Abstract  Vanadium, a dietary micronutrient, is now proving to be a promising anti-tumour agent. The present study was conducted to ascertain its anti-neoplastic potential against an experimental mammary carcinogenesis. Female Sprague-Dawley rats at 50 days of age were treated with 7,12-dimethylbenz(alpha)anthracene (DMBA; 0.5 mg per 100 g body weight) by a single tail vein injection in an oil emulsion. Vanadium (ammonium monovanadate) at a concentration of 0.5 p.p.m. was supplemented in the drinking water and given ad libitum to the experimental group immediately after the carcinogen treatment and it continued until the termination of the study (24 weeks for histological, immunological and biochemical observations and 35 weeks for morphological findings). It was found that vanadium treatment brought about substantial protection against DMBA-induced mammary carcinogenesis. This was evident from histological findings that showed substantial repair of hyperplastic lesions following supplementation of vanadium alone. There was a significant reduction in incidence (P < 0.05), total number, multiplicity (P < 0.01), size of palpable mammary tumours and delay in mean latency period of tumour appearance (P < 0.001) following vanadium supplementation compared to the DMBA control. The immunohistochemical localization of metallothionein (a prognostic marker for breast cancer) showed reduced expression with vanadium treatment. Further, DNA fragmentation in the mammary tissue of the vanadium-treated group indicated apoptosis. In this group, vanadium also caused a significant decrease in the number (P < 0.002) and focal area (P < 0.05) of gamma-glutaminetranspeptidase-positive hepatic foci. The results clearly show the anti-neoplastic potential of vanadium.

Abstract  In the present study, the authors evaluated the anticancer mechanism of vanadium, a dietary micronutrient and an important pharmacological agent, on a defined model of chemically induced rat mammary carcinogenesis in vivo and on human breast cancer cell line MCF7 in vitro. Female Sprague-Dawley rats were treated with 7,12-dimethylbenz(alpha)anthracene (0.5 mg/100 g body weight) by a single tail vein injection in an oil emulsion to induce mammary preneoplasia. Vanadium (ammonium monovanadate) at a concentration of 0.5 ppm (4.27 mu mol/l) was supplemented in drinking water and given ad libitum to the experimental groups for 24 weeks. Histological finding showed substantial repair of hyperplastic lesions. There was a significant reduction in incidence, multiplicity (34%, p < 0.01), size of palpable mammary tumors and delay in mean latency period of tumor appearance. Immunohistochemical analysis in vivo indicated a decrease in cell proliferation (24.68% p < 0.05) and an increase among the TUNEL-positive apoptotic cells along with strong expressions of p53 and Bax, and downregulation of Bcl2 proteins in the mammary tissue of vanadium-treated animals. Further, MCF7 cells were cultured in minimal essential medium and were treated with 100, 175 and 250 mu M of vanadium (ammonium monovanadate) for 36 hr. Exposure of MCF7 cells to vanadium led to induction of apoptosis in a dose-dependent manner. It was found further that vanadium treatment brought about a prominent cell cycle arrest and chromosomal condensation, leading to apoptosis (42.62 %, p < 0.05). Results of both the in vivo and in vitro study demonstrate that vanadium has the potential to be developed into an anti-breast cancer drug in the near future. (c) 2006 Wiley-Liss, Inc.

Abstract  This study analyzes the effects of sodium tungstate and vanadyl sulphate in the fructose-overloaded rat, a model of metabolic syndrome. Fructose (9 weeks) increased blood pressure, triglycerydemia, glycemia, and reduced release of vasodilator prostaglandins (prostacyclin and prostaglandin E2 ) in the mesenteric vascular bed. Sodium tungstate prevented those alterations; meanwhile vanadyl sulfate only prevented the increase in glycemia. In conclusion, the present experiments showed that sodium tungstate is more effective than vanadyl sulfate for the treatment of experimental metabolic syndrome in rats.

Abstract  The physiological significance of vanadium (Va) and its mechanisms of cardiovascular (CV) and renal toxicity (following chronic exposure) remain contradictory (Nechay 1984). Pentavalent vanadate (Va+5, as analogue of phosphate) and tetravalent vanadyl (resembling the size of Mg+2) have many potential sites of action. However, it is yet to be established whether CV and renal effects of Va involve inhibition and/or stimulation of various enzymatic activities (for instance, Na+, K+, ATPase and adenylate cyclase, respectively) and are influenced by other ions (like Na+, K+, Mg+2 and Mn+2) and/or by the redox and metabolic states of the involved cells. Contradictory results also concern the possibility that Va is implicated in certain types of arterial hypertension (Carmignani et al 1990).

