PubMed Health⌕ Search

Biomedical subjects

F W Sunderman

Publications and source records attributed to F W Sunderman.

At least 19 recordsLinked to original sources
PubMed2001

Nasal toxicity, carcinogenicity, and olfactory uptake of metals.

Occupational exposures to inhalation of certain metal dusts or aerosols can cause loss of olfactory acuity, atrophy of the nasal mucosa, mucosal ulcers, perforated nasal septum, or sinonasal cancer. Anosmia and hyposmia have been observed in workers exposed to Ni- or Cd-containing dusts in alkaline battery factories, nickel refineries, and cadmium industries. Ulcers of the nasal mucosa and perforated nasal septum have been reported in workers exposed to Cr(VI) in chromate production and chrome plating, or to As(III) in arsenic smelters. Atrophy of the olfactory epithelium has been observed in rodents following inhalation of NiSO4 or alphaNi3S2. Cancers of the nose and nasal sinuses have been reported in workers exposed to Ni compounds in nickel refining, cutlery factories, and alkaline battery manufacture, or to Cr(VI) in chromate production and chrome plating. In animals, several metals (eg, Al, Cd, Co, Hg, Mn, Ni, Zn) have been shown to pass via olfactory receptor neurons from the nasal lumen through the cribriform plate to the olfactory bulb. Some metals (eg, Mn, Ni, Zn) can cross synapses in the olfactory bulb and migrate via secondary olfactory neurons to distant nuclei of the brain. After nasal instillation of a metal-containing solution, transport of the metal via olfactory axons can occur rapidly, within hours or a few days (eg, Mn), or slowly over days or weeks (eg, Ni). The olfactory bulb tends to accumulate certain metals (eg, Al, Bi, Cu, Mn, Zn) with greater avidity than other regions of the brain. The molecular mechanisms responsible for metal translocation in olfactory neurons and deposition in the olfactory bulb are unclear, but complexation by metal-binding molecules such as carnosine (beta-alanyl-L-histidine) may be involved.

Animals↗
PubMed1998

Interactions of serine proteinases with pNiXa, a serpin of Xenopus oocytes and embryos.

In a previous study, kinetic assays showed that pNiXa, an Ni(II)-binding serpin of Xenopus oocytes and embryos, strongly inhibits bovine chymotrypsin, weakly inhibits porcine elastase, and does not inhibit bovine trypsin. In this study, analyses by SDS-PAGE and gelatin zymography showed that an SDS-resistant complex is formed upon the interaction of pNiXa with bovine chymotrypsin. No such pNiXa-enzyme complex was detected after pNiXa interactions with porcine elastase, bovine trypsin, or human cathepsin G. The major products of pNiXa cleavage by the four proteinases were partially sequenced by Edman degradation. The cleavage products were also tested by immunoblotting with an antibody to the His-cluster of pNiXa, and by radio-blotting with 63Ni(II). These assays showed that chymotrypsin and elastase cleave pNiXa at the P1-P1 (Thr-Lys) peptide bond near the C-terminus, while trypsin and cathepsin G cleave pNiXa at specific peptide bonds near the N-terminus, within an interesting 26-residue segment, rich in Lys and Gln, that separates the His-cluster of pNiXa from the rest of the molecule. The segment lacks homology to other serpins, but resembles a domain of Xenopus POU3 transcription factor. This study identifies the specific sites for interactions of four serine proteinases with pNiXa, indicates that pNiXa inhibition of chymotrypsin involves a serpin-like mechanism, and shows that 63Ni(II)-binds to the His-cluster of pNiXa.

Amino Acid Sequence↗
PubMed1996

Zn(2+)-induction of metallothionein in myotomal cell nuclei during somitogenesis of Xenopus laevis.

The localization of metallothionein in control and Zn-exposed embryos of Xenopus laevis was studied by whole-mount immunohistochemical staining. The embryos were grown according to the FETAX (Frog Embryo Teratogenesis Assay: Xenopus) protocol from N/F stage 8 to stage 47, with or without addition of ZnCl2 (300 microM) to the medium. At stages 27, 38, 42, 45 and 47, control and Zn-exposed embryos were fixed in buffered formalin, and whole mounts were stained by an immunoperoxidase technique, using monoclonal murine antibody to equine metallothionein. Staining of metallothionein was evident in myotomal cell nuclei of developing somites by stage 27, stomatodeum, oropharynx, and gills by stage 38, developing kidneys (mesonephros) by stage 45, and liver by stage 47. The staining of metallothionein at these sites was more intense in Zn-exposed embryos than controls. The central nervous system (especially the spinal cord) and the yolk mass were faintly stained for metallothionein in controls and Zn-exposed embryos. Staining of metallothionein in myotomal cell nuclei was most prominent at stage 38, diminished at stages 42 and 45, and practically disappeared by stage 47. This is the first report that metallothionein is expressed in myotomal cell nuclei of Xenopus embryos during normal somitogenesis and becomes increased when the embryos are exposed to teratogenic levels of Zn2+.

