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

Background 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 of toxic effects on melanocytes under conditions of epidermal barrier dysfunction remain lacking. Methods Epidermal barrier dysfunction model mice were continuously exposed to a ZnO NP-containing suspension for 14 and 49 consecutive days in vivo. Melanoma-like change and molecular mechanisms were also verified in human epidermal melanocytes treated with 5.0 µg/ml ZnO NPs for 72 h in vitro. Results ZnO NP application for 14 and 49 consecutive days induced melanoma-like skin lesions, supported by pigmented appearance, markedly increased number of melanocytes in the epidermis and dermis, increased cells with irregular nuclei in the epidermis, recruited dendritic cells in the dermis and dysregulated expression of melanoma-associated gene Fkbp51, Trim63 and Tsp 1. ZnO NPs increased oxidative injury, inhibited apoptosis, and increased nuclear factor kappa B (NF-κB) p65 and Bcl-2 expression in melanocytes of skin with epidermal barrier dysfunction after continuously treated for 14 and 49 days. Exposure to 5.0 µg/ml ZnO NPs for 72 h increased cell viability, decreased apoptosis, and increased Fkbp51 expression in melanocytes, consistent with histological observations in vivo. The oxidative stress–mediated mechanism underlying the induction of anti-apoptotic effects was verified using the reactive oxygen species scavenger N-acetylcysteine. Conclusions 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. Graphical Abstract

ZnO NPs induce miR-342-5p mediated ferroptosis of spermatocytes through the NF-κB pathway in mice

“…Numerous studies have shown that ZnO NPs-induced toxicity is associated with NF-κB, Nrf2, and HIF-1α/BNIP3/LC3B-mediated mitochondrial autophagy pathways [ 55 – 57 ], and this study focuses more on NF-κB pathway based on transcriptome analysis. NF-κB is a sequence-specific DNA-binding transcription factor that is over-activated in almost all cancers [ 58 ] and plays a central role in the initiation and progression of oxidative stress [ 44 , 59 , 60 ], there are multiple evidence shows that the NF-κB signaling pathway is closely connected with cell apoptosis and ferroptosis [ 20 , 61 , 62 ]. As a NF-κB/p65-regulated factor, ZnO NP is involved in the inflammatory responses thereby delaying the recovery of skin diseases and leading to acute lung injury [ 56 , 58 , 63 ].…”

“…NF-κB is a sequence-specific DNA-binding transcription factor that is over-activated in almost all cancers [ 58 ] and plays a central role in the initiation and progression of oxidative stress [ 44 , 59 , 60 ], there are multiple evidence shows that the NF-κB signaling pathway is closely connected with cell apoptosis and ferroptosis [ 20 , 61 , 62 ]. As a NF-κB/p65-regulated factor, ZnO NP is involved in the inflammatory responses thereby delaying the recovery of skin diseases and leading to acute lung injury [ 56 , 58 , 63 ]. MicroRNA is a kind of key non-coding RNA (ncRNAs), 18–22 nt, which mainly binds to gene’s 3′UTR and regulates their expression In KGN cells, the NF-κB signaling pathway was negatively regulated by miR-93-5p to promote apoptosis and ferroptosis [ 62 ].…”

Zinc oxide nanoparticles inhibit malignant progression and chemotherapy resistance of ovarian cancer cells by activating endoplasmic reticulum stress and promoting autophagy

“…A study has shown that ZnO-NP treatment may lead to prostate cancer cell apoptosis and death (26). ZnO-NPs stimulate oxidative stress to induce melanoma-like skin lesions and apoptosis of melanoma cells in mice with epidermal barrier dysfunction through the activation of the NF-κB pathway (27,28). A recent study indicated that ZnO-NPs can promote OC cell death, thus inhibiting the progression of OC (29).…”

Green synthesis and Biomedical Applications of Zinc Oxide Nanoparticles. Review

“…The obtained results showed that, in a mouse model of epidermal barrier dysfunction, topical exposure to ZnO NPs causes these particles to penetrate the stratum basale of the epidermis, leading to the development of melanoma-like lesions on the skin. Additionally, both in vivo and in vitro, persistent exposure to ZnO NPs caused an anti-apoptotic effect in melanocytes through activating NF-κB pathways through oxidative stress [128].…”