Effects of sodium pyridinethione on the uptake and distribution of nickel, cadmium and zinc in pregnant and non-pregnant mice

Oral administration of sodium pyridinethione together with 63Ni2+, 109Cd2+ or 65Zn2+ to non-pregnant mice resulted in very markedly increased levels of the metals in several tissues in comparison with animals given the metals alone. For 63Ni2+ the sodium pyridinethione induced a strong labelling of the pancreatic islets and of the melanin of pigmented tissues. A considerable radioactivity was also obtained in the peripheral and central nervous system. For 109Cd2+ a strong radioactivity was observed in the red pulp of the spleen and the neurohypophysis and, in addition, in the liver and the kidney. For 65Zn2+ the distribution pictures in mice given 65Zn2+ only were similar to those seen in mice given the metal together with sodium pyridinethione, although the radioactivity in all tissues of the latter animals was much higher than in the former. All 3 metals were shown to form lipophilic complexes with pyridinethione (the nickel and zinc complexes being more lipophilic than the cadmium complex) and a facilitated penetration of the complexed metals through the cellular membranes is probably important for the observed results. Differences in the stability of the complexes in the body may be one factor of importance for the marked differences in the obtained distribution pictures but other factors may also be involved, as discussed in the paper. Experiments in pregnant mice showed markedly increased levels of 63Ni2+ and 65Zn2+ in the foetuses as a result of the sodium pyridinethione administration, whereas for 109Cd2+ only a small increase was observed. Our results suggest that effects on the disposition of metals may be important for the toxicity of the pyridinethiones.     

Effect of sodium pyridinethione on the uptake and distribution of nickel in rats,ferrets and guinea-pigs

Oral administration of sodium pyridinethione together with Ni²⁺ (using ⁶³Ni²⁺ as a tracer) to rats, ferrets and guinea-pigs produced highly increased tissue levels of the metal in several tissues in comparison with animals given the Ni²⁺ alone. Ni²⁺ forms a lipophilic complex with pyridinethione and it can be assumed that a facilitated passage of the Ni²⁺ across the cellular membranes of various tissues is important for the observed effects. Pigmented tissues (e. g. the eye melanin), the pancreatic islets, the nervous system and striated muscles showed high levels of Ni²⁺ in animals given sodium pyridinethione. However, in some instances marked species differences were observed. Thus, microautoradiography indicated an uptake of Ni²⁺ both in the β- and α-cells in the pancreatic islets in the rat, whereas in the guinea-pig only some cells (probably the α-cells) accumulated high levels of Ni²⁺. In the ferret sodium pyridinethione induced a high uptake of Ni²⁺ in the heart muscle, which was not seen in the other species. The Ni²⁺ is probably taken up in the various tissues complexed to pyridinethione. Within the tissues the complex may dissociate and the Ni²⁺ may bind to some endogeneous tissue components. The affinity of the Ni²⁺ for the endogeneous ligands in relation to the affinity for the pyridinethione may be of importance for the effects on the disposition of the Ni²⁺. The species variations may be related to differences in the structural conformations of the endogeneous Ni²⁺-binding ligands. Received: 25 October 1993/Accepted: 25 January 1994     

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.     

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.     

Effect of cadmium and nickel on expression of CatSper 1 and 2 genes in mice

This study was designed to investigate the effect of the administration of cadmium and nickel on the histology of the testes, sperm parameters, and the expression of CatSper 1 and CatSper 2 genes in adult male mice. Despite the vital role of CatSper genes in male fertility, very little is known about the factors that regulate their expression. Thirty-two adult male mice were randomly allocated into four groups. The control group received no treatment. The sham group was injected with normal saline. The cadmium and nickel groups were injected with 2?mg/kg/day of cadmium chloride or 5?mg/kg/day of nickel chloride for 2-weeks as models for testicular injury. Histological study and the analysis of their sperm were performed according to WHO’s guidelines for the examination of human sperm. In addition, a prooxidant antioxidant balance assay and real-time PCR were performed 35?days after the treatment, as the duration of spermatogenesis cycle in mice is 35?days. The data were analyzed using SPSS software using ANOVA. Both nickel and cadmium injections caused a reduction in sperm parameters as well as a decrease in the thickness of the germinal epithelium. The administration of cadmium caused down-regulation in the expression of both CatSper1 and CatSper2 genes. Only cadmium increased the PAB values.     