Animals↗
PubMed1996

Characterization of pNiXa, a serpin of Xenopus laevis oocytes and embryos, and its histidine-rich, Ni(II)-binding domain.

A Ni(II)-binding serpin, pNiXa, is abundant in Xenopus oocytes and embryos. Kinetic assays show that purified pNiXa strongly inhibits bovine alpha-chymotrypsin (Ki = 3 mM), weakly inhibits porcine elastase (K1 = 0.5 microM), and does not inhibit bovine trypsin. The reversible, slow-binding inhibition of alpha-chymotrypsin by pNiXa is unaffected by Ni(II). Ovochymase in egg exudates is inhibited by pNiXa, but to a limited extent, even at high pNiXa concentrations. An octadecapeptide that models the His-rich domain (-HRHRHEQQGHHDSAKHGH-) of pNiXa forms six-coordinate, octahedral Ni(II)-complexes when the N-terminus is acetylated, and a square-planar Ni(II)-complex when the N-terminus is unblocked. Spectroscopy reveals two distinct types of octahedral Ni(II)-coordination to the N-acetylated octadecapeptide, involving, respectively, 3-4 and 5-6 imidazole nitrogens; the octadecapeptide undergoes partial, reversible precipitation in pH- and Ni(II)-dependent fashion, suggesting an insoluble, Ni(II)-coupled (Hx)n-dimer. Such (Hx)n-peptide interaction is confirmed by an enzyme-linked biotinavidin assay with N-biotin-KHRHRHE-amide and N-acetyl-KHRHRHE-resin beads, which become coupled after adding Ni(II) or Zn(II). H2O2 oxidation of 2'-deoxyguanosine to mutagenic 8-hydroxy-2'-deoxyguanosine is enhanced by the octahedral Ni(II)-octadecapeptide complex, although the effect is more intense with the square-planar Ni(II)-octadecapeptide complex. Immunoperoxidase staining of whole mounts with pNiXa antibody shows that pNiXa is distributed throughout gastrula-stage embryos and is localized during organogenesis in the brain, eye, spinal cord, myotomes, craniofacial tissues, and other sites of Ni(II)-induced anomalies. Patterns of pNiXa staining are similar in controls and Ni(II)-exposed embryos. Binding of Ni(II) to pNiXa may cause embryotoxicity by enhancing oxidative reactions that produce tissue injury and genotoxicity. Although the natural target proteinases for pNiXa inhibition have not been established, pNiXa may be an important regulator of proteolysis during embryonic development.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1996

Metal carcinogenesis in total joint arthroplasty. Animal models.

As early as 1956, laboratory investigations into the carcinogenicity of modern dental and orthopaedic alloys were undertaken. Such studies were prompted by the observation that workers, particularly in nickel and chromate refining, had increased risks of nasal and lung tumors. For the past 25 years, sporadic case reports have documented the development of malignant neoplasms proximate to an orthopaedic implant. Although the results of epidemiologic studies have not shown an excessive number of tumors in patients receiving stainless steel or superalloy implants, the possibility of carcinogenesis, given the corrosive environment in which metal implants exist, has prompted ongoing laboratory studies. Leaching of metal ions from implants, the synovial processing of metallic wear debris, and the effects of exposure to intraarticular metal particles have been the subjects of numerous laboratory studies. The results of these studies are summarized and recommended parameters for future laboratory investigations are given.

Alloys↗
PubMed1995

The 40 kDa 63Ni(2+)-binding protein (pNiXc) on western blots of Xenopus laevis oocytes and embryos is the monomer of fructose-1,6-bisphosphate aldolase A.