Abstract  Vanadium (mostly as vanadyl) was found to induce arterial hypertension by acting on peptidergic and catecholaminergic systems as well as on Ca2+ homeostasis in vascular and cardiac myocells.

Abstract  Haematological effects of oral administration of ammonium metavanadate 0.19 mmol V/kg/day, vanadyl sulphate 0.15 mmol V/kg/day, and bis(maltolato)oxovanadium (i.v.) 0.18 mmol V/kg/day in drinking water for 12 weeks were investigated in Wistar rats. Some selected haematological indices of the peripheral blood, including haematocrit, haemoglobin, erythrocyte count, reticulocyte percentage, leukocyte count and its differential count, platelet count, and osmotic fragility of the erythrocyte were determined using the standard methods. It was found that, throughout the 12-week experimental period, there were no significant differences between the untreated controls and various groups of vanadium-treated rats in all of the parameters measured. It is thus concluded that ammonium metavanadate, vanadyl sulphate, and bis(maltolato) oxovanadium (i.v.), at least at the doses and at the duration of treatment employed, do not produce significant haematological toxicity in rats.

Abstract  The effect of vanadate, an agent that in rats exerts potent vasoconstrictor and diuretic action on blood pressure, cardiac output, total peripheral resistance and plasma and extracellular fluid volume, was investigated in normal rats and in rats with diminished renal excretory function. In normal rats, chronic dietary vanadate did not affect blood pressure, but induced an increase in total peripheral resistance and a decrease in cardiac output, plasma and extracellular fluid volume. In rats with diminished renal excretory function, vanadate increased blood pressure and total peripheral resistance without affecting cardiac output, plasma and extracellular fluid volume. The results indicate that this agent, with predominant vasoconstrictor action, does not cause sustained hypertension unless renal excretory function is diminished.

Abstract  Sodium metavanadate was tested for its effects on fetal development, reproduction, gestation and lactation in Sprague Dawley rats. Male rats were administered NaVO3 po at doses of 0, 5, 10 and 20 mg/kg/day for sixty days before mating with females which had received the same doses from 14 days previous to mating. These females received 0, 5, 10 and 20 mg NaVO3/kg/day during the periods of gestation and lactation. No significant adverse effects could be observed on: number of corpora lutea, implantations, live and dead fetuses, and resorptions. Significant decreases were observed in the development of the pups in all the vanadium -treated groups. All the doses used produced toxic effects in the offspring.

Abstract  Streptozotocin-diabetic and non-diabetic rats were given vanadyl sulphate in drinking water at concentrations of 0.5-1.5 mg/ml for one year. It was found that vanadyl treatment did not produce persistent changes in plasma aspartate aminotransferase, alanine aminotransferase, and urea, specific morphological abnormalities in the brain, thymus, heart, lung, liver, spleen, pancreas, kidney, adrenal, or testis, or abnormal organ weight/body weight ratio for these organs in either non-diabetic or diabetic animals. Treatment significantly reduced the incidence of the occurrence of urinary stones in non-diabetic rats. In diabetic animals vanadyl treatment significantly reduced the mortality rate and prevented the elevation of plasma levels of alanine aminotransferase and urea, the increases in organ size, and the occurrence of megacolon but did not affect the development of renal and testicular tumours. Plasma and tissue concentrations of vanadium were determined and found to have the following order of distribution: bone > kidney > testis > liver > pancreas > plasma > brain. Vanadium was retained in these organs at 16 weeks following vanadyl withdrawal while the plasma levels were beneath detection limits. It is concluded that vanadyl sulphate at antidiabetic doses is not significantly toxic to rats following a one-year administration in drinking water, but vanadium may be retained in various organs for months after cessation of treatment.

