Effect of maternal cadmium exposure on postnatal development and tissue cadmium,copper and zinc concentrations in rats

Administration of 60 ppm cadmium (Cd) in drinking water from the 1^st to the 20^th day of gestation to female rats did not affect the viability, body weight gain, food, and water consumption of offspring. The blood hemoglobin level was reduced in 2-week-old females and males but not in 16-week-old offspring. Hematocrit and serum glucose level were not affected at either age. Cadmium concentration in the intestinal wall was increased in both age groups, with marginal uptake in other organs. A decrease in copper (Cu) concentration was found in the brain of 2-week-old offspring of both sexes and of 16-week-old females. The brain zinc (Zn) concentration was decreased only in 16-week-old animals. The physical and neuromuscular development of offspring before weaning was not impaired by maternal Cd treatment. The alterations in Cu and Zn metabolism were associated with reduced locomotor activity and affected open-field behavior in adult offspring of either sex and with decreased avoidance acquisition in adult female offspring.The results obtained suggest a relationship between the reduced brain Cu and Zn levels and CNS dysfunction in adult offspring of female rats exposed to Cd during gestation.     

Effect of zinc on cadmium,copper and zinc contents in cadmium exposed rats

The effect of zinc (Zn) administration on the uptake and retention of cadmium (Cd), copper (Cu) and Zn in liver, kidneys and testes of cadmium exposed rats was investigated. Exposure to Cd caused a significant increase in the uptake of these metals in the 3 organs. The administration of Zn after the Cd exposure had little effect on the level of these metals.     

Protective effects of selenium (Se) and zinc (Zn) on cadmium (Cd) toxicity in the liver and kidney of the rat: histology and Cd accumulation

To assess the co-effect of Se and Zn on Cd accumulation in the liver and kidney and on their histology, male rats were exposed either to Cd, Cd+Zn, Cd+Se, or Cd+Zn+Se in their drinking water, during 35 days. Exposure to Cd resulted in its accumulation in the liver and kidney. In the Cd-Zn and Cd-Zn-Se groups, Cd contents in the two organs were significantly (p < 0.01) higher than those in the Cd group. Se did not induce any significant difference in hepatic and renal concentrations of Cd in comparison to Cd-treated group. Light microscopic examination indicated severe histological changes in the two organs under Cd influence. Se or Zn partially alleviated the damage observed in the liver. The same effect was remarked in the kidney with Se, but no differences in the renal histological structure have been observed between the Zn-Cd and the control groups. With Se and Zn simultaneous treatment during Cd exposure, the observed morphological changes had practically disappeared from the liver, but were only reduced in the kidney. CONCLUSION: Se and Zn can have a cooperative effect in the protection against Cd-induced structural damage in the liver but not in the kidney.     

Cadmium and zinc concentrations in fetal and maternal rat tissues after parenteral administration of cadmium during pregnancy

Cadmium (Cd) and zinc (Zn) concentrations were determined by solid sampling atomic absorption spectrometry (AAS) in rat maternal and fetal tissues after exposure to cadmium. Cadmium was administered subcutaneously as CdCl₂ in saline daily during pregnancy. Two experiments were performed. In expt. I we investigated the tissue concentration at day 19 (gestational age) after administration of several doses: 0, 1.1, 2.2, 4.4, and 8.8 mol Cd/kg/ day. In expt. II the course of the Cd and Zn concentrations during pregnancy was investigated by collecting samples at days 14, 16, 18 and 20, after daily injections of 4.4 mol Cd/kg. Cadmium concentrations in blood, maternal liver, placenta and fetal liver increased with dose and duration of exposure. Cadmium was heavily accumulated in the liver and transferred to the fetus only in small amounts. The zinc concentration in the maternal liver was positively correlated with the cadmium concentration. In the placenta the zinc concentration was not affected. Zinc in fetal liver was decreased from day 18 onward. Despite relatively high cadmium levels and decreased zinc levels in the fetus, we observed no adverse effects on various reproduction parameters, such as birth weights and obvious malformations.These investigations were financially supported by the Netherlands Technology Foundation (STW)     

Effects of cadmium exposure during pregnancy on cadmium and zinc concentrations in neonatal liver and consequences for the offspring

The effects of cadmium exposure during pregnancy (by means of daily subcutaneous injections of 4.4 mol/kg to the mother) on the neonates were investigated. No effect was observed on fetal or neonatal body weights, nor on neonatal liver weights. These parameters were examined up to 5 weeks after birth. The weight of neonatal thymuses was decreased 7 and 14 days after birth due to cadmium exposure of the mothers as compared with controls. This may be caused by zinc deficiency, because zinc concentrations in fetal and neonatal livers after cadmium exposure were found to be very low 20 days after conception and 5 h after birth. Cadmium concentration in neonatal liver decreased; however, cadmium in malignant liver increased as age increased. In the mother, cadmium was transferred to the milk, as it was demonstrated in the stomach contents of the pups. Simultaneous administration of zinc in amounts equimolar to cadmium did not have any noticeable effect on the amount of cadmium transferred to the fetus or on cadmium concentrations in any of the organs investigated. It could not prevent zinc deficiency in fetal and neonatal liver. In addition, growth retardation of the thymus from exposed pups could not be prevented by zinc administration.     