A Ni(2+)-binding protein (pNiXc, 40 kDa), present in Xenopus laevis oocytes and embryos, was isolated from mature oocytes by chromatography on DEAE-cellulose and cellulose phosphate, followed by FPLC on Ni-iminodiacetate-Agarose, or reverse-phase HPLC on a C-4 column. Size-exclusion HPLC showed that intact pNiXc is approximately 155 kDa, consistent with tetrameric structure. After cleavage with Lys-C proteinase or cyanogen bromide, six peptides were separated by HPLC and sequenced by Edman degradation, providing sequence data for 83 residues. Data-base search showed similarity of pNiXc to eukaryotic aldolases, with 96% identity to human aldolase A. pNiXc demonstrated aldolase activity with fructose 1,6-bisphosphate as substrate (Km, 30 microM Vmax 26 mumol min-1 mg-1); the aldolase activity was inhibited non-competitively by Cu2+, Cd2+, Co2+, or Ni2+. Equilibrium dialysis showed high affinity binding (Kd, 7 microM) of 1 mole of Ni per mole of 40 kDa subunit. Based on metal-blot competition assays, the abilities of metals to compete with 63Ni2+ for binding to pNiXc were ranked: Cu2+ >> Zn2+ > Cd2+ > Co2+. This study identifies pNiXc as the monomer of fructose-1,6-bisphosphate aldolase A, and raises the possibility that aldolase A is a target enzyme for metal toxicity.

Amino Acid Sequence↗
PubMed1995

Xenopus lipovitellin 1 is a Zn(2+)- and Cd(2+)-binding protein.

This report discusses the identification of a Zn(2+)- and Cd(2+)-binding protein of Xenopus laevis that is abundant in vitellogenic oocytes and in embryos from fertilization to stage 46. Oocyte or embryo homogenates were fractionated by SDS-PAGE, blotted onto nitrocellulose, and probed with 65Zn2+ or 109Cd2+. The resulting autoradiograms showed binding of both radionuclides to a protein, designated pCdZn. Freon extraction of oocyte and embryo homogenates showed pCdZn to be a yolk protein. When pCdZn was isolated from oocyte homogenates by ammonium sulfate precipitation, delipidation, and chromatography, it co-purified with lipovitellin 1. The amino acid composition of pCdZn closely resembled the reported composition of lipovitellin 1 and the molecular weight of purified pCdZn (approximately 115 kD) corresponded to reported values for lipovitellin 1 (111-121 kD). Amino acid sequence analyses of five peptides derived from pCdZn yielded 94% identity to the reported sequence of lipovitellin 1, deduced from the DNA sequence of the Xenopus vitellogenin A2 precursor gene. Based on these findings, pCdZn was identified as lipovitellin 1. This study suggests that lipovitellin 1 is the major storage protein for zinc in mature oocytes and developing embryos of Xenopus laevis.

Amino Acid Sequence↗
PubMed1995

Intraarticular carcinogenesis bioassays of CoCrMo and TiAlV alloys in rats.

Wear-debris powders of cobalt-chromium-molybdenum (CoCrMo) and titanium-aluminum-vanadium (TiAlV) alloys, which are widely used for orthopedic implants (eg, hip and knee prostheses), were tested for carcinogenic activity following intraarticular administration (20 mg/rat) to groups of 44 male Fischer-344 rats (Charles River Breeding Laboratories, North Wilmington, MA). Control groups received similar intraarticular injections of either a noncarcinogen (manganese powder, negative control rats) or a potent carcinogen (nickel subsulfide powder, positive control rats). The experimental groups of 8-12 rats were observed for 24 months after injection. No local tumors developed at the injection site in the negative control rats or in rats that received the CoCrMo or TiAlV powders; poorly differentiated or pleomorphic sarcomas developed at the injection site in 10 of the 12 positive control rats that were treated with nickel subsulfide. Incidences of primary tumors distant from the injection site did not differ significantly among the experimental groups. This study shows that, under experimental conditions, any carcinogenic activity of CoCrMo or TiAlV wear-debris powders is weak in comparison to nickel subsulfide. Based on this study and observations in other laboratories, intraarticular administration of test materials to rats provides a practical, reliable, and biologically relevant method for carcinogenesis testing of biomaterials used for orthopedic implants.

Alloys↗
PubMed1995

Effects of teratogenic exposures to Zn2+, Cd2+, Ni2+, Co2+, and Cu2+ on metallothionein and metallothionein-mRNA contents of Xenopus embryos.

