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Biomedical subjects

F W Sunderman

Publications and source records attributed to F W Sunderman.

At least 37 records · Page 2Linked to original sources
PubMed1993

A nickel-binding serpin, pNiXa, induces maturation of Xenopus oocytes and shows synergism with oncogenic ras-p21 protein.

A nickel-binding serine proteinase inhibitor, pNiXa (43 kDa), was isolated from Xenopus ovary and assayed for effects on oocyte maturation. Microinjection of pNiXa (0.12 pmol/50 nl) induced maturation in 60% of Xenopus oocytes, beginning at 4 hours and reaching completion by 9 hours. Microinjection of oncogenic ras-p21 protein (0.12 pmol/50 nl) induced maturation in 79% of oocytes, beginning at 6 hours and reaching completion by 12 hours. Microinjection of pNiXa in combination with ras-p21 protein had a synergistic effect on maturation, which occurred in 92% of oocytes, beginning at 4 hours and reaching completion by 9 hours. Oocyte maturation did not occur in control oocytes, which received a microinjection of bovine serum albumin. In oocytes exposed to a combination of pNiXa (0.12 pmol/50 nl, by microinjection) and progesterone (10 micrograms/ml, in the medium), maturation was intermediate (68% at 9 hours) between that induced by pNiXa (60%) or progesterone (85%) alone. This study shows (a) that pNiXa is a potent inducer of oocyte maturation, (b) that pNiXa's effect is synergistic with that of oncogenic ras-p21 protein, and (c) that pNiXa partially antagonizes progesterone induction of oocyte maturation.

Animals↗
PubMed1992

The interactions of zinc, nickel, and cadmium with Xenopus transcription factor IIIA, assessed by equilibrium dialysis.

Transcription factor IIIA (TFIIIA) was isolated from Xenopus ovary and treated with 1,10-phenanthroline to remove zinc. The interactions of apoTFIIIA with Zn2+, Ni2+, and Cd2+ were studied by equilibrium dialysis under anaerobic conditions (pH 7.0, 25 degrees C), using 65ZnCl2, 63NiCl2, and 109CdCl2 as the radioligands. The data for binding of Zn2+, Ni2+, and Cd2+ to apoTFIIIA were best-fitted by a model with two classes of binding sites. For Zn2+, the apparent dissociation constants (KdlZn and Kd2Zn) for the high- and low-affinity sites were 1.0 x 10(-8) and 2.6 x 10(-5) M; the apparent binding capacities of the two classes were 0.8 +/- 0.5 and 9.6 +/- 0.3 g-atoms of Zn/mol; the Hill coefficient was 1.18, consistent with positive cooperativity of Zn-binding sites. For Ni2+, the apparent KdlNi and Kd2Ni values were 2.3 x 10(-5) and 5.2 x 10(-4) M; the apparent binding capacities were 2.3 +/- 0.6 and 8.6 +/- 0.6 g-atoms of Ni/mol; the Hill coefficient was 1.20, consistent with positive cooperativity of Ni-binding sites. For Cd2+, the apparent KdlCd and Kd2Cd values were 2.8 x 10(-6) and 1.6 x 10(-4) M; the apparent binding capacities were 0.9 +/- 0.3 and 2.4 +/- 0.5 g-atoms of Cd/mol; the Hill coefficient was 0.53, consistent with negative cooperativity or heterogeneity of Cd-binding sites. This study has the following significance: First, it helps to resolve a controversy about the zinc content of purified TFIIIA. Second, it shows that the KdlZn of apoTFIIIA is less than the reported KdZn of thionein, consistent with the hypothesis that thionein modulates gene expression by competing with TFIIIA and other Zn-finger proteins for intracellular Zn2+ stores. Third, it confirms previous indirect evidence that the affinity of apoTFIIIA for Zn2+ is much greater than for Cd2+, and that the affinity for Cd2+ is greater than for Ni2+.

