metallothionein and Renal-Insufficiency

The toxic effect of cadmium varies with sex in experimental animals. Previous studies have demonstrated that pretreatment of male Fischer 344 (F344) rats with the female sex hormone progesterone markedly enhances the susceptibility to cadmium, suggesting a role for progesterone in the sexual dimorphism of cadmium toxicity. In the present study, we attempted to further elucidate the mechanism for sex differences in cadmium-induced toxicity in F344 rats. A single exposure to cadmium (5.0 mg Cd/kg, sc) was lethal in 10/10 (100 %) female compared with 6/10 (60 %) male rats. Using a lower dose of cadmium (3.0 mg Cd/kg), circulating alanine aminotransferase activity, indicative of hepatotoxicity, was highly elevated in the cadmium treated females but not in males. However, no gender-based differences occurred in the hepatic cadmium accumulation, metallothionein or glutathione levels. When cadmium (5.0 mg Cd/kg) was administered to young rats at 5 weeks of age, the sex-related difference in lethality was minimal. Furthermore, although ovariectomy blocked cadmium-induced lethality, the lethal effects of the metal were restored by pretreatment with progesterone (40 mg/kg, sc, 7 consecutive days) or β-estradiol (200 μg/kg, sc, 7 consecutive days) to ovariectomized rats. These results provide further evidence that female sex hormones such as progesterone and β-estradiol are involved in the sexual dimorphism of cadmium toxicity in rats.

Topics: Animals; Cadmium; Cadmium Poisoning; Dose-Response Relationship, Drug; Estradiol; Female; Glutathione; Hepatic Insufficiency; Kidney; Liver; Male; Metallothionein; Ovariectomy; Progesterone; Rats; Rats, Inbred F344; Renal Insufficiency; Sex Characteristics; Survival Analysis; Tissue Distribution

Cadmium inducing hepato- and nephro-toxicity can cause the alteration of protein expression such as metallothionein (MT), i.e. cadmium binding protein, and the metal transcription factor-1 (MTF-1), which plays a significant role in cellular responses to the heavy metal stress. To study the expression of these proteins, the cattle were classified into five groups resulting from the levels of cadmium in the kidneys. Next, the blood biochemical profiles were analyzed to estimate the liver and kidney functions. The expressions of MT and MTF-1 proteins both in the liver and kidneys were investigated by immunofluorescence method. This study found that the blood biochemical profiles were not correlated with the level of cadmium in these tissues; however, the expressions of MT and MTF-1 proteins were earlier detected in the bovine which had a low level of cadmium contamination (0.5 mg/kg). Thus, these proteins could be used as the sensitive markers to determine the cadmium in tissue.

Topics: Animals; Biomarkers; Cadmium; Cattle; DNA-Binding Proteins; Environmental Exposure; Fluorescent Antibody Technique; Liver Failure; Metallothionein; Renal Insufficiency; Soil Pollutants; Transcription Factor MTF-1; Transcription Factors

In this study, we compared results obtained in protein calorie malnourished (PCM) monkeys and controls given Cd2+ (5 mg Cd2+/kg body wt./day) orally for 24 weeks. After 16 weeks of Cd2+ exposure, an indolent renal failure develops in PCM monkeys which resulted in significant increase in urinary excretion of total protein, Cd2+, Zn2+ and Ca2+ as compared to corresponding to Cd(2+)-treated control group. In isolated proximal tubule brush border membrane vesicles (BBMV), Cd2+, Zn2+ and Ca2+ transport were significantly impaired in Cd(2+)-exposed PCM monkeys as compared to Cd(2+)-treated controls. The mechanism of higher urinary excretion of Cd2+, Zn2+ and Ca2+ was examined by analyzing the kinetic parameters of transport systems. The kinetic studies of Cd2+, Zn2+ and Ca2+ transport systems in the BBMV preparations of Cd(2+)-exposed PCM monkeys exhibited a significant decrease in Vmax and an appreciable increase in Km as compared to Cd(2+)-treated controls. These findings suggested that Cd2+ treatment of PCM monkeys caused either a decrease in the number of transporters in the brush border membrane or an increase in the number of less active transporters for Cd2+, Zn2+ and Ca2+. Furthermore, brush border membrane-bound enzymes, viz. alkaline phosphatase and leucine aminopeptidase, activities were significantly impaired in Cd(2+)-exposed PCM monkeys. Cadmium content in kidney cortex of Cd(2+)-exposed PCM monkeys was 3.34-fold higher than Cd(2+)-exposed controls. These findings also established that Cd2+ not bound to metallothionein (MT) was significantly higher in Cd-exposed PCM monkeys, which may be an important determinant in renal toxicity by interacting with sensitive sites in the renal cells and causing renal damage in Cd-exposed PCM monkeys.

Topics: Administration, Oral; Alkaline Phosphatase; Analysis of Variance; Animals; Biological Transport; Cadmium; Calcium; Diet, Protein-Restricted; Kidney; Kidney Cortex; Kinetics; Leucyl Aminopeptidase; Macaca mulatta; Male; Metallothionein; Microvilli; Protein-Energy Malnutrition; Proteinuria; Renal Insufficiency; Zinc