Genomic analysis, cytokine expression, and microRNA profiling reveal biomarkers of human dietary zinc depletion and homeostasis

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 108; no. 52; pp. 20970 - 20975
• Main Authors: Ryu, Moon-Suhn, Langkamp-Henken, Bobbi, Chang, Shou-Mei, Shankar, Meena N, Cousins, Robert J
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 27.12.2011; National Acad Sciences
• Subjects: Acrodermatitis; Adult; Analysis of Variance; Biological markers; Biological Sciences; Biomarkers; Biomarkers - blood; Blood; Blood cells; Cancer; Cell cycle; Cytokines; Cytokines - blood; Depletion; Depression; Diet; DNA microarrays; DNA Primers - genetics; Gene expression; Gene Regulatory Networks; Genes; Genomic analysis; Genomics; Genomics - methods; Homeostasis; Homeostasis - physiology; Humans; Immune response; Immunity; Male; Messenger RNA; Microarray Analysis; microarray technology; MicroRNA; MicroRNAs - blood; miRNA; Nutrient deficiency; Polymerase Chain Reaction; quantitative polymerase chain reaction; repletion; Ribonucleic acid; RNA; secretion; Tumor necrosis factor- alpha; Tumor Necrosis Factor-alpha - blood; Zinc; Zinc - blood; Zinc - deficiency
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1117207108

Implementation of zinc interventions for subjects suspected of being zinc-deficient is a global need, but is limited due to the absence of reliable biomarkers. To discover molecular signatures of human zinc deficiency, a combination of transcriptome, cytokine, and microRNA analyses was applied to a dietary zinc depletion/repletion protocol with young male human subjects. Concomitant with a decrease in serum zinc concentration, changes in buccal and blood gene transcripts related to zinc homeostasis occurred with zinc depletion. Microarray analyses of whole blood RNA revealed zinc-responsive genes, particularly, those associated with cell cycle regulation and immunity. Responses of potential signature genes of dietary zinc depletion were further assessed by quantitative real-time PCR. The diagnostic properties of specific serum microRNAs for dietary zinc deficiency were identified by acute responses to zinc depletion, which were reversible by subsequent zinc repletion. Depression of immune-stimulated TNFα secretion by blood cells was observed after low zinc consumption and may serve as a functional biomarker. Our findings introduce numerous novel candidate biomarkers for dietary zinc status assessment using a variety of contemporary technologies and which identify changes that occur prior to or with greater sensitivity than the serum zinc concentration which represents the current zinc status assessment marker. In addition, the results of gene network analysis reveal potential clinical outcomes attributable to suboptimal zinc intake including immune function defects and predisposition to cancer. These demonstrate through a controlled depletion/repletion dietary protocol that the illusive zinc biomarker(s) can be identified and applied to assessment and intervention strategies.