Search

The aim of this study was to determine the lung levels of metallothionein (MT), a free radical scavenger, because oxygen-derivated free radicals (ODFRs) have been involved both in reperfusion injury of transplanted lungs and in cardiac or renal allograft destruction. First, MT localization was evaluated in 14 normal human lung biopsy specimens. Then, in lung transplant recipients, MT content in BAL fluid (BALF) and its transcription rate in alveolar macrophages (AMs) were determined. The BALFs of 69 patients were separated into six groups: lung transplant recipients in clinically stable condition (CSR), those with acute rejection (AR), asymptomatic cytomegalovirus infection (ACMV), cytomegalovirus pneumonitis (CMVP), bronchiolitis obliterans syndrome (BOS), and patients without transplants who served as control subjects (NTCs). In normal lungs, 83% of AMs were positively stained. MT staining was also observed in pleural endothelial cells and basal cells from bronchial epithelium. In lung transplant recipients, MT levels in BALF were significantly higher in patients with CSR, AR, ACMV, and CMVP compared with NTCs, while during BOS, MT had a significantly lower level compared with other lung transplant groups. However, no difference among groups was found concerning MT-II messenger RNA expression in AMs, showing that, as in normal lung, AMs are not the only cells that produce MT. These data report for the first time to our knowledge MT cell distribution in human lung with specific emphasis on its enhanced levels after lung transplantation, even in the absence of complication. Possible correlation among MT levels, ODFRs, cytokine levels, and corticosteroid treatment during complications of lung transplantation are discussed.

The sodium salt of 2,3-dimercapto-1-propanesulfonic acid (DMPS), a potent chelating agent used in the treatment of inorganic and organic heavy metal intoxications was evaluated for developmental toxicity in pregnant Swiss mice. DMPS was administered by gavage at doses of 0, 75, 150 and 300 mg/kg per day on gestational days 6-15. Females were evaluated for body weight gain, food consumption, appearance and behavior, survival rates and reproduction data. Cesarean sections were performed on gestation day 18. There were no maternal toxic effects, and no treatment-related changes were recorded in the number of total implants, resorption, the number of live and dead fetuses, fetal body weight or fetal sex distribution data. Gross external, soft tissue and skeletal examination of the DMPS-treated fetuses did not show significant differences at any dose in comparison with the controls. Mineral analysis of maternal and fetal tissues revealed slight effects of DMPS on metabolism of calcium, magnesium, zinc, copper and iron. The results of this study in mice indicate that DMPS is not a developmental toxicant at levels up to 300 mg/kg per day.

The efficacy of several chelating agents in alleviating acute lead intoxication has been investigated in male Swiss mice. The relative effectiveness of diethylenetriaminepentaacetic acid (DTPA), ethyleneglycolbis-(beta-amino-ethylether)-N,N'-tetraacetic acid (EGTA), cyclohexanediaminetetraacetic acid (CDTA), L-cysteine, N-acetyl-L-cysteine (NAC), ascorbic acid, sodium diethyldithiocarbamate (DDC), 2,3-dimercaptosuccinic acid (DMSA) and sodium 2,3-dimercapto-1-propanesulfonate (DMPS) in reducing lethality of lead was examined. Significant increases in survival were noted with CDTA, ascorbic acid, DMSA, and DMPS. Therapeutic effectiveness (TEF) was determined for these compounds; TEF for ethylenediaminetetraacetic acid (EDTA) and for 2,3-dimercaptopropanol (BAL) was also determined; CDTA (2.33) and EDTA (1.73) showed the highest values. In subsequent experiments, the effect of the chelating agents on the distribution and excretion of lead was investigated. Lead acetate trihydrate was administered subcutaneously at doses of 37.8 mmol/kg (LD50), and fifteen minutes later, chelators were given intraperitoneally at doses approximately equal to one-fourth of their respective LD50 values. EDTA, DTPA and CDTA were the most effective agents in increasing the urinary excretion of lead, whereas DTPA, CDTA, and DDC increased significantly the fecal excretion of lead. EDTA, DDC, and CDTA were the most effective chelators in reducing the concentration of lead found in various tissues. On the basis of these results, CDTA may be considered as an alternative in the treatment of acute lead poisoning.