Xenopus laevis embryos were analyzed for metallothionein by silver-saturation assay and metallothionein-mRNA by reverse transcriptase/polymerase chain reaction following exposures to the following metal chlorides at levels that caused > 95% malformations and < 7% mortality: Zn2+ (300 microM); Cd2+ (18 microM); Ni2+ (56 microM); Co2+ (1,800 microM); and Cu2+ (5.6 microM). At the beginning of the exposure (stages 8), metallothionein-mRNA and metallothionein levels averaged 2.0 x 10(6) copies/embryo and 19 pmol/embryo, respectively. In control embryos at stages 26, 36, 42, and 46, metallothionein-mRNA content averaged 9, 37, 104, and 97 copies x 10(6)/embryo, and metallothionein content averaged 6, 11, 15, and 18 pmol/embryo. In Zn(2+) -exposed embryos at the same stages, metallothionein-mRNA content averaged 116*, 11,400*, 3,210*, and 14 copies x 10(6)/embryo and metallothionein content averaged 10, 18*, 46*, and 90* pmol/embryo; in Cd(2+)-exposed embryos, metallothionein-mRNA content averaged 22, 7,170*, 1,783*, and 240 copies x 10(6)/embryo and metallothionein content averaged 8, 14, 33*, and 56* pmol/embryo, respectively (*P < 0.05 versus controls). Exposure-response curves (Cd2+, 1-18 microM; Zn2+, 3-300 microM) indicated that Cd2+ was 3- to 5-times more potent than Zn2+, based on metallothionein-mRNA response at stage 36 and metallothionein response at stage 46. In Ni(2+)-, Co(2+)-, or Cu(2+)-exposed embryos, metallothionein-mRNA and metallothionein contents did not differ significantly from controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Abnormalities, Drug-Induced↗
PubMed1995

Protein Hpn: cloning and characterization of a histidine-rich metal-binding polypeptide in Helicobacter pylori and Helicobacter mustelae.

Helicobacter pylori is a human gastrointestinal pathogen involved in gastritis, duodenal ulcers, and gastric neoplasia. This microorganism produces large amounts of a urease which, like all known ureases, has nickel in the active site. We have identified a protein in clinical isolates of H. pylori and an identical protein in the ferret pathogen Helicobacter mustelae that strongly binds Ni2+ and Zn2+. This protein has been named Hpn to emphasize its origins in H. pylori and its affinity for nickel. The encoding hpn gene, cloned and expressed in Escherichia coli ER1793, has an open reading frame (180 bp) that specifies a protein with a calculated molecular mass of 7,077 Da and with the same amino-terminal sequence as that of wild-type Hpn. The deduced sequence of Hpn consists of 60 amino acids, of which 28 (47%) are histidines. The hpn gene does not map with the urease gene cluster on the H. pylori chromosome. An Hpn-negative, isogenic H. pylori strain, generated by hpn gene deletion and grown on blood agar, had the same urease activity that wild-type cells did. Thus, the role of Hpn in helicobacters is unknown.

Amino Acid Sequence↗
PubMed1994

The problem of latency in the development of tumors following exposure to nickel compounds.

Six previously published animal studies of tumor production have been reviewed, in order to relate time interval between exposure to nickel and development of tumor formation. Biopsies at intervals before final tumor formation, in some of these experiments, were reviewed to define interim changes between exposure and tumor diagnosis. Correlation between rat and human life span was used to suggest a latency of human tumor expectancy following exposure to nickel.

Animals↗
PubMed1994

Tentative reference values for nickel concentrations in human serum, plasma, blood, and urine: evaluation according to the TRACY protocol.

Published reports of Ni concentrations in human serum or plasma, whole blood, and urine have been reviewed in order to establish a database of reference values. In keeping with the TRACY program as previously applied to Hg, reports were evaluated in the categories of description of sample population, specimen collection and processing, analytical methods, and data presentation. Based on these considerations, eight studies of Ni in serum were deemed suitable for establishing reference levels in the general population. In five of these studies, the mean values for serum Ni concentration were < 0.3 microgram/l and the upper limits were < or = 1.1 micrograms/l. Six studies of Ni in urine were found suitable, and in four of these the mean values of Ni were < or = 2.0 micrograms/l and the upper limits were < or = 6.0 micrograms/l. Fewer studies on Ni in whole blood have been reported, and the Ni content of blood remains uncertain.

Humans↗
PubMed1994

Lipovitellin 2 beta is the 31 kD Ni(2+)-binding protein (pNiXb) in Xenopus oocytes and embryos.

