The Role of CXCL13 in GC-1 Cell Cycle Arrest Induced by Titanium Dioxide Nanoparticles Through JAK2/STAT3 Signaling Pathway.

Abstract

Titanium dioxide nanoparticles (TiO₂ NPs) can induce the cell cycle arrest in spermatogonia, and the JAK2/STAT3 signaling pathway plays a pivotal role in cell cycle progression, but the specific upstream regulatory mechanisms are not completely clarified. The purpose of this study was to investigate whether CXCL13 regulated the JAK2/STAT3 signaling pathway to participate in cell cycle arrest after mouse spermatogonia cell line (GC-1) exposure to TiO₂ NPs. The GC-1 cells were treated with TiO₂ NPs at different concentrations (0, 10, 20, 30, and 40 μg/mL) for 24 h to detect cell viability, cell cycle distribution, CXCL13 protein, JAK2/STAT3 pathway-related proteins, and cell cycle-related proteins. The CXCL13 recombinant protein was used to verify the role of CXCL13 in cell cycle and JAK2/STAT3 signaling pathway. TiO₂ NPs inhibited cell viability; regulated cell cycle-related proteins including remarkably decreased Cyclin D1, CDK4, Cyclin E1, and CDK2 as well as increased p21; and induced cell cycle arrest at the G0/G1 phase. TiO₂ NPs inhibited the levels of CXCL13 protein and weakened the activation of the JAK2/STAT3 signaling pathway by reducing the levels of p-JAK2/JAK2 and p-STAT3/STAT3 proteins. Furthermore, CXCL13 mitigated the suppression of the JAK2/STAT3 signaling pathway and the G0/G1 cell cycle arrest caused by TiO₂ NPs. Taken together, TiO₂ NPs downregulated the expression of CXCL13 to inhibit the activation of downstream JAK2/STAT3 signaling pathway, eventually inducing cell cycle arrest at the G0/G1 phase. These results provide a novel insight for complemented understanding of the mechanisms of TiO₂ NPs-induced cell cycle arrest in GC-1 cells.