Effects of Zinc Exposure on Zinc Transporter Expression in Human Intestinal Cells of Varying Maturity

Objectives: Zinc (Zn) homeostasis in adults is achieved principally through a balance between intestinal absorption and excretion involving adaptive mechanisms programmed by levels of dietary Zn. Zn absorption in infants is not as tightly regulated as that in adults, which may induce potential toxicity in infants due to the relatively high capacity of Zn absorption. We hypothesized that intestinal Zn homeostasis is developmentally regulated and depends on intestinal maturation, which in turn affects Zn transporter regulation. Materials and Methods: Cultured human fetal (FHs 74 Int, F) and adult (Caco-2: undifferentiated, U; differentiated, D) intestinal cells were used to determine developmental differences in Zn uptake and effects of Zn exposure on Zn transporters. Results: Zn uptake rates in F and U cells were higher compared with D cells (F, 9-fold; U, 3-fold). F cells were more intolerant to Zn exposure than were U or D cells (LD50 = 67.9 +/- 5.3; 117.0 +/- 5.2; 224.4 +/- 3.7 mu mol/L, respectively). Two mechanisms were involved in developmental regulation of Zn homeostasis: differential Zn transporter expression and differential response to Zn exposure. In F cells, zinc-regulated transporter (ZRT)/iron-regulated transporter (IRT)-like protein (Zip) 4 expression was undetectable; Zn (50 mu mol/L) increased levels of Zn transporter (ZnT) 1, ZnT2, and metallothionein-1 mRNA and ZnT1 protein. U and D cells had higher mRNA expression of ZnT1 (U: 5-fold; D: 7-fold, respectively) and ZnT2 (U: 2-fold; D: 9-fold, respectively) than F cells, and D cells also had higher Zip4 expression (3-fold) than U cells. In U cells, Zn exposure increased Zip4 protein level, but not membrane-associated abundance. However, in D cells, Zn exposure decreased both the Zip4 protein level and membrane-associated abundance. Conclusions: Zn absorption is developmentally regulated through intestinal Zn efflux and sequestration and import mechanisms, which may be responsible for differences in Zn absorption observed between infants and adults.