germanium and Body-Weight

Adipose tissue inflammation induced by macrophage infiltration through the MCP-1/CCR2 pathway is considered to play a pivotal role in the development of visceral obesity and insulin resistance. In the present study, therefore, we examined whether pharmacological inhibition of CCR2 is effective against the development of diet-induced metabolic disorders.. C57BL/6 mice were fed a high fat and sucrose diet with or without propagermanium (CCR2 inhibitor, 5 or 50 mg/kg BW/day) for 12 weeks from 6 weeks of age. Then we analyzed lipid and glucose metabolism and tissue inflammation in the liver and adipose tissues along with serum markers in those mice.. Propagermanium treatment slightly decreased body weight gain and visceral fat accumulation in diet-induced obese (DIO) mice. Further, propagermanium suppressed macrophage accumulation and shifted adipose tissue macrophage polarization from the pro-inflammatory (M1) state to anti-inflammatory (M2) state in DIO mice. Expressions of TNF-alpha and MCP-1 mRNA in adipose tissue were reduced by propagermanium treatment, indicating that propagermanim suppressed inflammation in adipose tissue. Propagermanium treatment also ameliorated glucose tolerance, insulin sensitivity, and decreased hepatic triglyceride in DIO mice. Thus, propagermanium improved diet-induced obesity and related metabolic disorders, such as insulin resistance and hepatic steatosis by suppressing inflammation in adipose tissue. Our data indicate that inhibition of CCR2 could improve diet-induced metabolic disorders, and that propagermanium may be a beneficial drug for the treatment of metabolic syndrome.

Topics: Adipose Tissue; Animal Feed; Animals; Body Weight; Fatty Liver; Germanium; Inflammation; Insulin Resistance; Lipids; Male; Mice; Mice, Inbred C57BL; Obesity; Organometallic Compounds; Propionates; Receptors, CCR2; Tumor Necrosis Factor-alpha

The semiconductor element, germanium (Ge), is essential for the manufacture of modern integrated circuits. Because of its anti-tumor and immunomodulative effects, Ge-containing compounds are also used as health-promoting ingredients in food. However, some histological studies have shown the toxic effects of Ge-containing compounds on various organs, including the central nervous system. Even now, the effect of germanium on auditory system function is not completely clear. To clarify this question, brainstem auditory evoked potentials (BAEPs) were applied to examine the effect of germanium dioxide (GeO(2)) on the ascending auditory pathway. Since the voltage-gated sodium channel is important to neuron activation and nerve conduction, the effect of GeO(2) on voltage-gated sodium channels was also examined. The result revealed GeO(2) elevated the BAEPs threshold dose-dependently. GeO(2) also prolonged latencies and interpeak latencies (IPLs) of BAEPs, but the amplitudes of suprathreshold intensities (90dB) did not show any obvious change. In addition, the results of whole cell patch clamp studies indicated GeO(2) reduced inward sodium current. These results suggest the toxic effect of GeO(2) on the conduction of the auditory system, and that inhibitory effect of GeO(2) on the voltage-gated sodium channels might play a role in GeO(2)-induced abnormal hearing loss.

Topics: Animals; Auditory Pathways; Body Weight; Cell Line, Tumor; Dose-Response Relationship, Drug; Electrophysiology; Evoked Potentials, Auditory, Brain Stem; Germanium; Ion Channel Gating; Male; Mice; Neurons; Patch-Clamp Techniques; Rats; Rats, Wistar; Sodium Channel Blockers; Sodium Channels

Single- and 13-week repeated-dose toxicities of Geranti Bio-Ge Yeast, organic germanium fortified yeasts, were investigated in rats. Both sexes of Sprague-Dawley rats were orally administered once at a dose of 2,000 mg/kg in single-dose toxicity or daily for 13 weeks at doses of 500, 1,000 or 2,000 mg/kg in repeated-dose toxicity tests. In single-dose toxicity test to determine dose levels in repeated-dose toxicity study, the body weight gain was suppressed at 2,000 mg/kg, although no death, clinical signs and pathological findings related to the treatment were observed. In repeated-dose toxicity test, there were no clinical signs in animals administered up to 2,000 mg/kg, except one rat died due to a gavage error. In addition, no significant changes in feed consumption and body weight gain were obtained during the treatment period, in spite of week-to-week fluctuation of water consumption. There were no considerable changes in ophthalmoscopy, urinalysis, hematology and serum biochemistry, except a significant decrease in albumin/globulin ratio in males treated with 1,000 mg/kg. In contrast, a significant increase in relative heart weight was observed in both male and female rats treated with a high dose (2,000 mg/kg) of Geranti Bio-Ge Yeast. In microscopic examination, mild lesions were found sporadically in both control and treatment groups in a dose-independent manner. In spite of some alterations in water consumption, serum biochemistry and organ weights, such effects were not considered to include toxicopathological significance, based on the lack of dose-dependency, consistent time-course and gender relationship. Taken together, it is suggested that no observed adverse effect level (NOAEL) of Geranti Bio-Ge Yeast is considered to be over 2,000 mg/kg in rats, and that long-term oral intake in humans might not exert adverse effects.

