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UVB exposure enhanced the dermal penetration of zinc oxide nanoparticles and induced inflammatory responses through oxidative stress mediated by MAPKs and NF-?B signaling in SKH-1 hairless mouse skin.

ABSTRACT: Besides titanium dioxide (TiO₂), zinc oxide (ZnO) nanoparticles (NPs) are commonly used in sunscreen formulations as protective agents against exposure to ultraviolet radiation. Although the majority of prior studies have concluded that NPs do not penetrate healthy skin, compromised skin slightly enhanced metal oxide NP penetration. However, a question arises regarding the possible toxic consequences if consumers who had applied sunscreens containing ZnO-NPs were exposed to environmentally relevant doses of UVB. Considering this, we planned a study where SKH-1 hairless mice were topically exposed to a 5% and/or 10% dose of ZnO-NPs (<50 nm and <100 nm) either alone or along with UVB (50 mJ cm^-2). In two additional groups, mice were treated with either bulk ZnO-NPs (<5 ?m) or with ZnO-NPs (<5 ?m) and subsequently UVB (50 mJ cm^-2). Animals of all groups were sacrificed after 6, 24 and 48 h and the Zn ion content in the skin was measured. In addition, estimation of ROS generation, histopathology, myeloperoxidase (MPO) activity, immunohistochemistry for COX-2 and western blot analysis for MAPKs, p-I?B?, p-NF-?B, and COX-2 were also carried out. Significant increases in the Zn ion in exposed skin were seen. Enhanced ROS generation and MPO activity were also found in ZnO-NPs followed by UVB exposed groups at all three time points. Similarly, hyperplasia and over-expression of COX-2 were also greater in ZnO-NPs and UVB exposed groups than in the ZnO-NPs and UVB only groups. The expression of MAPKs, and transcription factors NF-?B along with COX-2 were also enhanced significantly in ZnO-NPs and the UVB treated group. Collectively, our findings suggest that UVB exposure enhanced ZnO-NP penetration in mouse skin and possibly dissolution of these ZnO-NPs takes place during this process, causing significant Zn ion generation leading to oxidative stress by ROS generation which subsequently activates MAPK-NF-?B signaling and increases COX-2 and inflammation.

SUBMITTER: Pal A

PROVIDER: S-EPMC6062152 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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UVB exposure enhanced the dermal penetration of zinc oxide nanoparticles and induced inflammatory responses through oxidative stress mediated by MAPKs and NF-κB signaling in SKH-1 hairless mouse skin.

Pal Anu A Alam Shamshad S Chauhan Lalit K S LKS Saxena Prem N PN Kumar Mahadeo M Ansari Ghazi N GN Singh Dhirendra D Ansari Kausar M KM

Toxicology research 20160408 4

Besides titanium dioxide (TiO<sub>2</sub>), zinc oxide (ZnO) nanoparticles (NPs) are commonly used in sunscreen formulations as protective agents against exposure to ultraviolet radiation. Although the majority of prior studies have concluded that NPs do not penetrate healthy skin, compromised skin slightly enhanced metal oxide NP penetration. However, a question arises regarding the possible toxic consequences if consumers who had applied sunscreens containing ZnO-NPs were exposed to environmen ...[more]

PMID: 30090412

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Project description:Estrogen receptors (ER), including ER-α and ER-β, are known to regulate multiple biologic responses in various cell types. The expression of ER-β is lost in various cancers. ER-β agonists were shown to modulate inflammation, cancer cell proliferation, and differentiation. Here, we investigated the cancer chemopreventive properties of Erb-041, an ER-β agonist, using a model of UVB-induced photocarcinogenesis in SKH-1 mice. Erb-041 significantly reduced UVB-induced carcinogenesis. Tumor numbers and volume were reduced by 60% and 84%, respectively, in the Erb-041-treated group as compared with UVB (alone) control. This inhibition in tumorigenesis was accompanied by the decrease in proliferating cell nuclear antigen (PCNA), cyclin D1, VEGF, and CD31, and an increase in apoptosis. The lost ER-β expression in squamous cell carcinomas (SCC) was significantly recovered by Erb-041 treatment. In addition, the UVB-induced inflammatory responses were remarkably reduced. Myeloperoxidase activity, levels of cytokines (interleukin (IL)-1β, IL-6, and IL-10), and expression of p-ERK (extracellular signal-regulated kinase) 1/2, p-p38, p-IκB, iNOS, COX-2, and nuclear NF-κBp65 were diminished. The number of tumor-associated inflammatory cells (GR-1(+)/CD11b(+) and F4/80(+)) was also decreased. Tumors excised from Erb-041-treated animal were less invasive and showed reduced epithelial-mesenchymal transition (EMT). The enhanced expression of E-cadherin with the concomitantly reduced expression of N-cadherin, Snail, Slug, and Twist characterized these lesions. The WNT/β-catenin signaling pathway, which underlies pathogenesis of skin cancer, was found to be downregulated by Erb-041 treatment. Similar but not identical changes in proliferation and EMT regulatory proteins were noticed following treatment of tumor cells with a WNT signaling inhibitor XAV939. Our results show that Erb-041 is a potent skin cancer chemopreventive agent that acts by dampening the WNT/β-catenin signaling pathway.

Dataset Information

UVB exposure enhanced the dermal penetration of zinc oxide nanoparticles and induced inflammatory responses through oxidative stress mediated by MAPKs and NF-?B signaling in SKH-1 hairless mouse skin.

Publications

UVB exposure enhanced the dermal penetration of zinc oxide nanoparticles and induced inflammatory responses through oxidative stress mediated by MAPKs and NF-κB signaling in SKH-1 hairless mouse skin.

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