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Biomedical subjects

J M Quinn

Publications and source records attributed to J M Quinn.

At least 19 recordsLinked to original sources
PubMed2001

A novel osteoblast-derived C-type lectin that inhibits osteoclast formation.

We have cloned and expressed murine osteoclast inhibitory lectin (mOCIL), a 207-amino acid type II transmembrane C-type lectin. In osteoclast formation assays of primary murine calvarial osteoblasts with bone marrow cells, antisense oligonucleotides for mOCIL increased tartrate-resistant acid phosphatase-positive mononucleate cell formation by 3-5-fold, whereas control oligonucleotides had no effect. The extracellular domain of mOCIL, expressed as a recombinant protein in Escherichia coli, dose-dependently inhibited multinucleate osteoclast formation in murine osteoblast and spleen cell co-cultures as well as in spleen cell cultures treated with RANKL and macrophage colony-stimulating factor. Furthermore, mOCIL acted directly on macrophage/monocyte cells as evidenced by its inhibitory action on adherent spleen cell cultures, which were depleted of stromal and lymphocytic cells. mOCIL completely inhibited osteoclast formation during the proliferative phase of osteoclast formation and resulted in 70% inhibition during the differentiation phase. Osteoblast OCIL mRNA expression was enhanced by parathyroid hormone, calcitriol, interleukin-1alpha and -11, and retinoic acid. In rodent tissues, Northern blotting, in situ hybridization, and immunohistochemistry demonstrated OCIL expression in osteoblasts and chondrocytes as well as in a variety of extraskeletal tissues. The overlapping tissue distribution of OCIL mRNA and protein with that of RANKL strongly suggests an interaction between these molecules in the skeleton and in extraskeletal tissues.

Amino Acid Sequence↗
PubMed2001

Hydroxyapatite particles are capable of inducing osteoclast formation.

Hydroxyapatite (HA) coatings have been used to improve implant fixation by promoting bone formation around the prosthesis. A macrophage response to HA particulates has been noted around loosened HA-coated prostheses. As biomaterial wear particle-associated macrophages are known to be capable of differentiating into osteoclasts that are capable of bone resorption, we examined whether particulate HA could similarly induce macrophage-osteoclast differentiation. HA-associated macrophages were isolated from granulomas, formed by subcutaneous implantation of HA, and co-cultured with UMR 106 osteoblast-like cells in the presence of 1,25-dihydroxyvitamin D(3) for up to 14 days on glass coverslips and bone slices. HA-associated macrophage-osteoclast differentiation was evidenced by the formation of numerous multinucleated tartrate resistant acid phosphatase (TRAP)-positive cells which formed lacunar resorption pits on bone slices. Polymethylmethacrylate (PMMA) particle-associated macrophages, isolated from subcutaneous PMMA-containing granulomas, caused significantly more osteoclast formation and bone resorption than HA-associated macrophages. These results indicate that macrophages responding to HA particles are capable of osteoclast differentiation. They also suggest that particles derived from uncemented (HA-coated) implants are likely to induce less osteoclast formation and osteolysis than cemented implants.

Journal Article↗
PubMed2001

Bone morphogenetic protein 2 stimulates osteoclast differentiation and survival supported by receptor activator of nuclear factor-kappaB ligand.