Animals↗
PubMed1992

Teratogenicity of cadmium chloride in the South African frog, Xenopus laevis.

The teratogenicity of cadmium chloride was tested by the FETAX (Frog Embryo Teratogenesis Assay: Xenopus) procedure. In five assays, groups of Xenopus embryos were grown in media containing concentrations of 0.75-56 mumol/l; controls were incubated in medium without cadmium chloride. Exposures began 5 h post-fertilization and ended 101 h post-fertilization. In control groups, > 95% of embryos survived at 101 h and the incidence of malformations was < 7%. In Cd(2+)-exposed groups, concentration-dependent mortality and numerous malformations were observed, including gut malrotation, ocular anomalies, bent notochord, misshapen fin, facial dysplasia, cardiac deformities and dermal blisters. Other abnormalities included stunted growth and hypopigmentation. The minimum concentration of cadmium chloride that inhibited growth was 18 mumol/l. The median embryolethal concentration (LC50) was 32 (SE +/- 4) mumol/l; the median teratogenic concentration (EC50) was 3.7 (SE +/- 1) mumol/l; the teratogenic index (TI = LC50/EC50) was 8.6. This study demonstrates that cadmium chloride is teratogenic for Xenopus laevis and provides a standardized experimental model for studying the molecular mechanisms of cadmium teratogenesis.

Abnormalities, Drug-Induced↗
PubMed1992

pNiXa, a Ni(2+)-binding protein in Xenopus oocytes and embryos, shows identity to Ep45, an estrogen-regulated hepatic serpin.

A Ni(2+)-binding protein (pNiXa, 45 kD, pI 8.5) discovered in Xenopus embryos, was isolated from oocytes. Based on amino acid sequences, pNiXa belongs to the serpin superfamily and shows identity to the cDNA sequence of Ep45, an estrogen-regulated hepatic serpin that contains an (HX)n-motif found in eukaryotic transcription factors. Nondenatured pNiXa, purified by Ni-affinity chromatography, inhibited bovine alpha-chymotrypsin. The presence of pNiXa in embryos when they are susceptible to Ni2+, the high avidity of pNiXa for Ni2+, and the (HX)n-motif point to pNiXa as a molecular target of Ni(2+)-teratogenesis.

Amino Acid Sequence↗
PubMed1992

The history of proficiency testing/quality control.

The history and origins of proficiency testing of clinical laboratories are reviewed. Since the introduction of proficiency testing in the late 1940s, dramatic improvement in laboratory performance has been demonstrated. Nonetheless, the poor performance found two decades earlier was summoned to support the passage of the Clinical Laboratory Improvement Act of 1967 (CLIA '67).

Chemistry, Clinical↗
PubMed1991

Teratogenicity of cobalt chloride in Xenopus laevis, assayed by the FETAX procedure.

The teratogenicity of cobalt chloride (CoCl2) was tested by the FETAX (Frog Embryo Teratogenesis Assay: Xenopus) procedure in the South African frog, Xenopus laevis. In five assays, beginning at 5 h post-fertilization, groups of Xenopus embryos were incubated for 96 h in media that contained CoCl2 at concentrations ranging from 1.8 x 10(-6) to 1.8 x 10(-2) mol/L; control groups were incubated in the same medium without added CoCl2. At 101 h post-fertilization, surviving embryos were counted, fixed in formalin, and examined by microscopy to score malformations and measure head-to-tail lengths. In control embryos, survival was greater than or equal to 95% and malformations were less than or equal to 5%. Malformations were found in greater than 99% of embryos exposed to Co2+ levels greater than or equal to 56 mumol/L. Co2+)-exposed embryos showed a concentration-related pattern of malformations, comprising gut malrotation, ocular anomalies, kinked tail, craniofacial dysplasia, cardiac deformities, and dermal blisters. Other concentration-dependent abnormalities, not categorized as malformations, included stunted growth, edema, ventral distention, and hypopigmentation. The median embryolethal concentration (LC50) of CoCl2 was 10.4 (SE +/- 0.4) mmol/L; the median teratogenic concentration (EC50) was 25 (SE +/- 2) mumol/L; the teratogenic index (TI = LC50/EC50) was 416 (SE +/- 13), indicating that CoCl2 is a potent teratogen for Xenopus laevis.