Oxalate was transported in vitro by intestinal brush border cells from rabbit and human by a non-energy-dependent diffusion mechanism. An oxalate-binding protein that had an approximate molecular weight of 73,000 was identified in the human intestine (ileum), was localized in the cytosol cell fraction, and was affected by calcium and magnesium, which increased the oxalate binding.

The effects of repeated ip administration of gallic acid, 4,5-dihydroxy-1,3-benzenedisulfonic acid (Tiron), diethylenetriaminepentaacetic acid (DTPA), and 5-aminosalicylic acid (5-AS) on the distribution and excretion of uranium were assessed in male Swiss mice. Only Tiron significantly increased the amount of uranium excreted into urine and feces. A significant decrease in the concentration of uranium in liver, spleen and bone was observed after administration of Tiron, whereas injection of gallic acid or DTPA resulted in a significant decrease in the concentration of the metal in the liver. The results show that Tiron was consistently the most effective chelator of those tested in the treatment of uranium poisoning after repeated daily administration of the metal.

Four groups of pregnant Wistar rats, each of which consisted of 15 animals were administered 0, 12, 14 and 48 mg/kg/day of cobalt (II) chloride from the 14th day of gestation through 21 days of lactation. The offspring were observed for mortality, body weight, body and tail length and general symptomatology after 1, 4 and 21 days of nursing. The number of litters was higher for the control group. The survival ratios were also higher for the control group. Besides, a dose-dependent delay in the growth of the living young could be observed. No significant differences in organ weights in the animals killed 21 days after birth were observed. The blood parameters analysed did not show differences between the treated and control pups. Cobalt produced toxic effects on the mothers, affecting the late gestation as well as the postnatal development of the pups.

Aluminum nitrate was administered by gavage to four groups of pregnant Sprague-Dawley rats from the 14th day of gestation through 21 days of lactation at doses of 0, 180, 360 and 720 mg/kg/day. These doses did not produce overt fetotoxic effects. However, the growth of the offspring was significantly less from birth and during all the period of lactation for the higher doses of aluminum nitrate. Although very few toxic effects could be observed for the 180 mg/kg/day group (or 13 mg Al/kg/day), this quantity is similar to the amounts ingested by some people in special medical treatment (10 mg Al/kg/day). Therefore, it would seem that high amounts of aluminum should not be ingested during the periods of gestation.

Four zinc compounds (acetate, nitrate, chloride and sulfate) were administered po or ip to rats and mice. The LD50 values were determined. Animals were observed for 14 days. The majority of deaths occurred during the first 48 hr. The clinical and physical signs appearing after intoxication included miosis, conjunctivitis, decreased food and water consumption and hemorrhages and hematomas in the tail. These changes decreased with time which would suggest a quick elimination of zinc. To determine the effect of 6 chelating agents on the toxicity of zinc, various doses of zinc acetate (66-330 mg/kg) were given ip to male mice followed by the injection of one of the chelators. DTPA, D-PA, CDTA and EDTA were the most effective. CDTA and DTPA were also the most effective in increasing the urinary excretion of zinc. DTPA appears to be the most effective agent of those tested in the prevention of acute zinc intoxication. However, CDTA may be considered as a possible alternative.