Abstract  Oral vanadate treatment is effective in normalizing blood glucose in both Type I and Type II diabetics. Using Sprague Dawley rats we examined the effectiveness of such treatment in amelioration of hyperglycemia in diabetic pregnancy and its effect on fetal growth in both normal and diabetic pregnant dams. Initiation of vanadate treatment to diabetic and normal pregnant dams increased blood vanadium levels in both groups, but this concentration in the diabetic pregnant group reached approximately twice the value present in the normal group. Despite this high blood vanadium level in the diabetic pregnant dams, oral vanadate treatment was not effective in normalizing blood sugar in this group. Additionally, vanadate treatment was found to be toxic during diabetic pregnancy, causing death to 45% of the test animals. Maternal blood vanadium had a negative effect on fetal development, markedly reducing the number of live fetuses per pregnancy. In summary, oral vanadate treatment is toxic and ineffective during diabetic pregnancies and interferes with fetal growth and development in both normal and diabetic pregnancy.

Abstract  Learning can be severely impaired as a consequence of exposure to environmental pollutants. Vanadium (V), a metalloid which is widely distributed in the environment, has been shown to exert toxic effects on a variety of biological systems including the nervous system. However, studies exploring the impact of vanadium on learning are limited. Herein, we investigated the effects of oral administration of sodium metavanadate (SMV) (15, 20 and 25mg/kg/day for 2weeks) on spatial learning using Morris water maze (MWM). Our results showed that pre-training administration of sodium metavanadate impaired learning in Morris water maze. Analyzing the role of cholinergic system in SMV-induced learning deficit, we found that bilateral intra-hippocampal infusion of nicotine (1μg/side) during training could significantly diminish the SMV-induced learning impairment. We next examined the expression of choline acetyltransferase (ChAT) and vesicular acetylcholine transporter (VAChT) as cholinergic markers in CA1 region of hippocampus as well as in medial septal area (MSA). Our molecular analyses showed that vanadium administration decreased ChAT and VAChT protein expression, an effect that was attenuated by nicotine. Altogether, our results confirmed the toxic effects of SMV on spatial acquisition, while also pointing to the neuroprotective effects of nicotine on SMV-induced impairments in learning capabilities. These findings might open a new avenue for the prevention of vanadium adverse effects on spatial learning and memory through activation of cholinergic signaling pathway.

Abstract  Vanadium compounds are able to interact with living cells exerting a variety of biological effects. The pentavalent form is the most stable and toxic form of the element. In systems in vitro pentavalent vanadium is an effective genotoxic agent, inducing DNA damage and chromosome malsegregation at low doses. On the other hand, no adequate in vivo data are available for the characterization of the genotoxic hazard following oral intake, the most relevant route of human exposure. In this study, the genotoxic effects produced by the oral intake of sodium ortho-vanadate (Na(3)VO(4)) were investigated. Male CD-1 mice were treated for 5 weeks with a range of concentrations of Na(3)VO(4) in drinking water (0.75-1500 mg/l). Both micronuclei and primary DNA lesions as detected by comet assay were assessed in several tissues. Statistically significant increases of micronuclei in bone marrow were observed in mice receiving the two highest concentrations of Na(3)VO(4) (750 and 1500 mg/l). A significant increase of comet tail length was observed in splenocytes of mice receiving Na(3)VO(4) at 1500 mg/l, whereas no effect was observed in bone marrow and testis cells. No treatment-related effect on sperm chromatin structure or on testis cell population was observed. The determination of vanadium content in mouse tissues at the end of treatment highlighted a very low internal exposure, especially in soft tissues. Overall, the results obtained indicate that the genotoxic activity of pentavalent vanadium is expressed in vivo only following high dose exposure, possibly as a consequence of the poor bioavailability of the element.

Abstract  Lung collagen content in rats continuously exposed for two generations to 20 ppm vanadium as sodium metavanadate drinking solution was quantified by measurement of hydroxyproline in hydrolysates of whole lungs. The content of soluble and insoluble collagen isolated from the lungs of the same treated rats was also quantified by the same means. It was found that the content and composition of lung collagen for both F1 term fetuses and 21-day-old F1 pups of the treated group did not differ from the results obtained for control rats of the same age. However, total collagen and soluble collagen within lungs of adult F1 rats and F2 term fetuses were significantly lower than in non-treated controls, while the content of insoluble lung collagen of the same rats was significantly higher.