Abnormalities, Drug-Induced↗
PubMed1991

Teratogenicity of Ni2+ in Xenopus laevis, assayed by the FETAX procedure.

The teratogenicity of Ni2+ was tested by the FETAX (Frog Embryo Teratogenesis Assay: Xenopus) procedure in the South African frog, Xenopus laevis. In seven assays, beginning at 5 h postfertilization, groups of Xenopus embryos were incubated for 96 h in media that contained Ni2+ (added as NiCl2) at concentrations ranging from 1 x 10(-7) to 3 x 10(-3) mol/L; control groups were incubated in the same medium without added NiCl2. At 101 h postfertilization, surviving embryos were counted, fixed in formalin, and examined by microscopy to determine their developmental stages, malformations, and head-to-tail lengths. In control embryos, survival was greater than or equal to 95% and malformations were less than or equal to 7%. Malformations were found in greater than 95% of embryos exposed to Ni2+ concentrations greater than or equal to 5.6 mumol/L. The most frequent malformations in Ni(2+)-exposed embryos were ocular, skeletal, and intestinal deformities; less common malformations included facial, cardiac, and integumentary deformities. Other abnormalities, not categorized as malformations, included stunted growth, dermal hypopigmentation, and coelomic effusions or hemorrhages. The median embryolethal concentration (LC50) of Ni2+ was 365 (SE +/- 9) mumol/L; the median teratogenic concentration (EC50) was 2.5 (SE +/- 0.1) mumol/L; the Teratogenic Index (TI = LC50/EC50) was 147 (SE +/- 5), indicating that Ni2+ is a potent teratogen for Xenopus laevis. Experiments in which Ni(2+)-exposures were limited to specific 24 h periods showed that Xenopus embryos were most susceptible to Ni(2+)-induced malformations on the second and third days of life, during the most active period of organogenesis.

Abnormalities, Drug-Induced↗
PubMed1991

Detection of two Zn-finger proteins of Xenopus laevis, TFIIIA, and p43, by probing western blots of ovary cytosol with 65Zn2+, 63Ni2+, or 109Cd2+.

Two Zn-finger proteins, TFIIIA (a constituent of 7S RNP particles) and p43 (a constituent of 42S RNP particles), were detected in ovary extracts of juvenile Xenopus laevis females by in vitro binding of radiolabeled divalent metals. Proteins fractionated by SDS-PAGE (sodium dodecylsulfate-polyacrylamide gel electrophoresis) were transferred by Western blotting onto nitrocellulose membranes, probed with 65Zn2+, 63Ni2+, or 109Cd2+, and visualized by autoradiography. Detection limits for TFIIIA were approx 0.07 micrograms/well by 109Cd(2+)-probing, 0.13 micrograms/well by 65Zn(2+)-probing, and 0.26 mu/well by 63Ni(2+)-probing. Protein p43 was more clearly visualized by probing with 63Ni2+ than with 65Zn2+ or 109Cd2+. After purified TFIIIA was cleaved with cyanogen bromide, 65Zn2+, 109Cd2+, and 63Ni2+ distinctly labeled the 22 kDa middle fragment; 65Zn2+ and 109Cd2+ also labeled the 11 kDa N-terminal fragment, but did not label the 13 kDa C-terminal fragment. These results are consistent with the notion that the radioligands were bound to finger-loop domains of TFIIIA, which occur in the middle and N-terminal fragments. Based on the abilities of nonradioactive metal ions to compete with 65Zn2+ for binding to TFIIIA on Western blots, the relative affinities of the metals for TFIIIA were ranked as follows: Zn2+ = Cu2+ greater than or equal to Hg2+ greater than Cd2+ greater than Co2+ greater than or equal to Ni2+. Even at a 1000-fold molar excess, Mn2+ did not compete with 65Zn2+ for binding to TFIIIA. Probing Western blots with the radiolabeled metal ions greatly facilitates the detection, isolation, and quantitation of TFIIIA and p43.