Effect of cadmium and zinc on microbial adherence

A study has been made of the effect of cadmium chloride and zinc acetate on the adherence of Streptococcus faecalis, Escherichia coli and Candida albicans to buccal cells from man. Cadmium led to a significant decrease in the adherence of the three microorganisms tested. Zinc increased the adherence of S. faecalis and E. coli. These alterations in adherence were suppressed by chelating agents. S. faecalis grown in the presence of zinc or cadmium exhibited a decrease in adhesiveness. Pre-incubation of organisms with zinc interfered with the inhibitory effect of cadmium.     

Effect of parenteral cadmium on zinc in the liver and duodenum

The present work was performed to determine if the increased Zn in the liver of Cd-treated rats was related to the low-molecular-weight Zn-binding factor in the duodenal epithelium. The endogenous Zn increased significantly in the liver 24 h after the subcutaneous injection of Cd (1 $\text{mg}\text{kg}$ body weight). In the Zn group (only Zn given orally) and in the Cd + Zn group (administration of Zn to rats previously injected with Cd), the proportion of Zn associated with the low-molecular weight (MW) Zn-binding factor was 27% and 33%, respectively. This indicates that this binding factor was not influenced markedly by the injection of Cd.     

Zinc pyridinethione: Serum metabolites of zinc pyridinethione in rabbits,rats, monkeys,and dogs after oral dosing

The metabolites of zinc pyridinethione (ZPT) in the systemic circulation of female rabbits and monkeys and male rats and dogs were studied after 1 mg [¹⁴C]ZPT/kg body wt was administered by oral gavage. In all four species, the blood radioactivity concentration showed a complex kinetic pattern. An initial maximum at 1 to 8 hr after dosing coincided with the rapid formation and elimination of several polar metabolites, while a secondary broad peak or plateau paralleled the slow accumulation of a single metabolite. In rats, this latter metabolite was identified as 2-(methylsulfonyl)pyridine (MSP) by spectral and chromatographic comparisons with the synthetic compound. Its concentration in rat serum was proportional to the quantity of ZPT dosed over the range of 0.2 to 10 mg ZPT/kg. its presence as a long-lived circulating metabolite is significant for estimating the systemic load of ZPT. The biotransformations which produce MSP involve a multistep sequence of methylation, oxidation, and reduction. Three minor serum metabolites, 2-(methylthio)pyridine-1-oxide, 2-(methylthio)pyridine, and 2-(methylsulfinyl)pyridine-1-oxide, are apparently the intermediate compounds in the biotransformation of ZPT to MSP. Subchronic feeding of [¹⁴C]ZPT produced early signs of hindlimb paralysis in a rat in 6 days; the serum concentration of ZPT-derived metabolites increased linearly over this interval. Since MSP was the only major serum metabolite likely to accumulate, infusion studies were conducted to see if MSP would produce paralysis. Although the duration of infusion and the serum concentrations of MSP attained were greater than those predicted to produce paralysis from the ZPT feeding study, no paralysis was observed.     