Topics: Administration, Oral; Animals; Body Weight; Dose-Response Relationship, Drug; Drinking; Drug Administration Schedule; Eating; Female; Germanium; Heart; Male; Organ Size; Organometallic Compounds; Rats; Rats, Sprague-Dawley; Sex Factors; Yeasts

Single- and 13-week repeated-dose toxicities of Geranti Bio-Ge Yeast, organic germanium fortified yeasts, were investigated in dogs. Both sexes of Beagle dogs were orally administered once at a dose of 2,000 mg/kg in single-dose toxicity or daily for 13 weeks at doses of 500, 1,000 or 2,000 mg/kg in repeated-dose toxicity tests. In single-dose toxicity test, no animal dead, moribund, or showing clinical signs or changes in body weight gain was found. In repeated-dose toxicity study, there were no considerable changes in ophthalmoscopy and urinalysis. Several alterations were observed in electrocardiography, hematology and blood biochemistry, including heart rate, R-R interval, QT correcting, reticulocytes, activated partial thromboplastin time and albumin/globulin ratio in only male dogs, but not in females, administered with Geranti Bio-Ge Yeast in a dose-independent manner. In gross findings, several cases of abnormal findings were observed in both control and treatment groups, showing diffuse dark brown to black discoloration of liver, in a dose-independent manner. In microscopic examination, mild lesions, including cholestasis and inflammatory cell foci in liver, kidneys and prostate, were found sporadically in both control and treatment groups. In spite of some alterations in electrocardiography, hematology, blood biochemistry, gross and microscopic findings, such effects were not considered to include toxicopathological significance, based on the marginal changes within normal ranges and lack of dose-dependency, consistent time-course and gender relationship. Taken together, it is suggested that no observed adverse effect level (NOAEL) of Geranti Bio-Ge Yeast is considered to be 2,000 mg/kg in dogs, and that long-term treatment in clinical trials might not exert adverse effects.

Topics: Administration, Oral; Animals; Body Weight; Dogs; Dose-Response Relationship, Drug; Drug Administration Schedule; Eating; Electrocardiography; Female; Germanium; Heart; Kidney; Liver; Male; Organ Size; Organometallic Compounds; Prostate; Sex Factors; Toxicity Tests; Yeasts

Two acute (4 hr) and one subacute (4 wk) inhalation toxicity studies on germanium dioxide (purity > or = 99%, mean particle size 1.7-2.6 microns) were conducted in young adult Wistar rats. In the acute studies, exposure of two groups of five rats of each sex to maximum attainable concentrations of either 3.10 g amorphous or 1.42 g hexagonal germanium dioxide/m3 for 4 hr was not lethal. In the subacute study, four groups of five rats of each sex were exposed to 0, 16, 72 and 309 mg hexagonal germanium dioxide/m3 for 6 hr/day, 5 days/wk during 4 wk. Two additional groups of 5 rats per sex, exposed either to 0 or to 309 mg/m3, were kept for a 33-day post-exposure period. At the end of the treatment period, changes were observed only in rats of the high concentration group: these changes were decreased body weight gain (both sexes), decreases in haematocrit (females) and thrombocyte count (both sexes), and increases in neutrophil count (both sexes) and white blood cell count (females). On clinical chemistry evaluation, decreased fasting blood glucose (females), decreased total protein concentration (both sexes), increased plasma alanine aminotransferase and aspartate aminotransferase activities (females), increased plasma urea nitrogen (males) and increased plasma bilirubin level (females) were observed. In addition, urinary volume was elevated, and urine density and pH were lowered in both sexes. Relative weights of kidneys, spleen, heart and lungs were higher than in controls. Microscopic examination revealed effects on renal tubular epithelium. Effects on growth, kidneys, and liver were still present at the end of the 33-day recovery period. It was concluded that the 4-hr LC50 value of amorphous germanium dioxide was greater than 3.10 g/m3 and that of the hexagonal form greater than 1.42 g/m3. The no-adverse-effect-level in the 4-wk study using hexagonal germanium dioxide was 72 mg/m3.