Bone is a major storage site for TGFbeta superfamily members, including TGFbeta and bone morphogenetic proteins. It is believed that these cytokines are released from bone during bone resorption. Recent studies have shown that both RANKL and macrophage colony-stimulating factor are two essential factors produced by osteoblasts for inducing osteoclast differentiation. In the present study we examined the effects of bone morphogenetic protein-2 on osteoclast differentiation and survival supported by RANKL and/or macrophage colony-stimulating factor. Mouse bone marrow-derived macrophages differentiated into osteoclasts in the presence of RANKL and macrophage colony-stimulating factor. TGFbeta superfamily members such as bone morphogenetic protein-2, TGFbeta, and activin A markedly enhanced osteoclast differentiation induced by RANKL and macrophage colony-stimulating factor, although each cytokine alone failed to induce osteoclast differentiation in the absence of RANKL. Addition of a soluble form of bone morphogenetic protein receptor type IA to the culture markedly inhibited not only osteoclast formation induced by RANKL and bone morphogenetic protein-2, but also the basal osteoclast formation supported by RANKL alone. Either RANKL or macrophage colony-stimulating factor stimulated the survival of purified osteoclasts. Bone morphogenetic protein-2 enhanced the survival of purified osteoclasts supported by RANKL, but not by macrophage colony-stimulating factor. Both bone marrow macrophages and mature osteoclasts expressed bone morphogenetic protein-2 and bone morphogenetic protein receptor type IA mRNAs. An EMSA revealed that RANKL activated nuclear factor-kappaB in purified osteoclasts. Bone morphogenetic protein-2 alone did not activate nuclear factor-kappaB, but rather inhibited the activation of nuclear factor-kappaB induced by RANKL in purified osteoclasts. These findings suggest that bone morphogenetic protein-mediated signals cross-communicate with RANKL-mediated ones in inducing osteoclast differentiation and survival. The enhancement of RANKL-induced survival of osteoclasts by bone morphogenetic protein-2 appears unrelated to nuclear factor-kappaB activation.

Animals↗
PubMed2001

Transforming growth factor beta affects osteoclast differentiation via direct and indirect actions.

Transforming growth factor beta (TGF-beta) is abundant in bone and has complex effects on osteolysis, with both positive and negative effects on osteoclast differentiation, suggesting that it acts via more than one mechanism. Osteoclastogenesis is determined primarily by osteoblast (OB) expression of the tumor necrosis factor (TNF)-related molecule receptor activator of NF-kappaB ligand (RANKL) and its decoy receptor osteoprotegerin (OPG), which are increased and decreased, respectively, by osteolytic factors. A RANKL-independent osteoclastogenic mechanism mediated by TNF-alpha has also been shown. Therefore, we investigated TGF-beta effects on osteoclast formation in culture systems in which osteoclastogenic stimulus is dependent on OBs and culture systems where it was provided by exogenously added RANKL or TNF-alpha. Both OPG and TGF-beta inhibited osteoclast formation in hemopoietic cell/OB cocultures, but the kinetics of their action differed. TGF-beta also inhibited osteoclastogenesis in cocultures of cells derived from OPG null (opg-/-) mice. TGF-beta strongly decreased RANKL messenger RNA (mRNA) expression in cultured osteoblasts, and addition of exogenous RANKL to TGFbeta-inhibited cocultures of opg-/- cells partially restored osteoclastogenesis. Combined, these data indicate that the inhibitory actions of TGF-beta were mediated mainly by decreased OB production of RANKL. In contrast, in the absence of OBs, TGF-beta greatly increased osteoclast formation in recombinant RANKL- or TNF-alpha-stimulated cultures of hemopoietic cells or RAW 264.7 macrophage-like cells to levels several-fold greater than attainable by maximal stimulation by RANKL or TNF-alpha. These data suggest that TGF-beta may increase osteoclast formation via action on osteoclast precursors. Therefore, although RANKL (or TNF-alpha) is essential for osteoclast formation, factors such as TGF-beta may powerfully modify these osteoclastogenic stimuli. Such actions may be critical to the control of physiological and pathophysiological osteolysis.

Animals↗
PubMed2001

Forecasting rehabilitation outcomes for degraded New Zealand pastoral streams.

To understand the timescales and magnitude of responses that can be expected following catchment and riparian rehabilitation, we forecast changes to selected stream ecosystem attributes following tree planting in a pastoral catchment. All planting scenarios were predicted to lead to decreases in daily maximum water temperature after 15-20 years to levels that would be suitable for sensitive invertebrate species. Cooling and reheating were rapid so that most benefits to water temperature along the mainstem were forecast to accrue from shading all of the stream channel network. All planting scenarios were predicted to increase sediment yields over the status quo over the 25-year timeframe examined, with maximal sediment yield occurring about 15 years after planting due to expected erosion of the streambanks under the developing forest shade. Sediment yield was greatest for full catchment planting over 25 years, although sediment yield would be lowest with this scenario over longer timescales. A macroinvertebrate biotic index was predicted to increase by 25% over 15 years if whole catchment afforestation were implemented, compared to 9% if only the 4th order mainstem were planted with riparian trees. The use of ecological forecasting to predict likely outcomes for a range of scenarios should prove useful for prioritising rehabilitation actions.

