Zinc Oxide Particles Can Cause Ovarian Toxicity by Oxidative Stress in Female Mice Model

Abstract

Yuanyuan Xu,1,2 Yu Zhao,2 Shanji Liu,2 Sidi Lv,3 Ling Chen,4 Wanzhen Wang,1 Yueying Feng,1 Fen Fu,1 Hengyi Xu2 1The Second Affiliated Hospital of Nanchang University, Nanchang, 330000, People’s Republic of China; 2State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang, 330047, People’s Republic of China; 3Second Clinical Medical College, Nanchang University, Nanchang, 330006, People’s Republic of China; 4The First Affiliated Hospital of Gannan Medical University, Ganzhou, 341001, People’s Republic of ChinaCorrespondence: Fen Fu, The Second Affiliated Hospital of Nanchang University, No. 1 Mingde Rode, Nanchang, 330000, People’s Republic of China, Tel [phone], Email [email protected] Hengyi Xu, State Key Laboratory of Food Science and Technology, Nanchang University, 235 Nanjing East Road, Nanchang, 330047, People’s Republic of China, Tel [phone]-ext-9520, Fax [phone], Email [email protected]: Zinc oxide nanoparticles (ZnO NPs) participate in all aspects of our lives, but with their wide application, more and more disadvantages are exposed. The goal of this study was to investigate the toxicity of ZnO NPs in female mice ovaries and explore its potential mechanism.Methods: In this study, adult female mice were orally exposed to 0, 100, 200, and 400 mg/kg ZnO NPs for 7 days. We explored the underlying mechanisms via the intraperitoneal injection of N-acetyl-cysteine (NAC), an inhibitor of oxidative stress, and salubrinal (Sal), an inhibitor of endoplasmic reticulum (ER) stress.Results: The results indicated that serum estradiol and progesterone levels declined greatly with increasing ZnO NPs dosage. Hematoxylin and eosin (HE) staining revealed increased atretic follicles and exfoliated follicular granulosa cells. Moreover, at the transcriptional level, antioxidant-related genes such as Keap1 and Nrf2, and ER stress-related genes PERK, eIF2α, and ATF4 were markedly upregulated. In addition, the expression of Caspase12, Caspase9, and Caspase3, which are genes related to apoptosis, was also upregulated in all ZnO NPs treatment groups. Serum malondialdehyde (MDA) content was remarkably up-regulated, whereas superoxide dismutase (SOD) activity was down-regulated. The 400 mg/kg ZnO NPs treatment group suffered the most substantial harm. However, ovarian damage was repaired when NAC and Sal were added to this group.Conclusion: ZnO NPs had toxic effects on the ovary of female mice, which were due to oxidative stress, ER stress, and the eventual activation of apoptosis.Graphical Abstract: Keywords: zinc oxide nanoparticles, ovary, oxidative stress, endoplasmic reticulum stress, apoptosis

Keywords

• zinc oxide nanoparticles
• ovary
• oxidative stress
• endoplasmic reticulum stress
• apoptosis