GSE183662
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-?B pathway
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-?B) 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-?B pathway in melanocytes. These findings suggest that ZnO NPs are potentially carcinogenic for skin with a damaged barrier function. Overall design: Skin mRNA profiles of WT and Cdc42 KO mice in the negative control group (no ZnO NP exposure) and WT and Cdc42 KO mice continuously treated with ZnO NPs for 14 days were generated by deep sequencing, in triplicate, using Illumina GAIIx.