Agriculture↗
PubMed2000

Coordinate copper- and oxygen-responsive Cyc6 and Cpx1 expression in Chlamydomonas is mediated by the same element.

Chlamydomonas reinhardtii activates the transcription of the Cyc6 and the Cpx1 genes (encoding cytochrome c(6) and coprogen oxidase) in response to copper deficiency. Mutational analysis of promoter regions of the Cyc6 and Cpx1 genes revealed a four nucleotide sequence, GTAC, which was absolutely essential for copper responsiveness. The Cyc6 promoter contains two copper response elements, each with a functionally important GTAC sequence, whereas the Cpx1 promoter contains only one. This may contribute to the stronger and more tightly regulated expression of the Cyc6 gene. Mutation or deletion of sequences flanking the GTACs implicates additional nucleotides contributing to copper-responsive expression, but none are absolutely essential. Metal ion selectivity of Cpx1 expression is identical to that described previously for Cyc6 and is restricted to the copper deficiency-induced Cpx1 transcript. The Cyc6 and Cpx1 genes are also induced by oxygen deficiency. Reporter gene constructs indicate that the induction occurs at the level of transcription and requires the same GTAC sequence that is critical for copper responsiveness. We suggest that components of the copper-responsive signal transduction pathway are used for some of the changes in gene expression in hypoxic cells.

Animals↗
PubMed2000

Expression of osteoclast differentiation factor at sites of bone erosion in collagen-induced arthritis.

OBJECTIVE: To investigate the cellular mechanism of bone destruction in collagen-induced arthritis (CIA). METHODS: After induction of CIA in DA rats, a histologic study of the advanced arthritic lesion was carried out on whole, decalcified joints from the hindpaws of affected animals. To conclusively identify osteoclasts, joint tissue sections were stained for tartrate-resistant acid phosphatase (TRAP) enzyme activity, and calcitonin receptors (CTR) were identified using a specific rabbit polyclonal antibody. The expression of messenger RNA (mRNA) for the osteoclast differentiation factor (also known as receptor activator of nuclear factor kappaB ligand [RANKL]) was investigated using in situ hybridization with a specific riboprobe. RESULTS: TRAP-positive and CTR-positive multinucleated cells were invariably detected in arthritic lesions that were characterized by bone destruction. Osteoclasts were identified at the pannus-bone and pannus-subchondral bone junctions of arthritic joints, where they formed erosive pits in the bone. TRAP-positive multinucleated cells were detected within synovium and at the bone erosive front; however, CTR-positive multinucleated cells were present only at sites adjacent to bone. RANKL mRNA was highly expressed in the synovial cell infiltrate in arthritic joints, as well as by osteoclasts at sites of bone erosion. CONCLUSION: Focal bone erosion in CIA is attributed to cells expressing definitive features of osteoclasts, including CTR. The expression of RANKL by cells within inflamed synovium suggests a mechanism for osteoclast differentiation and activation at sites of bone erosion. Inhibitors of RANKL may represent a novel approach to treatment of bone loss in rheumatoid arthritis.

Acid Phosphatase↗
PubMed2000

Fibroblastic stromal cells express receptor activator of NF-kappa B ligand and support osteoclast differentiation.