Animals↗
PubMed1991

Selection of low frequency tumor cells from cell culture by growth in nude mice.

Tissue cultures of tumor cells are frequently utilized to characterize chromosomal changes when direct cytogenetic preparations on tumors fail. The present study demonstrates that chromosomal markers found in direct tumor preparations can become undetectable in cell culture at variable rates presumably because of overgrowth of normal cell components in the culture. Injection of cultured tumor cells into nude mice followed by direct chromosomal preparations on the resulting nude mouse tumors can be used to select cells with the original tumor karyotype. This is true even when the tumor cell frequency in the culture is so low that they are not found in routine chromosomal preparations of the cultured cells. This technique can thus complement tissue culture findings and provide additional useful information about the original karyotype in cases where direct chromosomal preparations from tumors have failed.

Animals↗
PubMed1991

The effects of exposure to dietary nickel and zinc upon humoral and cellular immunity in SJL mice.

We are interested in potential interactions between environmental trace metal exposures and immune function. In particular, we have wondered whether dietary exposure to nickel and zinc cations can influence T and B cell proliferation and function. To study this question, we fed SJL female mice supplemental nickel and zinc sulfate from 4-8 weeks of age, and immunized the animals intraperitoneally (i.p.) with keyhole limpet hemocyanin (KLH) at 8 weeks. Eight days later, we measured antibody responses to KLH. Both IgG and IgM antibody responses to KLH were significantly depressed in vivo in the nickel fed animals (p less than 0.005). In vitro antigenic responsiveness to KLH of splenocytes from nickel fed animals was also depressed compared with control and zinc supplemented animals (p less than 0.002). This altered antigenic responsiveness persisted even after cells had been cultured for 5 days in standard media. The zinc supplemented diets did not seem to affect antibody responsiveness and proliferation. The proliferative responses of B cells to the mitogen lipopolysaccharide (LPS) were significantly depressed in Ni fed mice, but were not affected in the zinc fed animals. T cell mitogenic responses to concanavalin A were not affected in the nickel fed animals, and were enhanced in zinc fed animals. We conclude that dietary exposure to certain trace metals may induce persisting alterations in immunity in this animal model.

Analysis of Variance↗
PubMed1991

Cobalt in periprosthetic soft tissue. Observations in 6 revision cases.

Cobalt (Co) was analyzed in sera obtained before surgery and in biopsies of periarticular soft tissue from 7 control patients undergoing primary total hip arthroplasty and from 6 Co-exposed patients who developed aseptic loosening of the femoral component after hip arthroplasty (CoCrMo alloy, greater than 59 percent Co, metal-on-plastic type). Serum-Co concentrations were not elevated in the Co-exposed patients compared with control patients or healthy adults. In 5 of the 6 Co-exposed patients, Co concentrations were greatly increased in periprosthetic tissue sections 0-1 mm from the synovial surface (median 2.4 [2.1-27] micrograms Co/g) compared with corresponding sections from the control patients (median 0.4 [0.1-0.6] microgram Co/g). Co concentrations diminished in tissue sections at successive distances of 2-3 and 4-5 mm from the synovial surfaces. In the Co-exposed patients, Co concentrations in sera and periprosthetic soft tissues were not correlated, indicating that serum Co concentration is not a reliable index of the Co burden in periprosthetic soft tissue.

Adult↗
PubMed1990

Cross-shift and chronic effects of stainless-steel welding related to internal dosimetry of chromium and nickel.

