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Continuous ZnO nanoparticle exposure induces melanoma-like skin lesions in epidermal barrier dysfunction model mice through anti-apoptotic effects mediated by the oxidative stress–activated NF-κB pathway

ABSTRACT: Increasing interest in the hazardous properties of zinc oxide nanoparticles (ZnO NPs), commonly used as ultraviolet filters in sunscreen, has driven efforts to study the percutaneous application of ZnO NPs to diseased skin; however, in-depth studies for epidermal barrier dysfunction remain lacking. Our epidermal barrier dysfunction model develops large gaps between keratinocytes due to keratinocyte-specific Cdc42 knockout, allowing ZnO NPs entry to the stratum basale of the epidermis, impacting melanocytes. ZnO NP application for 14 and 49 consecutive days induced melanoma-like skin lesions, dysregulated melanoma-associated gene expression, increased oxidative injury, inhibited apoptosis, and increased nuclear factor kappa B (NF-κB) p65 and Bcl-2 expression in melanocytes. Exposure to 5.0 µg·mL−1 ZnO NPs for 72 h increased cell viability, decreased apoptosis, and increased Fkbp51 expression in melanocytes, consistent with histological observations. The oxidative stress–mediated mechanism underlying the induction of anti-apoptotic effects was verified using the reactive oxygen species scavenger N-acetylcysteine. The entry of ZnO NPs into the stratum basale of skin with epidermal barrier dysfunction resulted in melanoma-like skin lesions and an anti-apoptotic effect induced by oxidative stress, activating the NF-κB pathway in melanocytes. These findings suggest that ZnO NPs are potentially carcinogenic for skin with a damaged barrier function.

ORGANISM(S): Mus musculus

PROVIDER: GSE183662 | GEO | 2022/03/09

REPOSITORIES: GEO

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Project description:Dietary collagen hydrolysate has been conjectured to improve skin barrier function. To investigate the effect of long-term collagen hydrolysate administration on the skin, we evaluated stratum corneum water content and skin elasticity in intrinsic aged mice. Female 9-week-old hairless mice were fed a control diet, or a collagen hydrolysate-containing diet, for 12 weeks. The stratum corneum water content and skin elasticity were sequentially decreased by chronological aging in control mice. Intake of collagen hydrolysate significantly suppressed such changes. Moreover, we comprehensively analyzed gene expression in the skin of mouse, which had been administered collagen hydrolysate, using DNA microarray. Twelve weeks after start of collagen intake, no significant differences appeared in gene expression profile compared to that of control group. However, 12 weeks after administration, 135 genes were up-regulated and 448 genes were down-regulated in collagen group compared to control group. It is indicate that gene changes preceded changes of barrier function and elasticity. We focused on several genes correlated with functional changes in the skin. Gene Ontology terms, especially related to epidermal cell development, were signi?cantly enriched in up-regulated genes. These skin function-related genes had properties that facilitate epidermal production and differentiation and suppress dermal degradation. Thus, dietary collagen hydrolysate induced positive gene changes. In conclusion, our results suggest that alteration of gene expression at early stages after collagen administration affect skin barrier function and mechanical properties. Long-term oral intake of collagen hydrolysate improves skin dysfunction by regulating genes related to production and maintenance of the skin tissue. Nine-week-old female Hos:HR-1 hairless mice (Japan SLC Inc., Shizuoka, Japan) were used in this study. All mice were housed in plastic cages (4 mice/cage) in a temperature and humidity controlled room (24 ± 1°C and 50 ± 10% humidity) under a 12 hour light-dark cycle. Mice were given an AIN-93G (Oriental Yeast Co., Ltd., Tokyo, Japan) diet and water. The present study was approved by the Animal Committee of Meiji Seika Kaisha Ltd., Food & Health R&D Laboratories, with the animals receiving care under the Guiding Principles for the Care and Use of Laboratory Animals of this committee. All surgery was performed under isoflurane anesthesia, and all efforts were made to minimize suffering. Sixteen female mice were randomly divided into two groups (n = 8 /group) according to their body weight, stratum corneum water content, and skin elasticity. During the experimental period for 12 weeks, the control group was fed a control diet (AIN-93G) and the collagen group was fed a collagen diet consisting of a mixture of 2.0 g of collagen hydrolysate and 100 g of the control diet. Fish scale collagen hydrolysate was purchased from Nitta Gelatin Inc. (Osaka, Japan). This amount of collagen hydrolysate is approximately equivalent to oral ingestion of 2.0 g collagen hydrolysate/kg body weight/day.

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Continuous ZnO nanoparticle exposure induces melanoma-like skin lesions in epidermal barrier dysfunction model mice through anti-apoptotic effects mediated by the oxidative stress–activated NF-κB pathway

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