Effect of aurothioglucose on liver and kidney concentrations of copper, iron, manganese and zinc

Sixty male Swiss-Webster mice were given intraperitoneal injections of the gold-containing drug aurothioglucose in saline at 3 dose levels: 50, 200, and 400 mg/kg. Controls received i.p. injections of saline. Ten injections were administered over a 3-week period. After sacrifice, kidney and liver concentrations of gold, copper, zinc, iron, and manganese were determined by atomic absorption spectrophotometry and tissues were examined by light microscopy. Dose related increases in liver and kidney gold were found and kidney copper also increased significantly with increasing renal gold content. Kidney copper was 5.05 +/- 0.80 ppm in control animals, and 7.81 +/- 1.11 ppm, 13.01 +/- 2.49 ppm, and 17.11 +/- 4.02 ppm in mice receiving 50, 200, and 400 mg/kg aurothioglucose respectively. Renal zinc and liver zinc and copper were also significantly (P less than 0.01) increased in mice receiving the highest dose of aurothioglucose. There were no other statistically significant differences in tissue concentrations among the various groups of animals for the other liver and kidney metal concentrations determined. Tubular epithelial cells of aurothioglucose-dosed animals often had cytoplasmic vacuoles which contained granular brown-gold material; this effect was dose-related.     

The influence of high dietary zinc on tissue disposition and urinary excretion of cadmium,zinc, copper and iron after repeated parenteral administration of cadmium to rats

The administration of a high dietary supplement of zinc sulphate (2000 ppm) to rats for 28 days produced no effect upon growth rate of the animals but caused an increased food intake. The supplement had no effect upon the reduction of growth rate caused by the daily injection of cadmium chloride (1.5 mg/kg). Zinc-supplemented animals showed an increased accumulation of zinc in the liver and kidney, plasma zinc levels were significantly increased and there was an elevated excretion of zinc in the urine compared to control animals. Cadmium-treated, zinc-supplemented animals had a higher concentration of cadmium in the liver compared to animals treated only with cadmium. The high dietary zinc did not interfere with tissue or plasma concentration of copper and iron, nor did it influence the cadmium-induced changes in these metals. There was some indication however of a decreased urinary excretion of copper.     

Cadmium,zinc and copper relationships in kidney and liver of humans exposed to environmental cadmium

Cadmium, copper and zinc have been determined in kidney cortex, kidney medulla and liver from 51 cadmium-polluted and 122 nonpolluted autopsied subjects. Liver cadmium and zinc were significantly higher in the cadmium-polluted subjects than in the nonpolluted subjects. Kidney cadmium, copper and zinc were lower in the cadmium-polluted subjects because of renal damage. Significant correlations of the three metals were found in the kidney. In the liver the correlation coefficients were significant only between cadmium and zinc.     

Butylbiguanide concentration in plasma,liver, and intestine after intravenous and oral administration to man

Summary 50 mg¹⁴C-Butylbiguanide was administered intravenously to 4 diabetic patients and 100 mg¹⁴C-butylbiguanide orally to 5 further diabetics. The concentrations of the drug in plasma, intestinal fluid, intestinal epithelium and liver tissue were determined and the renal excretion of the biguanide measured. Irregularities in the plasma concentration curve were observed which appeared as systematic deviations from the ideal curve of a biexponential function. Because these deviations occurred only in the middle phase of the plasma concentration curve, it was nevertheless possible to calculate the pharmacokinetic parameters of butylbiguanide by use of a two-compartment open model. The principal pharmacokinetic parameters were determined according to this model after intravenous dosing and the following mean values were obtained:t _{1/2 ()}=4.6 h (=0.15 h^–1),C _P ⁰ =0.85µg/ml,V _D =218 l,V _T =157 l,V _P =62 l,k ₁₂=0.69 h^–1,k ₂₁=0.44 h^–1,k _el =0.54 h^–1. Within 48 h after administration, an average of 72.4% of the intravenous and 74.4% of the oral dose had been excreted in the urine. Total clearance (Cl _tot) averaged 536 ml/min and renal clearance (Cl _ren) 393 ml/min. High concentrations of butylbiguanide were observed in the intestinal fluid (100–700 mg/ml) 20–40 min after oral administration. It was found that the drug accumulates in intestinal fluid, intestinal epithelium and liver tissue, and that it is secreted into the intestinal lumen. The concentrations of butylbiguanide in intestinal and liver tissue were 10–46 times higher than in plasma. The secretion of biguanide into the intestinal lumen may occur via the bile or the intestinal mucosa, but there is no evidence of significant biliary excretion of butylbiguanide.     