Pregnant Sprague-Dawley rats were given orally a daily dose of 0, 5, 10 or 20 mg NaVO3/kg from the sixth through the fourteenth day of pregnancy. Fetal examinations were performed on day 20 of gestation. Sodium metavanadate was neither embryolethal nor teratogenic in rats when administered orally at 20 mg/kg/day or lower. Nevertheless, this dose was embryotoxic.

meso-2,3-Dimercaptosuccinic acid (DMSA) is a water-soluble effective antidote for the treatment of heavy-metal intoxications. Information concerning the developmental toxicity of DMSA, however, has not been available. In order to determine the potential developmental toxicity of DMSA, pregnant Swiss mice were given 0, 410, 820, or 1640 mg DMSA/kg/day subcutaneously on Days 6-15 of gestation. Maternal effects included a significant reduction in weight gain during the exposure and postexposure periods at 1640 mg/kg/day. Food consumption was similar to controls at all doses levels except for the high dose group in the post-treatment period. Results of hematological and serum biochemical analyses in the DMSA-treated groups were comparable to those of the controls. However, in light of the pronounced effects on maternal weight gain the dose of 1640 mg/kg/day would be maternally toxic. Significant increases in the number of resorptions and the incidence of stunting were found, along with a significant decrease in the number of live fetuses per litter, when the 1640 mg/kg/day group was compared with the controls. Significant reductions in fetal body weight and fetal body length means were also found when the 820 and 1640 mg/kg/day groups were compared with the controls. Consequently, these results indicate that DMSA would be embryo-toxic to mice at 1640 mg/kg/day and fetotoxic at 820 mg/kg/day. In contrast, very slight fetotoxicity was observed at 410 mg/kg/day. Gross external, internal soft tissue, and skeletal examinations of the fetuses revealed that DMSA was teratogenic in the mouse when given subcutaneously at 820 and 1640 mg/kg/day.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Perinatal and postnatal studies were performed in Swiss mice given uranium--as uranyl acetate dihydrate--at daily dosages of 0, 0.05, 0.5, 5, and 50 mg/kg from day 13 of pregnancy until weaning of the litters on day 21 post-birth. Postnatal development was monitored after 0, 4, and 21 d of lactation. At doses of 0, 0.05, 0.5, and 5 mg/kg.d, treatment with uranium had no significant effect on sex ratios, mean litter size, pup body weight, or pup body length throughout lactation. Significant decreases in the mean litter size on postnatal day 21, and in the viability and lactation indices were observed at the 50 mg/kg.d dose level. When comparing the "no observable effect level" (NOEL) for reproductive effects of uranium, with the concentrations of the metal usually ingested by men, a safety factor below 1,000 can be estimated.

Aluminium nitrate was tested for its effects on reproduction, gestation, and lactation in Sprague-Dawley rats, at dosages of 0, 180, 360 and 720 mg/kg/day. Mature male rats were treated orally for 60 days prior to mating with mature virgin female rats treated for 14 days prior to mating with treatment continuing throughout mating, gestation, parturition, and weaning of the litters. One-half of the dams in each group were killed on day 13 of gestation and the remaining dams were allowed to deliver and wean their offspring. Postnatal development was monitored. No adverse effects on fertility or general reproductive parameters were evident at doses employed in these studies. However, the survival ratios were higher for the control group. Moreover, a dose-dependent delay in the growth of the living young could be observed in aluminium treated groups. Therefore, it would seem that high amounts of aluminium should not be ingested during the periods of gestation.

To evaluate the developmental toxicity of uranium, 5 groups of 20 pregnant Swiss mice were given by gavage daily doses of 0, 5, 10, 25 and 50 mg/kg of uranyl acetate dihydrate on gestational days 6-15. Cesarean sections were performed on all females on gestation day 18. Fetuses were examined for external, visceral, and skeletal abnormalities. The results indicated that such exposure resulted in maternal toxicity as evidenced by reduced weight gain and food consumption during treatment, and increased relative liver weight. There were no treatment-related effects on the number of implantation sites per dam, or on the incidence of postimplantation loss (resorptions plus dead fetuses). The number of live fetuses per litter and the fetal sex ratio were not affected by the treatment. However, dose-related fetal toxicity, consisting primarily of reduced fetal body weight and body length, and an increased incidence of abnormalities was observed. Malformations (cleft palate, bipartite sternebrae) and developmental variations (reduced ossification and unossified skeletal variations) were noted at the 25 and 50 mg/kg per day test levels. Therefore, administration of uranyl acetate dihydrate during organogenesis in mice produced maternal toxicity at 5, 10, 25 and 50 mg/kg per day. The "no observable effect level" (NOEL) for fetotoxicity including teratogenicity was below 5 mg/kg per day, as some anomalies were observed at this dose. There was no evidence of embryolethality at any dosage level used in this study.