Abstract  BACKGROUND: Data shows vanadium protects pancreatic beta cells (BC) from diabetic animals. Whether this effect is direct or through the relief of glucose toxicity is not clear. This study evaluated the potential effect of oral vanadyl sulfate (vanadium) on glycemic status and pancreatic BC of normal and diabetic rats.

METHODS: Rats were divided into five groups of normal and diabetic. Diabetes was induced with streptozocin (40 mg/kg, i.v.). Normal rats used water (CN) or vanadium (1 mg/ml VOSO4, VTN). Diabetic rats used water (CD), water plus daily neutral protamine Hagedorn insulin injection (80 U/kg, ITD) or vanadium (VTD). Blood samples were taken for blood glucose (BG, mg/dL) and insulin (ng/dL) measurements. After two months, the pancreata of sacrificed rats were prepared for islet staining.

RESULTS: Pre-treated normal BG was 88 ± 2, and diabetic BG was 395 ± 9. The final BG in CD, VTD, and ITD was 509 ± 22, 138 ± 14, and 141 ± 14, respectively. Insulin in VTN (0.75 ± 0.01) and VTD (0.78 ± 0.01) was similar, higher than CD (0.51 ± 0.07) but lower than CN (2.51 ± 0.02). VTN islets compared to CN had larger size and denser central core insulin immunoreactivity with plentiful BC. CD and ITD islets were atrophied and had scattered insulin immunoreactivity spots and low BC mass. VTD islets were almost similar to CN.

CONCLUSION: Besides insulin-like activity, vanadium protected pancreatic islet BC, and the relief of glucose toxicity happening with vanadium had a little role in this action.

Abstract  Selected biochemical parameters were studied in the blood of outbred, male Wistar rats which daily received to drink deionized water (Group I, control) or solutions of: sodium metavanadate (SMV; 0.100 mg V/mL)-Group II; chromium chloride (CC; 0.004 mg Cr/mL)-Group III; and SMV-CC (0.100 mg V and 0.004 mg Cr/mL)-Group IV for a 12-week period. The diet and fluid intake, body weight gain, and food efficiency ratio (FER) diminished significantly in the rats of Groups II and IV, compared with Groups I and III. The plasma total antioxidant status (TAS) as well as the MDA and the L: -ascorbic acid level in the erythrocytes (RBCs) remained unchanged in all the groups, whereas the plasma L: -ascorbic acid concentration decreased markedly in Group II, compared with Group III. The activities of Cu,Zn-superoxide dismutase (Cu,Zn-SOD), catalase (CAT), cellular glutathione peroxidase (cGSH-Px), and glutathione reductase (GR) in RBCs remained unaltered in all the treated rats. However, the activity of glutathione S-transferase (GST) and the content of reduced glutathione (GSH) in RBCs decreased and increased, respectively, in Groups II, III, and IV, compared with Group I. A vanadium-chromium interaction which affected the GST activity was also found. To summarize, SMV and CC administered separately or in combination in drinking water for 12 weeks did not alter either lipid peroxidation (LPO) or the activities of Cu,Zn-SOD, CAT, cGSH-Px, and GR, which allows a conclusion that both metals in the doses ingested did not reveal their pro-oxidant potential on RBCs.

Abstract  The alterations in the levels/activities of selected biomarkers for detecting kidney toxicity and in the levels of some oxidative stress (OS) markers and elements were studied in male rats to evaluate biochemically the degree of kidney damage, investigate the role of OS in the mechanism of functional renal disorders, reveal potential biomarkers of renal function, and assess the renal mineral changes in the conditions of a 12-week sodium metavanadate (SMV, 0.125 mg V/mL) exposure. The results showed that OS is involved in the mechanism underlying the development of SMV-induced functional renal disturbances. They also suggest that the urinary cystatin C (CysCu) and kidney injury molecule-1 (KIM-1u) could be the most appropriate to evaluate renal function at the conditions of SMV intoxication when the fluid intake, excreted urinary volume (EUV), body weight (BW), and the urinary creatinine excretion (Creu) decreased. The use of such tests as the urinary lactate dehydrogenase, alkaline phosphatase, γ-glutamyltranspeptidase, and N-acetyl-β-D-glucosaminidase (LDHu, ALPu, GGTPu, and NAGu) seems not to be valid given their reduced activities. The use of only traditional biomarkers of renal function in these conditions may, in turn, be insufficient because their alterations are greatly influenced by the changes in the fluid intake and/or BW.

