Zinc supplementation reduces iron absorption through age-dependent changes in small intestine iron transporter expression in suckling rat pups.

Zinc (Zn) supplementation negatively affects iron (Fe) absorption; however, the molecular mechanisms are not understood. We determined effects of Zn supplementation during mid- and late infancy on intestinal Fe transport mechanisms using a suckling rat model. Suckled rat pups were supplemented with 0 (control), 300 (low), or 750 (high) microg Zn/d until weaning at postnatal day (PN) 20. At mid-(PN10) and late (PN20) infancy, tissue Fe distribution, Fe absorption, intestine DMT1, ferroportin-1 (FPN) and hephaestin expression, and localization and liver hepcidin expression were measured. During early infancy, DMT1 and FPN were localized intracellularly. Negative effects of Zn supplementation on Fe absorption were associated with increased small intestine Fe retention, decreased hephaestin, and increased FPN expression. During late infancy, both DMT1 and FPN were appropriately localized to the apical and basolateral membrane, respectively, and negative effects of Zn supplementation on Fe absorption were absent. Although FPN protein level was lower in Zn-supplemented pups, hephaestin protein level was increased, which may have facilitated enhanced Fe efflux. These results indicate that Zn supplementation reduced Fe absorption during early infancy as a consequence of increased intestinal Fe retention due to reduced hephaestin levels. These effects were age-dependent, further demonstrating that Fe transport regulation is not fully developed until weaning, which may have important implications regarding the safety and efficacy of Zn supplementation programs for infants.