Involvement of intestinal calcium transporter 1 and metallothionein in cadmium accumulation in the liver and kidney of mice fed a low-calcium diet
Introduction
Cadmium (Cd) is a nonessential metal and a prevalent environmental pollutant in industrial countries. The source of Cd intake is mostly food and drinking water, and Cd accumulates preferentially in the liver and kidney. Chronic Cd exposure causes renal damage in humans and other animals (Nordberg et al., 2007). Iron deficiency may be one of the nutritional problems that increase the importance of Cd toxicity as a public health issue, because intestinal absorption of Cd increases when the body's iron stores are depleted (Flanagan et al., 1978). A recent report demonstrated that iron depletion likely upregulates functional divalent metal transporter 1 (DMT1), an apical Fe2+ transporter, in the small intestine at the mRNA level; this increases Cd uptake from the gastrointestinal tract, with subsequent transfer of Cd to the circulation and body tissues (Park et al., 2002). Expression of the apical Fe transporter DMT1 and the basolateral Fe exporter metal transporter protein 1/feroportin (MTP1/FPN) is correlated with the Cd body burden in rats, suggesting an important role for DMT1 and FPN in Cd absorption (Ryu et al., 2004) and indicating that an essential metal can affect the metabolism of a nonessential metal such as Cd.
Calcium (Ca) deficiency is another worldwide health problem, and several studies have shown that the level of Ca in the diet can also contribute to the toxic effects of Cd. Larsson and Piscator (1971) found that rats exposed to Cd and fed a low-Ca diet accumulated approximately 60% more Cd in the liver and kidneys than rats similarly exposed to Cd but fed a sufficient amount of Ca. Washko and Cousins (1977) suggested that Cd retention is enhanced by a low-Ca diet and that the increased calcium binding protein activity caused by the Ca restriction is responsible for the observed increase in Cd uptake. In contrast, decreased expression of the T-type Ca2+ channel protects cells from Cd exposure by limiting Cd uptake in Cd-resistant MT-I/II knockout cells (Leslie et al., 2006). These reports suggest that Ca-related proteins, such as Ca transporters and channels, are important pathways for intestinal Cd absorption. Interestingly, Ca deficiency causes greater distribution of Cd to the kidneys than does Fe deficiency. Ratio of renal Cd concentration to hepatic Cd concentration (Cd[K/L]) was 2.4 in control group and 0.88 in Fe deficient (DF) group, respectively (control: FeDF = 1:0.37) (Park et al., 2002). On the other hand, Cd[K/L] was 3.7 in control group and 3.1 in CaDF group, respectively (control: CaDF = 1:0.84) (Washko and Cousins, 1977). However, the mechanism of the intestinal absorption and distribution of Cd in the Ca-deficient state is not yet clear.
Most Cd in the intestinal mucosa is bound to metallothionein (MT; Min et al., 1991). Our previous report suggested that mucosal MT in the small intestine traps Cd absorbed from the intestinal lumen and transports it to the kidney. A channel-like calcium transporter (CaT1) that mediates intestinal Ca absorption has also been cloned and characterized, and the regulation of its expression has been studied (Peng et al., 1999, Wood et al., 2001, Song et al., 2003, Meyer et al., 2006). However, very little is known about the role of CaT1 in the intestinal absorption and tissue distribution of Cd. In the present study, we sought to determine whether Ca deficiency affects the intestinal absorption and tissue distribution of orally administered Cd and whether intestinal expression of CaT1 and MT is increased in mice fed a low-Ca diet.
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Animals
Male mice (ddY strain, 5 weeks old) were purchased from Nihon SLC (Shizuoka, Japan). Mice were housed in plastic cages and maintained on a 12-h light–dark cycle. All mice were given one of two purified diets containing 0.5% Ca or 0.005% Ca in a base diet of AIN-93M (Oriental Yeast, Osaka, Japan) and water ad libitum. All animal experiments were carried out under the control of the Animal Research Committee of Osaka Ohtani University, in accordance with the Guidelines on Animal Experiments in
Results
The terminal weights of the body and several tissues did not differ significantly (p > 0.05) between mice fed 0.5% Ca (control diet) or 0.005% Ca (Ca-deficient diet; CaDF) for 4 weeks (data not shown). We measured the plasma and tissue concentration of Ca and Zn in CaDF mice over the period of Ca deficiency as shown in Fig. 1. Although the mice ingested less Ca than controls, the plasma and hepatic Ca concentration did not decrease. The renal Ca concentration decreased only at the 1st week. These
Discussion
The brush border membrane transporters for Cd have not yet been identified. The intestinal absorption of Cd is increased or decreased depending on the body iron status in animal and human models (Valberg et al., 1976, Flanagan et al., 1978, Kowal, 1988, Berglund et al., 1994, Schumann et al., 1996). These earlier reports suggested that the transport of Cd in mammals might be associated with the Fe transporter, which was identified as DMT1 (Fleming et al., 1997, Gunshin et al., 1997, Gunshin et
Acknowledgement
This study was supported by Scientific Research Grant C-17510050 from the Japanese Ministry of Education, Science, and Culture.
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