Abstract  Background: Currently, energy obtained from hypercaloric diets has been part of the obesity and type 2 diabetes mellitus (T2DM) epidemics from childhood to old age. Treatment alternatives have been sought from plants, minerals, and trace elements with metabolic effects. Vanadyl sulfate (VS) has been investigated as a hypoglycemic compound in animal and human studies showing effective insulin-mimetic properties. This characteristic encompasses several molecules that have beneficial pleiotropic effects. The aim was to determine the antiobesity, hypoglycemic, and hypolipidemic effects of VS on fructose-induced metabolic syndrome in aged rats.

Material and Methods: Five groups of male Wistar rats were made, each with six rats: two groups with normal diet (ND) and three with high-fructose diet (HFD). The first ND group was treated with saline solution (SS), the second with VS; treatment for HFD groups was in the first group with SS, second with VS, and third with metformin. Weight, body mass index (BMI), blood glucose, and lipidic profile were measured; water, food, fructose and energy consumption were also determined. All parameters were compared among groups.

Results and Discussion: Although obese rats treated with VS presented anorexia, oligodipsia, and a marked weight loss in the first two weeks. They recovered food and water intake in the third week with a slow recovery of some weight weeks later. VS normalized blood glucose level and decreased triglyceride and insulin levels in obese rats. These results suggest that vanadyl sulfate shows antiobesity, hypoglycemic, and hypolipidemic properties in old obese rats and could be useful as an alternative, additional, and potent preventive treatment for obesity and T2DM control in elderly obese and poorly controlled diabetic patients.

Conclusion: VS could play an important role in the treatment of metabolic syndrome, contributing to a decrease in obesity and T2DM, through different ways, such as euglycemia, satiety, weight loss, and lipid profile optimization, among others. However, more research is needed to confirm this suggestion.

Abstract  Carcinogen-induced early DNA lesions and metallothionein (MT) over-expression have been implicated in cell proliferation and thereby subsequent expression of premalignant phenotype of the cell. We have therefore investigated the chemopreventive potential of vanadium in a multi-biomarker approach, viz. 8-hydroxy-2' -deoxyguanosines (8-OHdGs), DNA single-strand breaks (SSBs), DNA-protein crosslinks (DPCs), chromosomal aberrations (CAs), in situ MT expression, and cell proliferation in rat liver preneoplasia. Hepatocarcinogenesis was induced in male Sprague-Dawley rats with a single, necrogenic, intraperitoneal (i.p.) injection of diethylnitrosamine (DEN) (200 mg/Kg body weight) at week 4 of the experimental protocol followed by promotion with phenobarbital (PB) (0.05% in basal diet), on and from week 8 and continued till 32 weeks in a long-term regimen. There was a significant and steady elevation of modified DNA bases 8-OHdGs (P < 0.0001; 90.69%) along with substantial increments of the extent of SSBs (P < 0.001) and CAs (P < 0.001) following DEN exposure. Supplementation of vanadium at a dose of 0.5 ppm abated the formations of 8-OHdGs (80.63%; P < 0.0001), SS-DNAs (P < 0.001) and SSBs/DNA unit (P < 0.01; 56.39%), DPCs (59.26%; P < 0.0001) and CAs (71.52%; P < 0.001) in preneoplastic rat liver studied at various time points. Low dose of vanadium treatment further reduced liver-MT immunoreactivity (P < 0.05) and BrdU-labeling index (P < 0.02) and a significant positive correlation (r=0.92; r(2) =0.85; P=0.0001) was noted between them. Continuous vanadium administration also decreased nodular incidence (66.67%) and nodule multiplicity (62.12%; P < 0.001) along with substantial improvement in the altered hepatocellular phenotype when compared to DEN+PB treatment alone. The study indicates that vanadium-mediated suppression of cell proliferation and resulting premalignant expression might be due to the observed reductions in hepatic 8-OHdGs, SSBs, DPCs, CAs, and MT immunoreactivity. Vanadium is chemopreventive for DEN-induced hepatocellular preneoplasia in rats.

