Effects of non-toxic zinc exposure on human epidermal keratinocytes

Abstract

Zinc is an essential microelement; its importance to skin is shown by severe skin symptoms in hereditary or acquired zinc deficiency, by the improvement of several skin conditions using systemic or topical zinc preparations and by the induced intracellular zinc release upon UVB exposure, which is the main harmful environmental factor to skin. Understanding the molecular background of the role of zinc in skin may help to gain insight into the pathology of skin disorders and to provide evidence for the therapeutic usefulness of zinc supplementation.Herein, we studied the effect of zinc chloride (ZnCl 2 ) exposure on the function of HaCaT keratinocytes, and we found that a non-toxic elevation in the concentration of extracellular zinc (100 µM) facilitated cell proliferation and induced significant alterations in the mRNA expression of NOTCH1, IL8, and cyclooxygenase-2. In addition, we detected increased heme oxygenase-1 (HMOX1) expression and non-toxic generation of superoxide in the first 4 h.Regarding the effect on UVB-induced toxicity, although the level of cyclobutane pyrimidine dimers in keratinocytes pre-treated with zinc for 24 h was reduced 3 h after UVB irradiation, we found significantly enhanced superoxide generation 10 h after UVB exposure in the zinc pre-exposed cells. The overall survival was unaffected; however, there was a decrease in the percentage of early apoptotic cells and an increase in the percentage of late apoptotic plus necrotic cells.Our results suggest that exposure of human keratinocytes to non-toxic concentrations of ZnCl 2 impacts gene expression, cell proliferation and the response to environmental stress in skin. It would be important to further examine the role of zinc in skin and to further clarify if this issue can affect our thinking about the pathogenesis of skin diseases.

Increases in Intracellular Zinc Enhance Proliferative Signaling as well as Mitochondrial and Endolysosomal Activity in Human Melanocytes

“…This is in accordance with a recently reported effect of Zn on human epidermal keratinocytes HaCaT [22]. Melanocytes are thought to form stable populations with a very low rate of proliferation which is associated with specific changes in cell cycle control elements [23].…”

“…Although generally positive for cells, such sustained mitochondrial activity may represent a challenge regarding the functional integrity of these same cells, particularly in circumstances in which this activity may contribute to the overwhelming of antioxidant defense systems and the induction of chronic oxidative stress. We have not focused on specific elements of ROS-dependent signaling here; nevertheless, it may be presumed that these elements were also involved, particularly in consideration of a similar study on epidermal keratinocytes [22]. In contrast, we did not observe similar mitochondria-stimulating effects of external Zn in melanoma cells, a finding which might be explained by the already existing high activity of this compartment or by the rapid buffering of free intracellular Zn levels, as is suggested at least somewhat by the less significant elevation of these levels in the exposed melanoma cells.…”

Textural, Structural and Biological Evaluation of Hydroxyapatite Doped with Zinc at Low Concentrations

“…The sedimentation of the particle is a problem for the cell viability assay only at the highest concentration and does not hinder our conclusions concerning the biological effect of Zn-HAp. However, the positive effect on cell survival observed for Zn:HAp with x Zn = 0.05 could be due to a higher release of Zn(II) ions that are known to stimulate cell proliferation at concentrations in the 100 µM range [44]. …”

Mechanistic studies of the toxicity of zinc gluconate in the olfactory neuronal cell line Odora

“…(Poss and Tonegawa, 1997) In response to the oxidative stress, antioxidant enzymes, including glutathione and superoxide dismutase were upregulated. Others have demonstrated that zinc exposure causes an increase in reactive oxygen species and nitric oxide, while depleting glutathione, and thereby causing cell death (Bishop et al, 2007; Chen and Liao, 2003; Emri et al, 2015; Kim and Koh, 2002; Pong et al, 2002; Seo et al, 2001; Takeyama et al, 1995). Since similar patterns of up-regulated genes were observed in Odora cells exposed to zinc, biochemical assays measuring intracellular glutathione and hydrogen peroxide levels in Odora cells exposed to zinc for 6, 12, and 24 h were performed.…”