Osteoclast formation in bone is supported by osteoblasts expressing receptor activator of NF-kappa B ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) expression. Numerous osteotropic factors regulate expression levels of RANKL and the RANKL decoy receptor osteoprotegerin (OPG) in osteoblasts, thereby affecting osteoclast differentiation. However, not only in RANKL widely expressed in soft tissues, but osteoclasts have been noted in extraskeletal lesions. We found that cultured skin fibroblastic cells express RANKL, M-CSF, and OPG messenger (mRNA). Stimulation by 1 alpha,25 dihydroxyvitamin D3 [1,25(OH)2D3] plus dexamethasone (Dex) augmented RANKL and diminished OPG mRNA expression in fibroblastic cells and caused the formation of numerous osteoclasts in cocultures of skin fibroblastic cells with hemopoietic cells or monocytes. The osteoclasts thus formed expressed tartrate-resistant acid phosphatase (TRAP) and calcitonin (CT) receptors and formed resorption pits in cortical bone. Osteoclast formation also was stimulated (in the presence of Dex) by prostaglandin E2 (PGE2), interleukin-11 (IL-11), IL-1, tumor necrosis factor-alpha (TNF-alpha), and parathyroid hormone-related protein (PTHrP), factors which also stimulate osteoclast formation supported by osteoblasts. In addition, granulocyte-macrophage-CSF (GM-CSF), transforming growth factor-beta (TGF-beta), and OPG inhibited osteoclast formation in skin fibroblastic cell-hemopoietic cell cocultures; CT reduced only osteoclast nuclearity. Fibroblastic stromal cells from other tissues (lung, respiratory diaphragm, spleen, and tumor) also supported osteoclast formation. Thus, RANKL-positive fibroblastic cells in extraskeletal tissues can support osteoclastogenesis if osteolytic factors and osteoclast precursors are present. Such mesenchymally derived cells may play a role in pathological osteolysis and may be involved in osteoclast formation in extraskeletal tissues.

Animals↗
PubMed1999

Induction of coproporphyrinogen oxidase in Chlamydomonas chloroplasts occurs via transcriptional regulation of Cpx1 mediated by copper response elements and increased translation from a copper deficiency-specific form of the transcript.

Coproporphyrinogen III oxidase, encoded by a single nuclear gene in Chlamydomonas reinhardtii, produces three distinct transcripts. One of these transcripts is greatly induced in copper-deficient cells by transcriptional activation, whereas the other forms are copper-insensitive. The induced form of the transcript was expressed coordinately with the cytochrome c6-encoding (Cyc6) gene, which is known to be transcriptionally regulated in copper-deficient cells. The sequence GTAC, which forms the core of a copper response element associated with the Cyc6 gene, is also essential for induction of the Cpx1 gene, suggesting that both are targets of the same signal transduction pathway. The constitutive and induced Cpx1 transcripts have the same half-lives in vivo, and all encode the same polypeptide with a chloroplast-targeting transit sequence, but the shortest one representing the induced form is a 2-4-fold better template for translation than are either of the constitutive forms. The enzyme remains localized to a soluble compartment in the chloroplast even in induced cells, and its abundance is not affected when the tetrapyrrole pathway is manipulated either genetically or by gabaculine treatment.

Amino Acid Sequence↗
PubMed1999

Activated T lymphocytes support osteoclast formation in vitro.

Osteoblastic stromal cells are capable of supporting osteoclast formation from hematopoietic precursors in the presence of osteotropic factors such as 1alpha,25(OH)(2)D(3), PTH, and IL-11. Osteoblastic stromal cells produce receptor activator of NF-kappaB ligand (RANKL), a type II membrane protein of the TNF ligand family, in response to these agents. Activated T lymphocytes also produce RANKL; however, the ability of this cell type to support osteoclast formation in vitro is unknown. Human PBMC-derived T cells, extracted using alphaCD3-coated magnetic beads, were cocultured with adherent murine spleen cells in the presence of Con A and a panel of cytokines. In the presence of Con A, bona fide osteoclasts were formed in vitro with activated T cells: IL-1alpha and TGFbeta further enhanced osteoclast numbers. PBMC-derived lymphocytes showed an increase in the mRNA expression of RANKL within 24 h of treatment with the same agents that were used to induce osteoclast formation. In synovial tissue sections with lymphoid infiltrates from RA patients, the expression of RANKL was demonstrated in CD3(+) T cells. The ability of activated T lymphocytes to support osteoclast formation may provide a mechanism for the potentiation of osteoclast formation and bone resorption in disease states such as rheumatoid arthritis.

Aged↗
PubMed1999

Calcitonin receptor antibodies in the identification of osteoclasts.

