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Titanium Dioxide Nanoparticles Induce Cell Cycle Arrest and Apoptosis through Inhibiting PI3K/AKT/mTOR Pathway in Spermatogonia

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Abstract

Titanium dioxide nanoparticles (TiO2 NPs) can result in the reduction of sperm numbers, but the mechanisms have not been well elucidated. The purpose of this study was to investigate the effects of TiO2 NPs on cell cycle and apoptosis in spermatogonia and to explore the role of PI3K/AKT/mTOR signaling pathway in this process. The mouse spermatogonia cell line (GC-1) was treated with TiO2 NPs at different concentrations (0, 25, 50, 75 and 100 μg/mL) for 24 h to detect cell viability, cell cycle, apoptosis, and key proteins related to cell cycle and PI3K/AKT/mTOR signaling pathway. The agonist (IGF-1) and inhibitor (LY294002) of PI3K were used to verify the role of PI3K/AKT/mTOR signaling pathway in cell cycle and apoptosis. TiO2 NPs significantly inhibited cell proliferation, induced cell cycle arrest at G0/G1 phase and resulted in apoptosis. TiO2 NPs downregulated the levels of cyclin-dependent kinases (CDKs) and cyclins, including CDK4, CDK2, Cyclin D1 and Cyclin E1, while upregulated the levels of p21 and p53 proteins. Furthermore, TiO2 NPs inhibited the PI3K/AKT/mTOR signaling pathway by decreasing the levels of p-PI3K, p-AKT and p-mTOR. IGF-1 reversed the G0/G1 phase arrest and apoptosis caused by TiO2 NPs. However, LY294002 aggravated the G0/G1 phase arrest and apoptosis resulting from TiO2 NPs. Collectively, TiO2 NPs induced cell cycle arrest at G0/G1 phase and apoptosis through inhibiting the activation of PI3K/AKT/mTOR pathway, which could be the main reason for the reduction in sperm numbers caused by TiO2 NPs.

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Data Availability

The datasets supporting the conclusions of this article are included within the article and its supplementary material, and the original data of this study will be made available upon reasonable request.

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Funding

This work was supported by the Corps science and technology planning project (2023AB049) and the National Natural Science Foundation of China (21966027, 81560536).

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  1. Ruoyun Dong and Xiaojia Meng contributed equally to this work.

Authors and Affiliations

  1. Department of Preventive Medicine / the Key Laboratory for Prevention and Control of Emerging Infectious Diseases and Public Health Security, the Xinjiang Production and Construction Corps, School of Medicine, Shihezi University, Shihezi, 832000, Xinjiang, China

    Ruoyun Dong, Hongmei Chang, Yuzhu Lei, Yunhua Hu, Yizhong Yan & Guanling Song

  2. The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China

    Xiaojia Meng

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  1. Ruoyun Dong
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  2. Xiaojia Meng
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  4. Yuzhu Lei
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Contributions

Guanling Song and Xiaojia Meng contributed to the study conception and design. Experimental execution was performed by Xiaojia Meng, Ruoyun Dong and Hongmei Chang. Data analyses were performed by Yuzhu Lei, Yizhong Yan and Yuhua Hu. The first draft of the manuscript was written by Ruoyun Dong, Xiaojia Meng and Guanling Song, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Guanling Song.

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Dong, R., Meng, X., Chang, H. et al. Titanium Dioxide Nanoparticles Induce Cell Cycle Arrest and Apoptosis through Inhibiting PI3K/AKT/mTOR Pathway in Spermatogonia. Biol Trace Elem Res (2023). https://doi.org/10.1007/s12011-023-03984-7

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