Zinc deficiency induces oxidative DNA damage and increases p53 expression in human lung fibroblasts.
Poor zinc nutrition may be an important risk factor in oxidant release and the development of DNA damage and cancer. Approximately 10% of the United States population ingests <50% of the recommended daily allowance for zinc, a cofactor in proteins involved in antioxidant defenses, electron transport, DNA repair and p53 protein expression. This study examined the effects of zinc deficiency on oxidative stress, DNA damage and the expression of DNA repair enzymes in primary human lung fibroblasts by the use of DNA microarrays and functional assays. Cellular zinc was depleted by 1) growing cells in a zinc-deficient medium and 2) exposuring cells to an intracellular zinc chelator, N,N,N',N'-tetrakis-(2-pyridylmethyl)ethylenediamine. Array data revealed upregulation of genes involved in oxidative stress and DNA damage/repair and downregulation of other DNA repair genes. Zinc deficiency in cells caused an increase in oxidant production (dichlorofluoroscein fluorescence) and a significant induction of single-strand breaks (Comet assay) and p53 protein expression (Western blot analysis). Thus, zinc deficiency not only caused oxidative stress and DNA damage, but also compromised the cells' ability to repair this damage. Zinc adequacy appears to be necessary for maintaining DNA integrity and may be important in the prevention of DNA damage and cancer.
Ho
Emily
E
University of California, Berkeley, CA 94720, USA.
Courtemanche
Chantal
C
Ames
Bruce N
BN
D015153:Blotting, Western; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D003470:Culture Media / Q000737:chemistry / Q000494:pharmacology; D004249:DNA Damage / Q000187:drug effects; D004260:DNA Repair / Q000235:genetics; D015536:Down-Regulation; D005029:Ethylenediamines / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D016877:Oxidants / Q000378:metabolism; D018384:Oxidative Stress / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D015854:Up-Regulation; D015032:Zinc / Q000172:deficiency*
D002614:Chelating Agents; D003470:Culture Media; D005029:Ethylenediamines; D016877:Oxidants; D016159:Tumor Suppressor Protein p53; D015032:Zinc; C044387:N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine