Regulation of metal transporters by dietary iron, and the relationship between body iron levels and cadmium uptake

Abstract

Iron (Fe) plays essential roles in biological processes, whereas cadmium (Cd) is a toxic and non-essential metal. Two metal transporters, divalent metal transporter 1 (DMT1) and metal transporter protein 1 (MTP1), are responsible for Fe transport in mammals. Here, we studied the effect of dietary Fe on the expression of these metal transporters in peripheral tissues, and the uptake by these tissues of Cd. Mice were fed an Fe-sufficient (FeS: 120 mg Fe/kg) or Fe-deficient (FeD: 2-6 mg Fe/kg) diet for 4 weeks. The total Fe levels in the body were evaluated by measuring tissue Fe concentrations. Tissue Cd concentrations were determined 24 h after the mice received a single oral dose of Cd. Animals fed a FeD diet showed depletion of body Fe levels and accumulated 2.8-fold higher levels of Cd than the FeS group. Quantitative real time RT-PCR revealed that whereas DMT1 and MTP1 were both ubiquitously expressed in all FeS peripheral tissues studied, DMT1 was highly expressed in brain, kidney, and testis, whereas MTP1 was highly expressed in liver and spleen. Depletion of the body Fe stores dramatically upregulated DMT1 and MTP1 mRNA expression in the duodenum as well as moderately upregulating their expression in several other peripheral tissues. The iron response element positive isoform of DMT1 was the most prominently upregulated isoform in the duodenum. Thus, DMT1 and MTP1 may play an important role in not only maintaining Fe levels but also facilitating the accumulation of Cd in the body of mammals.

Rapid Regulation of Intestinal Divalent Metal (Cation) Transporter 1 (DMT1/DCT1) and Ferritin mRNA Expression in Response to Excess Iron Loading in Iron-Deficient Rats

“…This up-regulation in irondeficient status has been observed in rats, [2][3][4] mice, 6) and humans. 5) Kim et al 6) have reported that the expression of DMT1 mRNA was 65 times higher in iron-deficient mice than in the controls. The up-regulation of DMT1 mRNA in rats has been shown by RT-PCR and northern blotting, and there have been several quantitative analyses.…”

“…Iron deficiency is well known to result in increased iron absorption in the small intestine, and increased expression of divalent metal transporter 1 (DMT1), which is located in the intestinal brush border, has also been observed. [2][3][4][5][6] DMT1 is the only non-heme iron transporter on the intestinal mucosal surface, according to results from global knockout mice. 7) On the other hand, intestinal iron absorption is inhibited for several days by excess iron loading, and this response to excess iron is called ''mucosal block.…”

Influence of injection timing on severity of cadmium-induced testicular toxicity in mice

“…If Cd accumulation levels in testes or cauda epididymis are different by injection timing, transporters like ZIP8, ZIP14 and DMT1 (Kim et al, 2007;Girijashanker et al, 2008), which involve in Cd transport into these organs, may contribute to the diurnal variation. Induction level of metallothionein, a well known and important defense factor against Cd toxicity, should also be considered (Siu et al, 2009).…”

The role of ZIP8 down‐regulation in cadmium‐resistant metallothionein‐null cells

“…To date, several candidate transporters and channels involved in cadmium uptake in mammalian cells have been proposed: calcium channel (Leslie et al, 2006), calcium transporter (Min et al, 2008), iron transporter (Ryu et al, 2004;Kim et al, 2007;Bannon et al, 2003), zinc transporter (Dalton et al, 2005;He et al, 2006;Wang et al, 2007;Liu et al, 2008) and magnesium transporter (Martine et al, 2008). However, the role of each transport system in cadmium uptake remains still elusive.…”