Osteoclasts are the cells responsible for bone resorption, and their number and rate of formation are critical in determining bone mass. To identify and quantify osteoclasts, as well as to study their formation in bone and in osteoclastogenic cultures, osteoclast-specific cell markers are required. Only the calcitonin receptor (CTR) expression unambiguously identifies osteoclasts and distinguishes them from macrophage polykaryons. However, present autoradiographic methods for CTR detection are cumbersome and time consuming. We have developed rabbit polyclonal antibodies specific for the C-terminal intracellular domain of the mouse and rat Cla CTR. These antibodies labeled HEK-293 cells stably transfected with CTR (but not untransfected HEK-293 cells). This labeling is abrogated by preabsorbing the antibodies with the recombinant antigen. The antibodies immunostained primary mouse and rat osteoclasts as well as osteoclasts in sections of mouse bone. Osteoclasts (both mononuclear and multinucleated) formed from mouse bone marrow or spleen cells cocultured with osteoblasts in the presence of 1,25 dihydroxyvitamin D3 and prostaglandin E2 were also specifically immunostained by the CTR antibodies. Cocultures incubated under conditions that did not allow osteoclastogenesis (i.e., omission of mediators or osteoblasts, or culture for less than 4 days) were not immunostained by CTR antibodies. Autoradiographic detection of 125I-labeled salmon calcitonin combined with CTR immunohistochemistry showed that both methods labeled the same cells. A CTR polyclonal antibody and monoclonal antibody F4/80 were used in combination to show immunofluorescence labeling of murine osteoclasts and macrophage populations, respectively, in marrow/osteoblast cocultures. These results indicate that simple and rapid CTR antibody-based methods can be used to identify osteoclasts, and can be used to characterize the antigenic profile of osteoclasts by using double immunofluorescence analysis.

Animals↗
PubMed1999

Localization of RANKL (receptor activator of NF kappa B ligand) mRNA and protein in skeletal and extraskeletal tissues.

RANKL (receptor activator of NFkappaB ligand) is a membrane-associated osteoblastic molecule, and along with macrophage-colony-stimulating factor, is crucial for osteoclast formation. RANKL is known to be strongly expressed in osteoblasts and lymphoid tissues. We have sought to determine the skeletal and extraskeletal sites of production of RANKL mRNA and protein using the techniques of in situ hybridization and immunohistochemistry. Expression of RANKL mRNA and protein were determined in the developmental progression of endochondral bone formation in mouse, intramembranous bone formation in a rabbit model (mRNA only), in human giant cell tumors of bone, and at extraskeletal sites in the mouse. RANKL mRNA was expressed in prehypertrophic and hypertrophic chondrocytes at day E15 embryonic mouse long bone, and its expression was maintained at these sites throughout development. In newborn and adult mice, high levels of RANKL mRNA were expressed in mesenchymal cells of the periosteum and in mature osteoblasts, while megakaryocytes within the marrow microenvironment expressed RANKL mRNA from 1 week of age. Immunohistochemical analysis revealed a similar localization pattern of RANKL protein at the sites described. In the intramembranous bone formation model, RANKL mRNA was expressed in mesenchymal cells and in actively synthesizing osteoblasts, but not in flattened lining osteoblasts or late osteocytes. Expression of RANKL mRNA and protein in osteoclasts was variable with those within resorption lacunae showing the strongest signal/staining. Likewise, expression varied in osteoclasts from giant cell tumor of bone with a minority of tartrate-resistant acid phosphatase-positive multinucleated cells having no detectable RANKL mRNA or protein. In extraskeletal tissues, RANKL mRNA and protein were detected in the brain, heart, kidney, skeletal muscle, and skin throughout mouse development, suggesting the possibility of several other functions of the molecule. RANKL was also developmentally regulated, as evidenced by its expression in the intestine, liver, and lung at E15 and newborn mouse but not in the adult.

Amino Acid Sequence↗
PubMed1999

The patient-related costs of care for sepsis patients in a United Kingdom adult general intensive care unit.

