Zinc, an essential micronutrient, functions as a catalytic, structural and regulatory component for numerous metabolic processes. The estimated prevalence of zinc deficiency worldwide remains substantially high at 31%. The lack of a reliable biomarker limits the identification of individuals requiring zinc interventions, and thus a specific and sensitive assessment tool for such condition is greatly needed.

To identify candidate markers holding the potential to indicate zinc status, a 24-d observational study comprised of acclimation, zinc depletion and repletion phases was conducted with healthy male subjects. Serum zinc levels were monitored throughout the 24-d period. On day 0, 6 and 10 of zinc depletion, buccal swabs and whole blood were collected for various molecular assays. Decreased serum zinc concentrations confirmed the zinc-depleted status of each participant along with a reduction in buccal MT transcript levels. Abundance of MT, ZnT1, ZnT4 and ZnT5 mRNA levels in peripheral blood mononuclear cells (PBMC) and ZnT1 and Zip3 transcripts in purified reticulocytes significantly decreased by dietary zinc depletion. The reduction of ZnT1 mRNA levels was measurable in whole blood RNA. Additionally, the presence of ZnT1 and Zip10 in the plasma membrane of erythrocytes, of which differential expression by zinc deficiency has been shown in mice, was confirmed. Increase in membrane dematin levels was observed in erythrocytes collected after zinc depletion. Microarray analysis with globin RNA-depleted whole blood RNA revealed 328 genes responsive to acute dietary zinc depletion. Bioinformatic analysis identified enriched pathways associated with cell cycle and immunity by the up-regulated and down-regulated genes, respectively. Depression in immunostimulated TNFα release by dietary zinc depletion confirmed the functional significance of zinc in immune responses. Furthermore, responses of serum miRNA to dietary zinc levels were measured.

Based on a comprehensive analysis of specimens from zinc-depleted human subjects, gene transcripts and proteins holding the potential of being zinc biomarkers were identified. These results also implicated impaired host defense and predisposition to cancer development as expected outcomes of dietary zinc deficiency. This trial was registered at clinicaltrials.gov as NCT01221129.