Evaluation of tissue disposition, myelopoietic, and immunologic responses in mice after long-term exposure to nickel sulfate in the drinking water

Female B6C3F1 mice were exposed to graded doses of nickel sulfate to determine a threshold response for myelotoxicity and immunotoxicity, and to identify which of the populations of lymphoreticular cells were most sensitive to the toxic effects of nickel. Animals were given free access to the chemical in the drinking water at 0, 1, 5, or 10 g/l for 180 d. Water consumption, blood and tissue nickel concentrations, body and organ weights, histopathology, immune responses, bone marrow cellularity and proliferation, and cellular enzyme activities were evaluated. There was no mortality. Mice in the 5-g/l and 10-g/l dose groups drank less water than controls; the responses measured in the 10-g/l group may have been due to a combination of dehydration and chemical toxicity. Decreases in body and organ weights were confined to mice in the 10-g/l dose group, except for the dose-related reductions in thymus weights. Blood nickel was measured at 4, 8, 16, and 23 wk of exposure. The mean blood nickel values showed increases between 4 and 8 wk that were proportional to time and dose; thereafter there was no substantial increase in blood nickel in any of the dose groups, except for an increase in the mean blood concentration in the 10-g/l group at 23 wk. The kidney was the major organ of nickel accumulation. The primary toxic effects of nickel sulfate were expressed in the myeloid system. There were dose-related decreases in bone marrow cellularity, and in granulocyte-macrophage and pluripotent stem-cell proliferative responses. In unfractionated bone marrow cells glucose-6-phosphate dehydrogenase enzyme activity from the hexose monophosphate shunt was more sensitive to nickel sulfate than were representative glycolytic or Krebs cycle enzymes, with 25-35% maximum inhibition at 5 g/l and 10 g/l. Aliquots of bone marrow cells were separated into enriched bands of lymphocytes, granulocyte-macrophages, and erythrocytes; enzyme inhibition that occurred in unfractionated bone marrow cell aliquots was only expressed after cell separation in the enriched granulocyte-macrophage cell population, suggesting that these committed stem cells were a primary target of nickel sulfate toxicity. There was one example of systemic immunotoxicity, reduction in the lymphoproliferative response to lipopolysaccharide, and it was regarded as secondary to the primary effect of nickel sulfate on the myeloid system, since this was the only significant change among a panel of seven immune parameters that were evaluated.     

Effects of low-dose perinatal cadmium exposure on tissue zinc and copper concentrations in neonatal mice and on the reproductive development of female offspring

It has been suggested that the toxic effects of cadmium (Cd) are the result of interactions with essential metals, such as zinc (Zn) and copper (Cu). Previous studies have shown altered Zn and/or Cu levels in the tissues of rodents that drank water supplemented with >50 ppm Cd. To evaluate the effects of lower level Cd exposure on maternal and neonatal Zn and Cu levels and on the reproductive organs of female offspring, mice were exposed to 0, 1 and 10 ppm Cd in the drinking water from conception to 10 days after birth. The Cd concentrations in the brains of the offspring were higher in the exposed group than in the control group at birth. In the kidneys and livers, the Cd concentrations were higher in the Cd-exposed group 10 days after birth. At birth, increased Zn concentrations were observed in the kidneys and livers of the Cd-exposed offspring, although the Cd concentrations in these tissues did not differ between the exposed and non-exposed groups. The hepatic Cu concentrations of the exposed mice tended to be lower than those of the control mice at birth and were significantly lower 10 days after birth. In addition, Cd exposure tended to delay the timing of vaginal opening and perturbed the estrous cycles of the female offspring. These findings suggest that perinatal Cd exposure, even at low levels, affects the Zn and Cu concentrations of neonates and the reproductive functions of female offspring.     

Absorption, distribution, and excretion of zinc pyridinethione in rabbits.

