Increased hepatic accumulation of ingested Cd is associated with upregulation of several intestinal transporters in mice fed diets deficient in essential metals

Essential metals (EMs) can affect the metabolism of nonessential metals. It has been suggested that Fe deficiency increases intestinal absorption of Cd via divalent metal transporter 1 (DMT1). To investigate whether EM nutritional status is a host risk factor for Cd accumulation, we studied the effect of nutritional status of Ca, Cu, Mg, Zn, and Fe that most often ingested by humans at levels below recommended dietary allowances on tissue accumulation of orally administered Cd. Mice were divided into groups and given different EM-deficient (EMDF) diets (CaDF, CuDF, MgDF, ZnDF, or FeDF) for 4 weeks. EMDF mice had significantly (p < 0.05) lower plasma or hepatic concentrations of the deficient EM than did mice receiving control diets. Hepatic Cd accumulation was significantly (p < 0.05) increased after oral Cd administration in all EMDF mice, but not in any EM-supplemented mice. Intestinal expression of mRNAs for the Fe-transporters DMT1 and ferroportin was increased in FeDF mice, but not in other EMDF mice, causing an increase in hepatic Fe concentration. Similarly, intestinal expression of mRNA for calcium transporter 1 was significantly increased in CaDF mice, but not in other EMDF mice. These results suggest that DMT1 is not the sole transporter of Cd, and that Cd is absorbed and accumulated through multiple pathways that maintain EM homeostasis in EMDF condition. Therefore, EM nutritional status is a risk factor for increasing hepatic accumulation of ingested Cd.