Topics: Administration, Inhalation; Animals; Body Weight; Dose-Response Relationship, Drug; Female; Germanium; Growth; Kidney; Male; Organ Size; Rats; Rats, Wistar; Sex Factors

The chemical properties of Ge are similar to Si. This study investigated whether Ge can substitute for, or is antagonistic to, Si in bone formation. Sixty male weanling Sprague-Dawley rats were randomly assigned to treatment groups of 12 and 6 in a 2 x 4 factorially arranged experiment. The independent variables were, per gram fresh diet, Si (as sodium metasilicate) at 0 or 25 micrograms and Ge (as sodium germanate) at 0, 5, 30, or 60 micrograms. Results confirmed that Ge does not enhance Si deprivation and provided evidence that Ge apparently can replace Si in functions that influence bone composition. When Si was lacking in the diet, calcium and magnesium concentrations of the femur were decreased; this was reversed by feeding either Ge and/or Si. Similar effects were found for zinc, sodium, iron, manganese, and potassium of vertebra. There were some responses to Si deprivation that Ge could not reverse; Ge did not increase femur copper, sodium, or phosphorus or decrease molybdenum of vertebra, effects that were evoked by Si supplementation. Additionally, some findings suggested that 60 micrograms Ge/g diet could be a toxic intake for the rat. On the other hand, some responses induced by Ge indicate that this element may be acting physiologically other than as a substitute for Si. Germanium itself affected bone composition. Germanium supplementation decreased Si and molybdenum in the femur and increased DNA in tibia. Regardless of the amount of Si fed, animals fed 30 micrograms Ge/g diet had increased tibial DNA compared to animals fed 0 or 60 micrograms Ge; however, tibial DNA of animals fed 30 micrograms Ge was not statistically different from those animals fed 5 micrograms Ge. Thus, Ge may be of nutritional importance.

Topics: Animals; Blood Proteins; Body Weight; Bone and Bones; Calcification, Physiologic; Copper; Diet; DNA; Germanium; Kidney; Male; Organ Size; Random Allocation; Rats; Rats, Sprague-Dawley; Silicon; Tibia; Zinc

In skeletal muscles from rats treated with germanium for 23 weeks, there were numerous ragged-red fibers and cytochrome-c oxidase (COX)-deficient fibers. Biochemically, germanium reduced the enzyme activities in the mitochondrial respiratory chain. Rotenone-sensitive NADH-cytochrome-c reductase as well as COX activities were markedly reduced, while succinate-cytochrome-c reductase was less severely, but significantly, affected. The histopathological findings in these muscles were similar to those seen in patients with mitochondrial encephalomyopathy, suggesting that germanium-induced myopathy may be a useful experimental model. Coenzyme Q10 administration appeared to be ineffective in preventing this experimental myopathy.

Topics: Animals; Body Weight; Coenzymes; Female; Germanium; Microscopy, Electron; Mitochondria, Muscle; Muscles; Muscular Diseases; Organ Size; Rats; Rats, Wistar; Ubiquinone

The modifying potential of allyl sulfide (AS), indole-3-carbinol (I3C) and carboxyethylgermanium sesquioxide (GE) on lesion development was examined in a wide-spectrum initiation model. Groups 1-4 were treated sequentially with diethylnitrosamine (DEN) (100 mg/kg, i.p., single dose), N-methylnitrosourea (MNU) (20 mg/kg, i.p., four doses at days 2, 5, 8 and 11), and N,N-dibutylnitrosamine (DBN) (0.05% in drinking water during weeks 3 and 4). Groups 5-7 received vehicles without carcinogens during the initiation period. Group 8 served as the untreated control. After this initiating procedure, groups 2-7 were administered a diet containing 0.5% AS or I3C and 0.05% GE. All surviving animals were killed 40 weeks after the beginning of the experiment and the target organs were examined. The induction of GST-P+ hepatic foci in rats treated with carcinogens was significantly inhibited by treatment with all three compounds. AS treatment significantly decreased the incidence of hepatic hyperplastic nodules, adenoma of the lung and thyroid, and papillary or nodular hyperplasia of the urinary bladder. Administration of GE also significantly inhibited the development of hepatic nodules and adenoma of the lung and thyroid. However, I3C only inhibited the hyperplastic nodules of the liver. These results demonstrated that this multi-organ initiation model could be useful in confirming organ-specific modification potential and, in addition, the inhibitory effect of AS, I3C and GE on liver, lung, thyroid and urinary bladder carcinogenesis.