Ninety welders from a stainless-steel fabricating plant were studied by pulmonary function tests and serum and urine chromium and nickel levels, cross-sectionally, and 31 were compared across a Monday shift. They had welded for a mean of 11 years, mean age was 44 years, and mean smoking duration was 20 years in 62 current smokers. Baseline spirometric tests were significantly reduced: FVC to 95.4 mean percentage of predicted (pop), FEV1 to 94.5 pop, FEF25-75 to 85.9 pop, and FEFR75-85 to 74.8 pop. Current smokers had greater reductions in flow rates and FVC than nonsmokers even after adjustment of their predicted values for the effects of duration of smoking. Neither alveolar volume at 104.3 pop nor diffusing capacity for carbon monoxide (single breath) at 98.5 pop was reduced. There were no significant changes in pulmonary function measurements across a Monday workshift in 31 welders, but in seven men who welded stainless steel, levels of serum chromium (Cr) rose 66% from 1.9 +/- 2.1 micrograms/liter and urinary Cr increased 22%. Serum nickel levels rose only 7%, although they were elevated before shift, 1.1 +/- 0.4 micrograms/liter (compared with 0.21 +/- 0.20 micrograms/liter in controls), and urinary nickel levels did not increase. Eleven years of welding had reduced vital capacities and expiratory flows. Monday stainless-steel welding raised the serum and urine chromium levels (measures of internal dosimetry for exposure) but did not decrease pulmonary function values.

Adult↗
PubMed1990

Uptake and release of 63Ni2+ by Xenopus embryos during early cleavage stages.

Uptake and release of 63Ni was studied in dejellied Xenopus laevis embryos exposed to 63Ni2+ (0.3-30 mumol/l) for 0.5-h intervals during the period 1-4.5 h post-fertilization (i.e. from first cleavage to early blastula stage). At first cleavage, the mean uptake of 63Ni by embryos was 12-17 times that by non-fertilized eggs, suggesting that conversion of the vitelline envelope to the fertilization envelope enhanced integumental permeability to 63Ni2+. 63Ni uptake by embryos at the 1-2-cell stage averaged 1.8-2.5 times that at the early blastula stage. An average of 5% of total 63Ni in washed embryos was recovered in isolated fertilization envelopes, indicating that 63Ni2+ passed through the envelope into internal compartments. Progressive increases of 63Ni uptake were seen with increasing exposure levels; after exposure during 1-1.5 h post-fertilization to the highest concentration of 63Ni2+ (30 mumol/l), 63Ni uptake averaged 11.4 (SD +/- 5.1) pmol/embryo. Rapid efflux of 63Ni was noted after 63Ni2(+)-exposed embryos were transferred to nickel-free medium; mean 63Ni contents at 0.25 h and 2 h post-exposure diminished to 50% and 15% of the initial values, regardless of the exposure level. The finding that Xenopus embryos are permeable to 63Ni2+ during early cleavage stages provides a convenient experimental system to investigate the embryotoxicity and teratogenicity of nickel.

Animals↗
PubMed1990

Detection of lipid peroxidation in lung and in bronchoalveolar lavage cells and fluid.

Inhalation of toxic materials such as asbestos, silica, 100% oxygen, ozone, or nitrogen dioxide may lead to an increased production of reactive oxygen metabolites which may initiate lipid peroxidation. Measurement of lipid peroxidation in cells and fluid obtained by bronchoalveolar lavage (BAL), as well as in lung tissue, may aid in monitoring the development and extent of pulmonary damage after inhalation of a toxic substance. In this study, we employed a sensitive assay for detection of malondialdehyde (MDA), a breakdown product of lipid peroxidation. By separation of the adduct with thiobarbituric acid, using a reverse phase high pressure liquid chromatographic technique, we accurately and sensitively measured the content of MDA in BAL cells, lavage fluid, and lavaged lung tissue homogenates of rats. The amounts of sample required for detection of MDA were small enough possibly to be applied to use with human specimens; in addition, recovery of added MDA was acceptable with all types of samples. Inclusion of a metal chelator in the preparation of samples appeared necessary to prevent metal-catalyzed propagation of lipid peroxidation during the assay. Overall, the method described here using samples from rats may be applicable to detecting lipid peroxidation in BAL samples from humans.