Effect of oral cadmium exposure during pregnancy on maternal and fetal zinc metabolism in the rat

To study the effect of cadmium exposure on maternal and fetal zinc metabolism, rats were exposed to 0, 5, 50, or 100 ppm Cd in the drinking water on Days 6 through 20 of pregnancy. In comparison to controls, fetal and maternal weights were slightly reduced in the 50- and 100-ppm groups, but not the 5-ppm group. Multiple regression analysis revealed that in the 50-ppm group, but not in the 100-ppm group, the decrease in fetal weight was not solely a consequence of decreased maternal weight. Cd accumulated in a dose-dependent manner in both maternal organs and fetuses, although the absolute concentrations in fetuses were very low as compared to those of maternal tissues. In the 50- and 100-ppm groups, zinc concentrations were significantly increased in maternal liver and kidney, and significantly decreased in fetal liver. The changes in tissue Zn concentrations were accompanied by altered Zn-metalloenzyme activities in both maternal and fetal tissues. These findings support the hypothesis that Cd-induced maternal zinc retention is responsible for fetal Zn deprivation and impaired fetal growth.     

Differential effects of cadmium administration on peripheral blood granulocytes in rats

Infiltration of circulatory inflammatory cells is a common histopathological finding in target organs following cadmium administration, but there is paucity of data concerning their activity. In this study, the effects of sublethal (1 mg/kg) cadmium on peripheral blood polymorphonuclear (PMN) cells were examined 48 h following administration in rats, when tissue (liver and lung) infiltration of these cells was observed. Cadmium administration resulted in systemic inflammatory cytokine and acute phase response with an increase in circulatory neutrophil numbers and cells that express CD11b molecules. Rise in basic aspects of oxidative activity including intracellular myeloperoxidase (MPO), reactive oxygen (nitroblue tetrazolium/NBT cytochemical assay) and nitrogen (Griess assay) species production was observed in PMNs from cadmium-administered rats. A decrease in levels of mRNA for IL-1β, TNF-α and IL-6 was noted, but production of these cytokines was affected differentially. Described effects of cadmium on PMNs add further to the understanding of inflammatory potential of this environmental contaminant.     

The effect of dietary cadmium on zinc,copper and iron levels in the bone of rats

The effect of continuous oral administration of cadmium (Cd) (75 ppm) on the concentrations of zinc (Zn), Copper (Cu) and iron (Fe) in the bone of rats was investigated. Accumulation of Cd in the femur was low but increased with time. After 8 weeks of Cd exposure, femur Zn and Fe levels were significantly decreased and remained low throughout the period of cadmium treatment. After 48 weeks, Cd exposed animals had Zn and Fe concentrations in the femur of 63% and 51% of controls, respectively. The femur Cu concentration was unchanged at 36 weeks but at 48 weeks it was 76% of control animals.     

Metallothionein induction in the liver, kidney, heart and aorta of cadmium and isoproterenol treated rats

Metallothionein (MT), induced in different organs in response to heavy metals and oxidative conditions, exerts antioxidant properties and thus could be implicated in cardiovascular physiopathology. The aim of this study was to investigate the capacity of cadmium (Cd) and isoproterenol to induce in vivo MT not only in rat liver and kidneys but also in heart and aorta. Tissue MT levels, catalase (CAT) and glutathione peroxidase (GPX) activities were assayed at different times after Cd or isoproterenol injection. Cd induced a dose-dependent induction of MT with a higher response in the liver than in the kidney, aorta and heart. The hepatic increase was early (12 h) and maintained (72 h), whereas the elevation was maximal around 48 h for the other organs. Isoproterenol induced a transient (12 h) hepatic and a biphasic (12 and 36 h) renal and cardiac increase. CAT activity was decreased in the liver and increased in the heart with the higher Cd doses. Isoproterenol increased the cardiac GPX activity. In conclusion, the results demonstrate that MT can be induced in rat liver and kidneys but also in heart after a Cd or isoproterenol injection. This enhancement of cardiac and vascular MT levels could be used to study the potential protective effect of MT in cardiovascular diseases.     