The distribution and excretion was determined after the intravenous, oral, and dermal administration of [¹⁴C]- and [⁶⁵Zn]zinc pyridinethione (ZPT) to rabbits. After intravenous administration, the ¹⁴C disappeared from the blood rapidly and within 6 hr, 75% was excreted into the urine while the concentration of ⁶⁵Zn in the blood remained relatively constant and only 0.5% was excreted into the urine. The tissue concentrations of ⁶⁵Zn were about 10 times higher than ¹⁴C 6 hr after administration, with 5% of the ¹⁴C remaining in the major organs and 55% of the ⁶⁵Zn. After oral administration of ZPT, 45% of the ¹⁴C and 0.03% of the ⁶⁵Zn was excreted into the urine within 6 hr. Eight hours after dermal application of ZPT, 0.5% of the ¹⁴C was excreted into the urine, and the same amount was found in the major organs of the rabbit. Less than 0.002% of the dermally applied ⁶⁵Zn was found in the urine and 0.008% was found in the major organs. Therefore, this study demonstrates that the organic and inorganic portions of the molecule dissociate in their distribution and excretion from the body, the ¹⁴C portion is excreted from the body much more rapidly than the ⁶⁵Zn. Both portions of the molecule can penetrate the skin to a limited extent, but the zinc portion does so less readily.     

The effect of zinc on the dithiocarbamate-induced mobilization of cadmium deposits in mice

In comparison with similar experiments in which no zinc acetate was used, the addition of small amounts of zinc acetate to sodium N-methyl-N-dithiocarboxyglucamine produces a significant increase in the amount of cadmium mobilized from the liver and kidneys of mice loaded ip with 10 mg CdCl2.2.5H2O/kg 2 wk prior to the initiation of treatment. Neither treatment results in the transport of significant amounts of cadmium to the brain. The injection of zinc acetate alone did not produce this effect. Experiments in which zinc acetate in drinking water was administered to cadmium-loaded animals showed that the liver and kidney cadmium levels were significantly increased, presumably via zinc-mediated processes in which cadmium from other organs was mobilized to the liver and kidneys.     

镉对小鼠脾脏淋巴细胞转化率的影响及锌的保护作用

镉广泛应用于电池、电镀、合金、油漆和塑料等工业,是一种在环境中极难生物降解的重金属,是环境持久性有毒物质.其可以参与大气和水循环,同时通过食物链逐级浓缩,最后以极高的浓度通过污染的食物、饮用水和吸烟等进入高等动物体内,属于疑似环境内分泌干扰物.     

Effect of cadmium ingestion on cadmium and zinc profile in male and female rat liver cytosol

A study of the changes in rat liver cytosol zinc and cadmium metalloprotein profiles obtained by G-75 Sephadex chromatography of male and female rats given oral cadmium chloride chronically at different low doses showed that the changes were dose related. Marked disturbances in the zinc-containing regions of the protein profile preceded any extensive formation of metallothionein, and the earliest signs of cadmium metalloprotein formation involved three equally prominent regions, a high molecular weight region (I), the metallothionein region (V) and a low molecular weight region (VI). The low molecular weight region (estimated at 3500 daltons) is of interest in that it is a newly recognized zinc-containing region even in the controls. Significant quantitative differences were found between males and females. Female livers consistently contained higher concentrations of cadmium and zinc. There also were important quantitative differences in the zinc and cadmium-containg cytosol fractions of the protein profiles of livers of males and females exposed to oral cadmium.     

Effect of phenytoin on calcium disposition in pregnant and nonpregnant mice

The effect of phenytoin (DPH) on absorption and distribution of calcium in the male, female, and pregnant female mouse was evaluated. Pretreatment with phenytoin (80 mg/kg, ip × 5 days) significantly reduced the po absorption of ⁴⁵Ca in all three treatment groups. Distribution studies at 24 hr demonstrated that DPH pretreatment reduced femur bone concentration of IV administered ⁴⁵Ca to 40% of control value in all treatment groups. No significant effect of DPH was observed in the 24-hr soft tissue (liver, kidney, and brain) accumulations of ⁴⁵Ca. Fetal (Day 18) concentrations of radioactivity at 24 hr following ⁴⁵Ca administration were 25-fold greater than maternal soft tissue and approximated values observed in maternal bone, but no significant effect on fetal concentrations of ⁴⁵Ca was observed in phenytoin-pretreated mice. These results suggest that the fetal active uptake system of calcium differs significantly from intestinal or bone active transport systems and is probably not affected by chronic phenytoin therapy.