Animals↗
PubMed1990

Carcinogenesis bioassays of nickel oxides and nickel-copper oxides by intramuscular administration to Fischer-344 rats.

Five nickel oxides and nickel-copper oxides, with chemical compositions, physicochemical properties, and biological characteristics that were previously reported, were tested for carcinogenicity by administration to groups of male Fischer-344 rats as a single im injection (20 mg Ni/rat). Two additional groups of rats received injections of the glycerol vehicle (Negative Controls) or nickel subsulfide (alpha Ni3S2, 20 mg Ni/rat, Positive Controls). Within the observation period of 2 yr post-injection, the following numbers of sarcomas developed at the injection site: Negative Controls, 0/15; Positive Controls, 15/15; Compound A (INCO black NiO, prepared at less than 650 degrees C), 6/15; Compound B (grey NiO, calcined at 735 degrees C), 0/15; Compound F (green NiO, calcined at 1,045 degrees C), 0/15; Compound H (oxidized Ni-Cu matte, Ni/Cu = 2.5:1, calcined at 850 degrees C), 13/15; Compound I (oxidized Ni-Cu matte, Ni/Cu = 5:1, calcined at 850 degrees C), 15/15. The Ni- and Ni/Cu-oxides that induced sarcomas (Compounds A, H, and I) had measurable dissolution rates in body fluids and were strongly positive in an erythrocytosis stimulation assay, demonstrating Ni bioavailability. Compound A contained detectable Ni[III] and Compounds H and I contained Cu, plus traces of Fe, Co and S, which may all promote oxygen free-radical reactions. In contrast, the compounds that did not induce sarcomas (Compounds B and F) were essentially insoluble in body fluids, did not stimulate erythrocytosis, and were practically devoid of Ni[III], Cu, Fe, Co, or S. Thus, the bioavailability of nickel and the presence of constituents that promote oxygen free-radical reactions evidently influence the carcinogenicity of nickel oxides and related compounds.

Animals↗
PubMed1989

Cobalt, chromium, and nickel concentrations in body fluids of patients with porous-coated knee or hip prostheses.

Co, Cr, and Ni concentrations were determined by electrothermal atomic absorption spectrophotometry in serum and urine specimens collected from a group of 28 patients at intervals of from 1 day to 2.5 years after total knee or hip arthroplasty with porous-coated prostheses fabricated of Co-Cr alloy (ASTM F-75-82). Two control groups were also tested: (a) 42 healthy adults and (b) 16 orthopaedic patients after total knee or hip arthroplasty with porous-coated prostheses fabricated predominantly of Ti-Al-V alloy (ASTM F-136-84). All prostheses contained polyethylene components to avoid metal-to-metal contact. Mean Co concentrations in serum and urine were slightly increased in patients with Co-Cr knee implants at 6-120 weeks after surgery, compared with (a) preoperative values, (b) corresponding values in patients with Co-Cr hip implants, and (c) corresponding values in control patients with Ti-Al-V knee and hip prostheses. Substantially increased Co levels were observed in serum and urine of two patients at 7 weeks and 22 months postarthroplasty, associated with loosening of the prostheses; one of the patients also had elevated Cr levels in serum and urine. Although ASTM F-75-82 and F-136-84 alloys contain very little Ni (less than 1.0 and less than 0.2% Ni, respectively, by wt), mean Ni concentrations in serum and urine were greatly increased at 1-2 days after implantation of Ti-Al-V and Co-Cr prostheses, diminishing by 2 weeks. The postoperative hypernickelemia and nickeluresis may reflect contamination of the operative field with Ni-containing particles from the drills, cutting jigs, and drilling jigs, or it may represent a previously unrecognized pathophysiological response to surgery.

Adult↗