Effect of thiocarbamate derivatives on copper,zinc, and mercury distribution in rats and mice

Oral treatment of rats with tetramethylthiuram disulphide (TMTDS), 0.1% mixed in the food (corresponding to 20–30 mol daily) for one week, increased the brain levels of endogenous copper and zinc to 120% and 170%, respectively, of the control levels.Mice injected with HgCl₂ (2.5 mol/kg) were used to study further the effect of DDC (diethyldithiocarbamate), disulfiram, TMTDS or CS₂ on heavy metal distribution. The brain levels of Hg were significantly increased in mice given DDC or TMTDS. Disulfiram and CS₂ increased the brain levels marginally.Pregnant rats exposed to HgCl₂ (0.5 mol/kg) were also included in the studies. Treatment with DDC (0.5 mmol/kg) immediately after the mercury injection, increased the maternal brain concentration of mercury considerably, as measured after 24 and 78 h. The kidney levels were also increased. In the foetuses, the brain and liver levels were transiently increased after treatment with diethyldithiocarbamate.The observations support the hypothesis that the neurotoxicity of diethyldithiocarbamate and other thiocarbamates may be related to changes in heavy metal metabolism.     

Effect of cadmium on hepatic and renal gluconeogenic enzymes in female rats

Earlier, we have reported that cadmium (Cd) induced gluconeogenesis in male rats. Since females are as much exposed to cadmium as are males, this study was conducted to determine Cd effects on gluconeogenesis in female rats. Adult female rats were injected intraperitoneally (i.p.) with Cd at dose levels of 0.25, 0.75 and 1.25 $\text{mg}\text{kg}$ body weight per day for 4 weeks. The controls received saline for the same length of time. Daily food consumption and body weight gain were recorded. At the end of 2 and 4 weeks, 4 rats from each group were killed. Extension of treatment with 1.25 mg Cd for 4 weeks resulted in extreme Cd toxicity killing all animals before the completion of full treatment period. There were no significant changes in total body weight gain and weights of liver and kidney due to Cd. Serum protein increased significantly in animals receiving 0.75 and 1.25 mg Cd for 4 and 2 weeks, whereas serum glucose increased only in animals injected with 1.25 mg Cd for 2 weeks. SGOT and SGPT were elevated (P < 0.01) in dose- and time-dependent fashion. Activities of three key gluconeogenic enzymes glucose-6-phosphatase (G-6-Pase), fructose-1,6-diphosphatase (FD-Pase), and phosphoenolpyruvate carboxykinase (PEPCK) in liver and kidney were induced significantly (P < 0.01) in animals injected with 0.75 mg for 2 and 4 weeks and 1.25 mg for 2 weeks, and these increases were dose- and time-related. These results suggest that Cd alters hepatic and renal gluconeogenesis in female rats also.     

Time-dependent accumulation of inorganic mercury in subcellular fractions of kidney,liver, and brain of rats exposed to methylmercury

Accumulation of inorganic mercury in subcellular fractions of the kidney, liver, and brain of rats was studied during 48 days after a single injection of 25 mg/kg of methylmercury chloride. The highest ratio of inorganic to total mercury was seen in the cytosol of kidney, 80% of the total being as inorganic mercury at day 48. The ratio in the mitochondria and microsomes of kidney attained a maximum level (about 50% of the total as inorganic) at day 26–37. In the liver, the ratio was strikingly low in the cytosol and microsomes as compared to the light and heavy mitochondria where about 40% of the total was present as inorganic maximally at day 26. The ratio in the brain, determined up to day 15, was very low as compared with the kidney and liver, showing less than 3% of the total in the mitochondria, microsomes, and cytosol, and 5.4% in the myelin fraction. The high accumulation of inorganic mercury in the cytosol of kidney was closely related to metallothionein-like component, while those in the mitochondria and microsomes of kidney and in the mitochondria of liver were exclusively bound to high molecular weight proteins even after deoxycholate treatment.This work was supported in part by a grant from the Japanese Environment Agency and by the Grant-in-Aid for Scientific Research from the Ministry of Education of Japan     

Absorption and distribution of cadmium (Cd), copper and zinc following oral subchronic low level administration to rats of different binding forms of cadmium (Cd-acetate, Cd-metallothionein, Cd-glutathione)