Topics: Allyl Compounds; Animals; Body Weight; Diethylnitrosamine; Disease Models, Animal; Germanium; Indoles; Kidney; Liver; Liver Neoplasms, Experimental; Lung; Male; Methylnitrosourea; Neoplasms, Experimental; Nitrosamines; Organ Size; Rats; Rats, Inbred F344; Sulfides

An acute (4-hr) and a sub-acute (4-wk) inhalation toxicity study of germanium metal powder (purity 99.8%, mean particle size 2.0-2.4 microns) were carried out in young adult Wistar rats. Exposure of five male and five female rats to 3.86 or 5.34 g/m3 for 4 hr resulted in the death of one rat at each exposure level. Four groups of five male and five female rats were exposed to 0, 9.9, 65.1 or 251.4 mg/m3 for 6 hr/day, 5 days/wk for 30 days. Two additional (recovery) groups of five male and five female rats exposed to 0 or 251.4 mg/m3 were kept untreated for 31 days after exposure. At the end of the treatment period, fasting blood glucose was decreased in males exposed to the high concentration. In females of this group, blood creatinine and urea levels, and urine volumes were increased, but urine density was decreased. Increased blood creatinine levels and urine volume and decreased urine density were also observed in females exposed to 65.1 mg/m3. The absolute and relative lung weights were increased in rats in the mid-and high-concentration groups. Histopathological examination revealed: accumulation of particulate material in the lungs of all treated groups, accumulation of alveolar macrophages in the mid- and high-concentration groups, and alveolitis mainly in the high-concentration group. After the 4-wk recovery period, urine volume was increased in males that had been exposed to germanium. In exposed rats of both sexes, lung weights were still increased and histopathological changes were present, but to a lesser extent than at the end of the exposure period. It was concluded that the 4-hr LC50 value of germanium metal powder in rats is greater than 5.34 g/m3. The no-adverse-effect level in the 4-wk study was 9.9 mg/m3 air.

Topics: Administration, Inhalation; Aerosols; Animals; Body Weight; Female; Germanium; Lung; Male; Organ Size; Particle Size; Powders; Rats; Rats, Inbred Strains

Germanium (Ge; atomic number 32, atomic weight 72.6) belongs to IVb group of the Periodic Table and is found as a trace metal in soil, rocks, plants, and animals. It is widely used in industry because of its semiconductive nature. Some biological activities have been shown in Ge derivatives. Recently, patients with persistent renal damage after chronic ingestion of germanium dioxide (GeO2)-containing compounds have been reported in Japan. This study aimed to investigate subacute nephrotoxicity of GeO2 in Lewis male rats. The rats were treated orally with GeO2 for 13 weeks (GeO2 group) and were compared with those treated with GeO2 for only the first 4 weeks (GeO2-4-week group) and with untreated controls. Renal dysfunction was demonstrated by the increased serum creatinine, BUN, and serum phosphate and decreased creatinine clearance. Liver dysfunction was observed as demonstrated by the increased GOT and GPT, and hypoproteinemia by the decreased total protein and albumin in the GeO2 group. However, daily urinary protein excretion or urinalysis did not differ among the groups. Kidney weight and Ge content of tissues were significantly elevated in the GeO2 group. With the light microscope, vacuoles and the depositions of PAS-stained particles, which correspond to electron-microscopic dense granules in the swollen mitochondria, were predominantly observed in distal tubular epithelium in the GeO2 group. Even in the GeO2-4-week group of rats, serum creatinine was increased and the above-mentioned histological abnormalities were observed, but were less intense.

Topics: Acute Kidney Injury; Animals; Body Weight; Eating; Germanium; Kidney Tubular Necrosis, Acute; Kidney Tubules, Distal; Male; Metabolic Clearance Rate; Microscopy, Electron; Mitochondrial Swelling; Organ Size; Rats

The preventive effect of zinc for the toxic actions of germanium and selenium on bone metabolism was investigated in the femoral diaphysis of weanling rats. Germanium tetrachloride (1.53-30.60 mumol Ge/100 g b.w.) and selenium tetrachloride (1.53-7.65 mumol Se/100 g) was administered orally for 3 days. The doses of 1.53 and 7.65 mumol Ge/100 g caused a significant increase in DNA content although alkaline phosphatase activity was not altered significantly. By the dose of 30.60 mumol Ge/100 g, both alkaline phosphatase activity and DNA content were decreased significantly. Administration of selenium (1.53 and 7.65 mumol/100 g) produced significantly decreases in alkaline phosphatase activity and DNA content. The decreases of the enzyme activity and DNA content caused by administration of germanium (30.60 mumol/100 g) and selenium (7.65 mumol/100 g) were prevented completely by simultaneous injection of zinc sulfate (7.65 mumol Zn/100 g) for 3 days. Administration of zinc also produced appreciable increase in alkaline phosphatase activity and DNA content. The present study indicates that germanium and selenium disturbs bone metabolism in weanling rats, and that this disturbance is reversed by zinc.

Topics: Alkaline Phosphatase; Animals; Animals, Newborn; Body Weight; Bone and Bones; Bone Development; DNA; Femur; Germanium; Male; Rats; Rats, Inbred Strains; Selenium; Zinc

Topics: Animals; Arsenic; Body Weight; Chromium; Diet; Female; Germanium; Growth; Kidney; Liver; Longevity; Lung; Male; Mice; Mortality; Myocardium; Neoplasms; Rats; Spleen; Tin; Trace Elements; Vanadium