OBJECTIVE: To determine the patient-related costs of care for critically ill patients with severe sepsis or early septic shock. DESIGN: Retrospective, longitudinal, observational study during a 10-month period. SETTING: Adult general intensive care unit (ICU) in a university hospital located in the United Kingdom. PATIENTS: The study population consisted of 213 patients admitted consecutively to the ICU during a 10-month period. Thirty-six patients were identified using standard definitions as having developed sepsis and analyzed by group (according to the day on which sepsis was diagnosed): Group 1 patients were septic at admission to ICU (n = 16); group 2 patients were septic on their second day in the ICU (n = 10); and group 3 patients developed sepsis after their second day in the ICU (n = 10). One hundred and seventy-seven ICU patients without sepsis were used as the comparative group (group 4). INTERVENTIONS: None. MAIN RESULTS: Patient-related costs of care, length of ICU stay, and ICU and hospital mortality rates were compiled. The median daily costs of care for patients in groups 1, 2, and 3 were $930.74 (interquartile range $851.59-$1,263.96); $814.47 ($650.89-$1,123.06), and $1,079.39 ($705.02-$1,295.96), respectively; these were significantly more than the group 4 patient's daily cost of $750.38 ($644.10-$908.55) (p < .01). The median total cost of treating the group 4 patients was $1,666.87 ($979.71-$2,772.03), significantly less than for the patients with sepsis (p < .01). The difference in total costs of care between the sepsis groups was also significant (p < .05), with a group 1 patient costing $3,801.55 ($1,865.28-$11,676.08), a group 2 patient costing $13,089.17 ($5,792.94-$22,235.18), and a group 3 patient costing $17,962.78 ($13,030.83-$28,546.73). Patients in groups 1, 2, and 3 stayed in the ICU for 3.3 days (1.3-11.3), 16.5 days (8.9-22), and 16.1 days (10.9-9), respectively. Significant differences were found among the three groups (p < 0.05), as well as between the patients with sepsis and those without (p < 0.001), whose median length of stay was 1.9 days (0.9-3.6). The ICU mortality rates were 50% each for groups 1 and 2, 60% for group 3, and 20% for group 4. Only one patient with sepsis and 16 patients without sepsis died in the hospital ward, producing overall mortality rates of 56% for group 1 and 29% for group 4. CONCLUSIONS: Patients with severe sepsis or early septic shock had a high mortality rate, spent prolonged periods of time in the ICU, and were significantly more expensive to treat than nonsepsis ICU patients.

APACHE↗
PubMed1998

Human tumour-associated macrophages differentiate into osteoclastic bone-resorbing cells.

Macrophages are commonly found within osteolytic secondary carcinomas in bone, but the manner in which these cells contribute to malignant bone resorption is uncertain. Macrophages isolated from primary breast carcinomas were co-cultured for up to 21 days with UMR 106 rat osteoblast-like cells on bone slices and glass coverslips in the presence and absence of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] and human macrophage colony stimulating factor (M-CSF). Cell cultures were then assessed for the presence of phenotypic markers of macrophage and osteoclast differentiation. Isolated cells were negative for osteoclast markers including tartrate-resistant acid phosphatase (TRAP), vitronectin receptor (VNR), and the ability to carry our lacunar bone resorption, but were positive for CD11b and CD14, macrophage markers which are not present on osteoclasts. In 21-day co-cultures of breast carcinoma tumour-associated macrophages (TAMs) and UMR 106 cells, incubated in the presence of 1,25(OH)2D3 and M-CSF, numerous TRAP- and VNR-positive multinucleated cells capable of extensive lacunar resorption were formed. Contact with UMR 106 cells and the presence of 1,25(OH)2D3 and M-CSF were absolute requirements for differentiation of human breast carcinoma TAMs into mature functional osteoclasts. TAM-osteoclast differentiation may represent an important cellular mechanism of osteolysis in metastatic skeletal carcinomas.

Bone Neoplasms↗
PubMed1998

Uranyl nitrate: 28-day and 91-day toxicity studies in the Sprague-Dawley rat.