In order to determine the embryotoxic and teratogenic potential of aluminum, pregnant Sprague-Dawley rats were treated by gavage with a daily dose of 180, 360, or 720 mg/kg of aluminum nitrate from the sixth through to the fourteenth day of gestation. Fetal examinations were performed on day 20. The number of corpora lutea, total implants, and resorptions as well as the number of live and dead fetuses in the treated animals were not significantly different from the control group. Therefore, embryolethality of aluminum cannot be induced (as a measure of percent dead and resorbed fetuses). However, exposure of rats to aluminum nitrate resulted in decreased fetal body weight and increased the incidence and types of external, visceral, and skeletal malformations and variations in all the treated groups. Consequently, teratogenic effects of aluminum-nitrate administration may result in rats given high oral doses that induce concomitant maternal toxicity.

To determine the potential developmental toxicity of cobalt, pregnant Sprague-Dawley rats were given by gavage a daily dose of 0, 25, 50; and 100 mg/kg cobalt(II) chloride on d 6-15 of gestation. Females were sacrificed on d 20. Maternal effects included significant reductions in weight gain and food consumption, particularly at 100 mk/kg.d. Hematocrit, hemoglobin concentration, mean corpuscular volume, mean corpuscular hemoglobin, and reticulocytes were increased significantly in the 100-mg/kg.d group. No treatment-related changes were recorded in the number of corpora lutea, total implants, resorptions, the number of live and dead fetuses, fetal size parameters, or fetal sex distribution data. Increased incidence of stunted fetuses per litter was the only adverse finding at 50 and 100 mg/kg.d group. However, this increase was not statistically significant. Examination of fetuses for gross external abnormalities, skeletal malformations, or ossification variations revealed that cobalt did not produce teratogenicity or significant fetotoxicity in the rat at doses as high as 100 mg/kg.d.

Uranyl acetate dihydrate was tested for its effects on reproduction, gestation, and postnatal survival in Swiss mice. Four groups of animals, each of which consisted of 25 males and 25 females, were administered 0, 5, 10, and 25 mg/kg/day of uranyl acetate dihydrate. Mature male mice were treated orally for 60 days prior to mating with mature virgin female mice treated orally for 14 days prior to mating. Treatment of the females continued throughout mating, gestation, parturition, and nursing of the litters. One-half of the dams in each group were sacrificed on Day 13 of gestation and the remaining dams were allowed to deliver and wean their offspring. Postnatal development was monitored after 0, 4, and 21 days of lactation. No adverse effects on fertility were evident at the doses employed in this study. Nevertheless, embryolethality could be observed in the 25 mg/kg/day group. Significant increases in the number of dead young per litter were seen at birth and at Day 4 of lactation in the 25 mg/kg/day group. The growth of the offspring was always significantly lower for the uranium-treated animals. However, the present results suggest that uranium does not cause any adverse effects on fertility, general reproductive parameters, or offspring survival at the concentrations usually ingested by man.

We isolated a mucoprotein from the urine of stone-formers that promotes the precipitation of oxalate. The mucoprotein has a molecular weight of 51,000 daltons and an isolectric point of 2.8. Although its hexuronic and stalic acid content is quite small, its glycine (31.3 per cent) and glutamic acid (12.2 per cent) content is high.