[Transport and Toxicity of Cadmium].

Cadmium is a nonessential heavy metal and an industrial and environmental pollutant. It has been known that cadmium must enter cells to cause damage. To understand the transport systems responsible for cadmium entry into cells, it is important to determine the precise mechanisms underlying cadmium toxicity. Numerous studies have sought to unravel the exact pathways by which cadmium enters various cells and the mechanisms by which it causes toxicity in the organs of human and animals. The purpose of this review is to present the progress made regarding the mechanisms of cadmium transport in various cells and the mechanisms underlying cadmium toxicity in organs.

Participation of metal transporters in cadmium transport from mother rat to fetus.

The mechanism of cadmium transport from mother to fetus remains unclear. In this study, we examined the roles of the metal transporters DMT1, ZIP, and ZnT and the metal-binding protein metallothionein in the transport of Cd from mother to fetus in Cd-exposed rats. Cadmium (as CdCl(2)) was administered to female Wistar rats at doses of 0, 1, 2, or 5 mg Cd/kg/day via gastric tube daily for six consecutive days each week for 7 weeks. The concentration of Cd, Zn, and Cu in the uterus and the placenta were then determined. Uterine and placental expression of genes encoding iso-MTs (I, II, and III) and the metal transporters DMT1, ZIP8, ZIP14, ZnT1, ZnT2 and ZnT4 was determined using real-time PCR. The Cd concentration in the placenta and uterus increased with the Cd dose, while the concentration of Cu decreased. Cadmium accumulation in the uterus and placenta resulted in a increase in MT-II gene expression, suggesting that MT-II prevents Cd transport to the fetus by trapping Cd in the uterus and placenta. Expression of the genes encoding DMT1, ZIP14 and ZnT2 was upregulated in the placenta in a dose-dependent manner. Relatively high expression level of the ZnT4 gene than the other ZnT genes (ZnT1 and ZnT2) was observed in the uterus and the placenta. Our results suggest that in the placenta the metal transporters DMT1 and ZIP14 involved in the uptake of Cd into the cytosol.

Health effects of low-level cadmium intake and the role of metallothionein on cadmium transport from mother rats to fetus.

Female Wistar rats were given Cd (as CdCl(2)) at a dose of 0, 1, 2, and 5 mgCd/kg/day by gastric tube daily for 6 consecutive days each week for 10 weeks. After the birth, newborn rats were sacrificed on day 1 and at 4 weeks. Mother rats were sacrificed after 4 weeks of lactation The concentrations of Cd in uterus and placenta, and metallothionein (MT) in the uterus of mother rats were determined. The concentrations of Cd in kidney and liver of newborn rats were also determined. Expression of iso-MT genes (I, II, and III) in the uterus of mother rats was measured using RT-PCR. The Cd concentration in the liver of newborn rats at the first day after birth was higher than in the kidney, while the concentration in the kidney of newborn rats at the fourth week after the birth was significantly higher than in the liver. The uterine MT concentration increased with accumulation of Cd; however, the MT concentration did not increase enough to prevent Cd transport to the fetus. On the other hand, it was considered that more Cd was transported as the chemical form of nonMT-Cd from mother rat, and accumulated in the liver rather than kidney of the fetus. Based on analyses of the Cd distribution in the liver and kidney of newborn rats, we speculate that MT in the uterus and placenta does not play a significant role in preventing Cd transport through the placenta from the uterus to the fetus.

Analysis of urinary metabolites of polycyclic aromatic hydrocarbons in incineration workers.

Incineration workers are exposed to various pyrolysis products of organic materials, heavy metals and polycyclic aromatic hydrocarbons (PAHs). In this study, the exposure of incineration workers to PAHs was evaluated by measuring urinary metabolites of pyrene and naphthalene. The concentrations of urinary 1-hydroxypyrene (1OHP), a metabolite of pyrene, and 2-naphthol (2NP), a metabolite of naphthalene, were measured among 100 workers in 4 different types of incinerators, both before and after their work shifts. These incinerators were two old types, one modern type and one outdoors. The medians of urinary 1OHP of before and after the work shifts obtained from all workers were 0.067 and 0.044 mug/gCr, respectively; and the medians of urinary 2NP were 7.5 and 10.0 mug/gCr, respectively. A significant increase of 2NP after the work shift was found at one old incinerator. A significant decrease of metabolites was found at the other old incinerator. Significant correlations were found between urinary metabolites and cigarettes smoked per day. The effect of smoking on urinary metabolite levels was also important. Significant correlations were found between urinary 1OHP and 2NP levels in all workers. In multiple regression analysis smoking habit and incinerator type were found as significant factors. The improvement of the work environment, through decreasing exposure to both tobacco smoke and hazardous work shift-related substances, should be an occupational health aim.

Transcriptome analysis of rat kidney cells continuously exposed to cadmium using DNA microarray.

To examine the transcriptional responses of rat kidney cells continuously exposed to cadmium, we performed DNA microarray analysis. Cadmium increased levels of expression of 27 genes, including genes for Mt1, Mt2, GSTa3 and B2m and reduced those of 4 genes.

A study of investigation of cadmium genotoxicity in rat bone cells using DNA microarray.

To examine the transcriptional responses of rat bone cells continuously exposed to cadmium, we performed DNA microarray analysis. Cadmium increased levels of expression of 13 genes, including genes for Spp1, and reduced those of 10 genes.

Cellular carbonyl stress enhances the expression of plasminogen activator inhibitor-1 in rat white adipocytes via reactive oxygen species-dependent pathway.

Carbonyl stress is one of the important mechanisms of tissue damage in vascular complications of diabetes. In the present study, we observed that the plasminogen activator inhibitor-1 (PAI-1) levels in serum and its gene expression in adipose tissue were up-regulated in aged OLETF rats, model animals of obese type 2 diabetes. To study the mechanism of PAI-1 up-regulation, we examined the effect of advanced glycation end products (AGEs) and the product of lipid peroxidation (4-hydroxy-2-nonenal (HNE)), both of which are endogenously generated under carbonyl stress. Stimulation of primary white adipocytes by either AGE or HNE resulted in the elevation of PAI-1 in culture medium and at mRNA levels. The up-regulation of PAI-1 was also observed by incubating the cells in high glucose medium (30 mm, 48 h). The stimulatory effects by AGE or high glucose were inhibited by antioxidant, pyrrolidine dithiocarbamate, and reactive oxygen scavenger, probucol, suggesting a pivotal role of oxidative stress in white adipocytes. We also found that the effect by HNE was inhibited by antioxidant, N-acetylcysteine and that a specific inhibitor of glutathione biosynthesis, l-buthionine-S,R-sulfoximine, augmented the effect of subthreshold effect of HNE. Bioimaging of reactive oxygen species (ROS) by a fluorescent indicator, 6-carboxy-2',7'-dichlorodihydrofluorescein diacetate, revealed ROS production in white adipocytes treated with AGE or HNE. These results suggest that cellular carbonyl stress induced by AGEs or HNE may stimulate PAI-1 synthesis in and release from adipose tissues through ROS formation.