Protective role of Nrf2 in zinc oxide nanoparticles-induced lung inflammation in female mice and sexual dimorphism in susceptibility

Autor: Radwa Sehsah, Wenting Wu, Sahoko Ichihara, Naozumi Hashimoto, Cai Zong, Kyoka Yamazaki, Harue Sato, Ken Itoh, Masayuki Yamamoto, Ahmed Ali Elsayed, Soheir El-Bestar, Emily Kamel, Gaku Ichihara
Rok vydání: 2022
Předmět:
Zdroj: Toxicology Letters. 370:24-34
ISSN: 0378-4274
Popis: Background Zinc oxide nanoparticles (ZnO-NPs) are used in various products such as rubber, paint, and cosmetics. Our group reported recently that Nrf2 protein provides protection against ZnO-NPs-induced pulmonary inflammation in male mice. The present study investigated the effect of Nrf2 deletion on the lung inflammatory response in female mice exposed to ZnO-NPs. Methods Twenty-four female Nrf2−/− mice and the same number of female Nrf2+/+ mice were each divided into three equal groups and each exposed to ZnO-NPs at either 0, 10 or 30 µg/mouse by pharyngeal aspiration. Bronchoalveolar lavage fluid (BALF) and lungs were collected 14 days later to quantify protein level, number of inflammatory cells, and for scoring inflammation histopathologically. The mRNA levels of Nrf2-depedent antioxidant enzymes and proinflammatory cytokine in lung tissue were measured. Results Exposure to ZnO-NPs increased all types of BALF cells and lung inflammation scores in both of female Nrf2−/− and Nrf2+/+ mice, and Nrf2 deletion enhanced ZnO-NPs-induced increase in the number of eosinophils in BALF. Nrf2 deletion enhanced ZnO-NPs-induced downregulation of GR and upregulation of HO-1 and TNFα. Nrf2 deletion decreased mRNA levels of CAT, GcLc and NQO1 and increased that for GcLm and MT-2. ZnO-NPs dose-dependently increased the level of oxidized glutathione (GSSG), and mRNA levels of proinflammatory cytokines/chemokines; KC, MIP-2, IL-6, IL-1β and MCP-1 only in wild-type mice, and Nrf2 deletion decreased total glutathione levels and upregulated the above proinflammatory cytokines/chemokines regardless of level of exposure to ZnO-NPs. Taken together with our previous results in male mice, our results showed a lower susceptibility of females to lung inflammation, relative to males, irrespective of Nrf2 deletion, and that enhancement of ZnO-NPs-induced upregulation of HO-1 and TNFα and downregulation of GR by deletion of Nrf2 is specific to female mice. Conclusion We conclude that Nrf2 provides protection in female mice against increase in BALF eosinophils, probably through down-regulation of proinflammatory cytokines/chemokines and upregulation of oxidative stress-related genes. The study also suggests lower susceptibility to lung inflammation in female mice relative to their male counterparts and the synergistic effects of sex and exposure to ZnO-NPs on mRNA expression of GR, HO-1 or TNFα.
Databáze: OpenAIRE
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