Although uranium (U) is a classic experimental nephrotoxin, there are few data on its potential long-term chemical toxicity. These studies were undertaken to derive a no-observed-adverse-effect level (NOAEL) in male and female Sprague-Dawley rats following 91-day exposure to uranium (as uranyl nitrate hexahydrate, UN) in drinking water. Following a 28-day range-finding study, five groups of 15 male and 15 female weanling rats were exposed for 91 days to UN in drinking water (0.96, 4.8, 24, 120, or 600 mg UN/L). A control group was given tap water (< 0.001 mg U/L). Daily clinical observations were recorded. Following the study, animals were euthanized and exsanguinated, and multiple hematological and biochemical parameters were determined. Necropsies were conducted, and multiple tissues were sampled for histopathological examination. The hematological and biochemical parameters were not affected in a significant exposure-related manner. Although there were qualitative and slight quantitative differences between males and females, histopathological lesions were observed in the kidney and liver, in both males and females, in all groups including the lowest exposure groups. Renal lesions of tubules (apical nuclear displacement and vesiculation, cytoplasmic vacuolation, and dilation), glomeruli (capsular sclerosis), and interstitium (reticulin sclerosis and lymphoid cuffing) were observed in the lowest exposure groups. A NOAEL was not achieved in this study, since adverse renal lesions were seen in the lowest exposed groups. A lowest-observed-adverse-effect level of 0.96 mg UN/L drinking water can be reported for both the male and the female rats (average dose equivalent 0.06 and 0.09 mg U/kg body wt/day, respectively).

Animals↗
PubMed1998

Uranyl nitrate: 91-day toxicity studies in the New Zealand white rabbit.

These studies were undertaken to derive a lowest-observed-adverse-effect level (LOAEL) in the New Zealand White rabbit following a 91-day exposure to uranium (U, as uranyl nitrate hexahydrate, UN) in drinking water. Males were exposed for 91 days to UN in their drinking water (0.96, 4.8, 24, 120, or 600 mg UN/L). Subsequently, females were similarly exposed for 91 days (4.8, 24, or 600 mg UN/L). Control groups were given tap water (< 0.001 mg U/L). Regular observations were recorded, and urine was collected periodically. Four males showed evidence of Pasteurella multocida infection and were excluded from the study. Following the study, all animals were euthanized, and multiple hematological and biochemical parameters were determined. Necropsies were conducted, and histopathological examination was performed. The hematological and biochemical parameters were not affected in a significant exposure-related manner. Dose-dependent differences consisted of histopathological changes limited primarily to kidney. Changes in renal tubules were characteristic of uranium toxicity. Based on changes in the tubular nuclei, the 91-day LOAEL for males in this study is 0.96 mg UN/L drinking water. The females drank 65% more water than the males, yet appeared to be less affected by the exposure regimen, although they also developed significant tubular nuclear changes in their lowest exposure group, deriving a LOAEL of 4.8 mg UN/L. Tissue uranium residue studies suggested that pharmacokinetic parameters for the males and females differ, possibly accounting for the difference in observed sensitivity to UN. An adverse effect of P. multocida infection cannot be excluded.

Animals↗
PubMed1998

Uranyl nitrate: 91-day exposure and recovery studies in the male New Zealand white rabbit.

This study was undertaken to examine the reversibility of renal injury in the male New Zealand White rabbit subsequent to a 91-day exposure to uranyl nitrate (UN) in drinking water, followed by various recovery periods. Specific pathogen-free (SPF) animals were exposed for 91 days to UN in their drinking water (24 or 600 mg UN/L). Control groups were given municipal tap water (< 0.001 mg U/L). Regular clinical observations were recorded, and urine was collected periodically. Recovery periods between the last UN exposure and termination were 0, 8, 14, 45, or 91 days. Following the study, all animals were anesthetized and terminated by exsanguination, and multiple hematological and biochemical parameters were determined. Necropsies were conducted, and histopathological examination was performed. Exposure-related histopathological changes were observed only at much higher doses than in our previous male rabbit study where non-SPF-free animals had been used. Minor increases in kidney to body weight ratios were observed in the high-dose groups following exposure and early recovery. Renal tubular injury with degenerative nuclear changes, cytoplasmic vacuolation, and tubular dilation was seen in the high-dose group, without consistent resolution even after 91 days recovery. Animals ingested approximately 33% more uranium per day in this study than did males in a comparable dose group in the previous study, yet their kidney tissue uranium residues were 30% lower. These results suggest that SPF rabbits are less sensitive to uranyl injury than the non-SPF animals. The lowest-observed-adverse-effect level is estimated to lie at or below 24 mg UN/L.

Animals↗