An Ni(2+)-binding protein (pNiXb, 31 kD) present in mature Xenopus laevis oocytes and in embryos from fertilization in N/F stage 42, was isolated and characterized. After oocytes or embryos were fractionated by PAGE, electroblotted onto nitrocellulose, and probed with 63Ni2+, pNiXb was detected by autoradiography. pNiXb, a yolk protein located in the embryonic gut, was purified from yolk platelets by ammonium sulfate precipitation, delipidation, gel filtration chromatography, and HPLC analysis. During these steps, pNiXb copurified with lipovitellin 2. The N-terminal sequence of purified pNiXb exactly matched that of Xenopus lipovitellin 2 beta, deduced from the DNA sequence of the Xenopus vitellogenin A2 precursor gene. Since pNiXb and lipovitellin 2 beta agree in N-terminal sequence, amino acid composition, and apparent molecular weight, they appear to be identical. Based on a metal-blot competition assay, the abilities of metal ions to compete with 63Ni2+ for binding to pNiXb were ranked: Zn2+ approximately Cu2+ approximately Co2+ > Cd2+ approximately Mn2+ > Sn2+. This study shows that Xenopus lipovitellin 2 beta is a metal-binding protein in vitro, and raises the possibility that it may function similarly in vivo.

Amino Acid Sequence↗
PubMed1994

Malformations persist after metamorphosis of Xenopus laevis tadpoles exposed to Ni2+, Co2+, or Cd2+ in FETAX assays.

This study was performed to determine whether malformations induced in Xenopus laevis embryos by exposures to divalent nickel, cobalt, or cadmium chlorides in FETAX assays persist after the tadpoles undergo metamorphosis to juvenile frogs. Embryos were exposed for four days to EC50 concentrations of Ni2+, Co2+, or Cd2+ under the standard conditions of FETAX assays; thereafter, the exposures were discontinued and the tadpoles were kept in aquaria through metamorphosis. Controls were treated similarly, without exposure to metals. At 13 weeks of age, surviving frogs were killed and examined for malformations. Control and metal-exposed groups of Xenopus did not differ significantly in their median ages at metamorphosis, mean body weights, or survival at 13 weeks. Overall incidences of malformations found in Ni(2+)-, Co(2+)-, or Cd(2+)-exposed frogs at 13 weeks of age were 55, 40, and 51%, respectively (P < 0.01 vs. 3% in controls). The malformations of metal-exposed frogs included retinal depigmentation, diastematomyelia, scoliosis, kyphosis, phocomelia, sacro-pelvic and hind-limb deformities, and dysplasia of the heart, kidney, ovary and gut.

Abnormalities, Drug-Induced↗
PubMed1993

Biological monitoring of nickel in humans.

The literature since 1985 on the biological monitoring of occupational, environmental, or iatrogenic exposures of humans to nickel is surveyed from the author's perspective. Urine and serum are the body fluids commonly analyzed for nickel. Nickel concentrations in urine specimens from unexposed persons usually exceed the current analytical detection limits, while nickel concentrations in their serum specimens are close to the detection limits. For this reason, and because urine collection is painless, noninvasive, and convenient, urine is more practical than serum for the biological monitoring of nickel-exposed workers. Electrothermal atomic absorption spectrometry with Zeeman background correction is currently the method of choice for the analysis of nickel in biological materials. Procedures for quality assurance and strategies for biological monitoring are summarized, as performed in the author's laboratory, and current reference values are listed for nickel concentrations in urine and serum specimens from healthy unexposed persons.

Environmental Monitoring↗
PubMed1993

Search for molecular mechanisms in the genotoxicity of nickel.

This paper reviews recent studies done in the author's laboratory on molecular mechanisms of nickel genotoxicity, using as an experimental model the teratogenic effects of bivalent nickel ions (Ni2+) in South Africa frogs (Xenopus laevis). A Ni(2+)-binding protein, pNiXa, was identified in Xenopus oocytes and embryos (molecular weight 45 kDa, isoelectric point approximately 8.5) with a strong homology to human alpha 1-antitrypsin, alpha 1-antichymotrypsin, and other serine proteinase inhibitors. CNBr peptides of pNiXa showed sequence identity to Ep45. Nondenatured pNiXa, purified by nickel affinity chromatography, inhibits bovine alpha 1-chymotrypsin. The possibility that pNiXa plays a key role in Ni2+ teratogenesis is indicated by (i) the avidity of pNiXa for Ni2+, (ii) the presence of pNiXa when the embryos are susceptible to Ni2+ teragenesis, and (iii) the potential of the (HX)n-motif to form Ni2+ complexes that could catalyze the formation of oxygen free radicals and thereby damage deoxyribonucleic acid (DNA) and chromosomes.

Abnormalities, Drug-Induced↗