TSH release. Lead did not interfere with the assay of TSH. To investigate the interaction of lead and calcium, 45Ca2+ kinetic analyses were done on rat pituitary slices after 1 hr incubation with 1.0 microM lead. The impaired late efflux was consistent with a decrease in the size and exchangeability of the tightly bound pool of intracellular microsomal or mitochondrial calcium. The rat pituitary cell model provides a model for the decreased TSH release of lead poisoning, supports the biological plausibility of a neuroendocrine effect on growth, and suggests that interference with calcium-mediated intracellular responses is a basic mechanism of lead toxicity.

Animals↗
PubMed1986

Erythrocyte arginase, pyrimidine 5'-nucleotidase (P5N), and deoxypyrimidine 5'-nucleotidase (dP5N) as indices of lead exposure.

The activities of three erythrocyte (rbc) enzymes, arginase, pyrimidine 5'-nucleotidase (P5N), and deoxypyrimidine 5'-nucleotidase (dP5N), were compared in 16 lead workers and 14 age matched controls as correlates of blood lead (PbB) and unextracted zinc protoporphyrin (EP) concentrations. Subjects with PbB of 0.9-2.5 microM (19-52 micrograms/dl) had 6.5 +/- 0.6 IU of P5N activity with uridine monophosphate (UMP) as substrate, significantly less (p less than 0.001) than the 12.0 +/- 0.7 IU activity of controls with PbB 0.3-0.6 microM (6-12 micrograms/dl). The mean activity of rbc dP5N with either deoxyuridine monophosphate (dUMP) or thymidine monophosphate as substrate, and of rbc arginase, did not differentiate the two groups. The correlation coefficients of ln PbB with the selected substrates for P5N and dP5N were: UMP, r = -0.75; dUMP, r = -0.61; TMP, r = -0.23. The correlation coefficient of ln PbB and arginase activity was -0.03. Rbc P5N (UMPase) is a significant correlate of PbB, equivalent to rbc protoporphyrin. HPLC assay of rbc UMPase activity is a sensitive and rapid assay that appears to meet criteria for a reliable clinical laboratory index of blood lead concentrations.

5'-Nucleotidase↗
PubMed1985

Abnormal erythrocyte pyrimidine nucleotides in uremic subjects.

Uremia causes major increases in the erythrocyte (RBC) purine nucleotides, presumably secondary to phosphate retention, but no previous study has been made of the pyrimidine nucleotides, normally absent from RBC. This investigation was prompted by demonstration of the abnormal presence of RBC pyrimidine nucleotides, primarily cytidine triphosphate (CTP) plus cytidine diphosphate-choline (CDP-C) and cytidine diphosphate-ethanolamine (CDP-E), in two types of congenital hemolytic anemia as well as in lead poisoning. These observations suggested an analogy to the RBC membrane dysfunction of uremia. This is a report of the identification of CDP-C and CDP-E as the predominant abnormal pyrimidine nucleotides in the RBC hemolysates of uremic subjects. High-performance liquid chromatography of hemolysates from uremic adults showed a 50% increase in purine nucleotides and the abnormal presence of pyrimidine nucleotides and diesters at approximately 10% of the concentration of the purine nucleotides. By means of UV spectra and 31P nuclear magnetic resonance, these were identified as CDP-C and CDP-E. The increased purine and abnormal pyrimidine nucleotides of uremic RBC were unrelated to the pre- or posthemodialysis state, allopurinol, levels of blood lead, copper and zinc, or RBC pyrimidine 5'-nucleotidase, the cytosolic enzyme that specifically dephosphorylates the pyrimidine nucleotides. Although the accumulation of CTP, CDP-C and CDP-E may be an epiphenomenon of phosphate retention, it also suggests a common pathway to the accelerated hemolysis of chronic renal insufficiency.

5'-Nucleotidase↗
PubMed1979

Environmental lead and children: the Omaha study.

Blood lead (Pb B) was determined in 1232 samples from 831 children in Omaha and correlated with air lead (Pb A) concentrations of 0.02-1.69 microgram/m3 from 1971 to 1977. A bivariate equation for ages 6-18 yr based on these data predicts an increase in Pb B of 1.4 microgram/dl as Pb A increases from 1 to 2 microgram/m3. Pb B increases 7 microgram/dl as the mean values for soil and house dust Pb increase from 100 to 750 microgram/g. Multiple regression analysis shows that the combined effects of air, soil, and house dust Pb account for 21% of the variance of Pb B, with a high intercorrelation of all 3 variables. Since the variance of repeat sampling in individuals accounted for 38% of the total variance of Pb B, approximately 40% is unexplained and requires measurement of Pb from dietary and other sources.

Adolescent↗
PubMed1978

Low level lead and inhibition of erythrocyte pyrimidine nucleotidase.

Pyrimidine 5'-nucleotidase (P5N, EC 3.1.3.5) appears to be a sensitive index of exposure to low level lead. In 21 children 2 to 5 years old with blood leads of 7 to 80 micrograms/dl there was a negative linear correlation of blood lead and red cell P5N: r = -0.60 (P less than 0.01), Y = -0.11X + 12.3. In rats, the enzyme assay was quantitatively similar to that of the human. A treatment group of 12 rats received lead acetate, 36 mg/kg/day, of lead as 0.17 M lead acetate for 24 days. The blood lead of treated rats increased from the control value of 8.3 +/- 1.3 to 36.0 +/- 0.5 on day 24; P5N decreased from 18.3 +/- 0.8 units to 9.0 +/- 1.0 and was below control values at a blood lead of 25. There was a significant negative linear correlation of blood lead and P5N: r = -0.85; n = 17; P less than 0.001; Y = 0.34X + 20.9 that was independent of the correlationship with the reticulocytes. At these levels of blood lead and P5N there was no significant change in the hexokinase, hemoglobin or red cell count and no evidence of stippling.

5'-Nucleotidase↗
PubMed1977

Effect of anemia on blood and tissue lead in rats.

The effect of anemia on the lead content of blood, red cells, and tissue was studied in rats given oral lead, 54 mg/kg-day for 6 days. The 16 rats made anemic (hematocrit, 26%) by bleeding on days 1, 3, and 5 had significantly higher concentrations of lead in the kidney, liver, red cells, blood, and brain (but not in the bone marrow). Increases in blood lead in anemic subjects were correlated with the concentrations in red cells, kidney, and liver. The greater increase in the lead content of all tissues of the anemic rats is consistent with increased lead absorption in anemia and is considered relevant to the clinical coexistence of anemia and lead poisoning.

Anemia↗