Male Wistar rats received by gavage saline or about 25 micrograms cadmium (Cd)/kg/day as Cd-acetate (Cd-Ac), Cd-metallothionein (Cd-MT) or Cd-glutathione (Cd-GSH) 5 times per week for 28 times. At all treatments 0.2-0.3% of the totally administered Cd dose was found in liver, kidneys, small intestine and pancreas, whereas none of the Cd forms applied resulted in a Cd accumulation in testes. Cd in small intestine was not increased by Cd-MT. However, it was raised by Cd-Ac and even more by Cd-GSH. A smaller increase in hepatic and renal Cd resulted from Cd-GSH than from Cd-Ac or Cd-MT. Cd in pancreas increased after Cd-GSH but not after Cd-Ac or Cd-MT. Copper (Cu) rose in small intestine and testes but decreased in kidneys independent of either Cd treatment. Concomitantly, zinc (Zn) was decreased in small intestine and testes. The tissue concentration of metallothionein (MT) was only marginally increased by all treatments. The highest value (80%) above controls) was found in small intestine after Cd-GSH. Intestinal Cd as well as testicular Cu were related to the tissue MT. Therefore, the distribution of Cd between various organs depends on the Cd form applied. There is some relationship to the distribution of Cu and Zn.     

川芎嗪、尼莫通对大鼠脑出血后局部脑血流量、脑水份含量及神经行为学干预作用的研究

目的 采用立体定向术和新鲜未肝素化血液注入尾状核而建立大鼠脑出血模型，观察用药物干预后的脑出血组较单纯及脑出血组在局部脑血流量（rCBF）、脑水份含量及神经行为学方面的变化。方法 用氢清除法分别测定血肿周围和远隔部位不同时限的rCＢＦ；用干－湿重法测定两组评分的改变。结果 川芎嗪、尼莫通干预后的脑出血组血肿周围及远隔部位的rCBF明显增加，脑水份含量降低，神经行为学明显改善，与单纯出血组比较有显著性差异（P≤0.05或0.01）。结论 川芎嗪、尼莫通对实验性脑出血有疗效。     

Effect of dietary zinc deficiency on hematological and biochemical parameters and concentrations of zinc, copper, and iron in growing rats

Zinc has a wide spectrum of biological activities and its deficiency has been related to various dysfunctions and alterations of normal cell metabolism. The effects of adequate Zn level (38 mg/kg diet, control) and two low levels that create Zn deficiencies (19 mg/kg diet, 1/2 of control and 3.8 mg/kg diet, 1/10 of control) were investigated in growing male and female rats for 10 weeks. This allowed for evaluation of the effects these Zn levels may have on body weight gain, specific organ weights, blood parameters, and serum concentrations of Zn, Cu and Fe. Rats fed Zn-deficient diets gained less (P<0.05) than the control groups. There was increase (P<0.05) in liver and spleen weights, and a decrease (P<0.05) in testes weight. However, brain, kidney, heart, and lung weights were not affected (P<0.05). Hematological parameters that were decreased (P<0.05) by Zn deficiency included hemoglobin (Hb), total erythrocyte count (TEC) and packed cell volume (PCV) with the magnitude being dose-dependent. Serum concentrations of total protein, globulin, glucose, and high density lipoprotein (HDL) also decreased (P<0.05) in a dose-dependent manner. Zn deficiency increased (P<0.05) total leukocyte count (TLC) and concentrations of serum albumin, total lipids, cholesterol, triglycerides and low density lipoprotein (LDL) in a dose-dependent manner. Serum concentrations of urea and creatinine were, however, not affected (P<0.05) by zinc deficiency. Zn-deficient rats had lower serum concentrations of Zn, Cu and Fe. These results showed that Zn deficiency has negative effects on growth rate, specific organ weights, hematological parameters, and serum levels of Zn, Cu and Fe, especially in rats fed the lowest Zn level.     

Arsenic accumulation, elimination, and interaction with copper, zinc and manganese in liver and kidney of rats

The arsenic accumulation, distribution and influences on metallothionein-1 (MT-1) expression and other trace elements in various organs were examined in rats orally exposed to sodium arsenate (iAs(V)). Rats received a dose of 0, 1, 10 and 100ppm of iAs(V) in drinking water daily for 4- and 16-weeks. Arsenic seems to be distributed in all of the tissues, and was accumulated relatively higher in the spleen, lung and kidney compared to the liver, and much lower in skin and cerebrum. High dose of iAs(V)-exposure significantly increased the concentration of copper in the kidney, but did not influence other trace elements such as zinc and manganese in the liver. The mRNA expression of MT-1 was dose-dependently increased by iAs(V)-exposure in the liver whereas it was decreased in the kidney. These data indicate that arsenic is widely distributed and significantly accumulated in various organs and influences on other trace elements, and also modulates MT-1 expression in the liver and kidney.