Abstract  The effects of sodium-arsenite (13466063), ammonium-molybdate (12027677), sodium-tellurate (10101834), sodium-tellurite (10102202), sodium-vanadate (13718268), and sodium-selenate (13410010), on growth and hemoglobin concentrations were studied in rats. Wistar-rats were fed salts of these elements at levels of 25 or 50 parts per million (ppm) of their diets. The effects upon growth, food consumption, mortality, and hemoglobin levels were examined. The rats were killed on the day 100 and autopsied. Only one rat given selenium lived 100 days, even at the 25ppm concentration. At the 50ppm concentration of selenium, the rats lived only a short time and lost body weight. At 25ppm arsenic and molybdenum had no effect on body weight. At 50ppm, a slight decrease in growth rate was seen. Tellurium produced lower body weights and lower food consumption. Vanadium produced lower body weights at 100 days. Rats receiving vanadium, especially at 50ppm, suffered diarrhea throughout the experiment. Of the five elements studied, selenium was the only one which affected hemoglobin concentrations; concentrations of hemoglobin were reduced and the rats with low hemoglobin died. The authors conclude that selenium was the most toxic of the elements investigated. The toxicity of the other elements decreased in the following order: vanadium, tellurium, molybdenum, and arsenic. All of these elements are present in soils of the western United States in concentrations high enough to produce toxic vegetation.

Abstract  The effects of 1, 10, or 40 micrograms/ml of vanadium, given for six or seven months as sodium metavanadate in drinking water on cardiovascular and biochemical variables and the electrolyte metabolism of male Sprague-Dawley rats were investigated. At the end of the exposure period, all animals exposed to vanadate had increased systolic and diastolic blood pressure. This effect was not dose dependent and heart rate and cardiac inotropism were not affected. The role of defective renal function and electrolyte metabolism in such effects was supported, in the rats exposed to 10 and 40 ppm of vanadium, by the following changes: (a) decreased Na, + K(+)-ATPase activity in the distal tubules of nephrons; (b) increased urinary excretion of potassium; (c) increase in plasma renin activity and urinary kallikrein, kininase I, and kininase II activities; (d) increased plasma aldosterone (only in the rats treated with 10 ppm of vanadium). The alterations in the rats exposed to 1 ppm of vanadium were: (a) reduced urinary calcium excretion; (b) reduced urinary kallikrein activity; (c) reduced plasma aldosterone. These results suggest that blood hypertension in rats exposed to vanadate depends on specific mechanisms of renal toxicity related to the levels of exposure.

Abstract  1. Male Wistar rats were given, for four weeks, a limited amount of food, or the amount of food and water equal to that consumed by rats drinking solely an aqueous solution of ammonium metavanadate instead of water (AMV) of 0.3 mg V/cm3 concentration. 2. In rats with limited access to food but free access to water, a significant decrease of body weight increment was observed, together with an increase of the haemoglobin level and a decrease in the percentage of reticulocytes and polychromatophilic erythrocytes in the peripheral blood. 3. In the rats which did not receive food and water ad libitum a significant decrease of the body weight increment and an increase of the haemoglobin level were noted. 4. In animals drinking the aqueous AMV solution instead of water the body weight increment diminished significantly, and so did the erythrocyte count and haemoglobin level, whereas the percentage of reticulocytes and polychromatophilic erythrocytes increased in the peripheral blood.

Abstract  OBJECTIVE: To investigate whether the reported insulin-like properties of vanadate may have hypertensinogenic actions in Sabra rats. DESIGN: Comparison of [3H]-deoxyglucose muscle uptake as well as blood pressure and its response to acute volume expansion and pressors infusions in 16 vanadate-treated (VT) and 12 control rats. METHODS: Rats drank either tap water or 0.2 g/l vanadate for 4 weeks. A trace amount of [3H]-deoxyglucose was administered intravenously to evaluate its plasma half-life and tissue uptake. Intra-arterial blood pressure was recorded in response to acute intravenous saline (4 ml/100 g body weight) and to incremental bolus injections of noradrenaline and angiotensin II (Ang II). RESULTS: Skeletal muscle uptake of [3H]-deoxyglucose was significantly higher in VT than in control rats. There was no difference between the blood pressure of VT or control rats; however, 2 h after saline loading the mean intra-arterial blood pressure was significantly higher in VT than in control rats. The Ang II-induced blood pressure rise was also significantly higher in VT rats. CONCLUSION: The insulin-like activity of vanadate may be associated with salt-sensitive hypertension.