Ti(3)C(2) (MXene) nanosheets disrupt spermatogenesis in male mice mediated by the ATM/p53 signaling pathway

BACKGROUND: Two-dimensional ultrathin Ti(3)C(2) nanosheets are increasingly being used in biomedical applications owing to their special physicochemical properties. But, the biological effects of its exposure on the reproductive system is still unclear. This study evaluated the reproductive toxicity of Ti(3)C(2) nanosheets in the testes. RESULTS: Ti(3)C(2) nanosheets at doses of 2.5 mg/kg bw and 5 mg/kg bw in mice caused defects in spermatogenic function, and we also clarified an underlying molecular mechanism of it in vivo and in vitro model. Ti(3)C(2) nanosheets induced an increase of reactive oxygen species (ROS) in testicular and GC-1 cells, which in turn led to the imbalance in oxidative and antioxidant systems (also known as oxidative stress). Additionally, oxidative stress often induces cellular DNA strand damages via the oxidative DNA damages, which triggered cell cycle arrest in the G1/G0 phase, leading to cell proliferation inhibition and irreversible apoptosis. ATM/p53 signaling manifest key role in DNA damage repair (DDR), and we demonstrate that ATM/p53 signaling was activated, and mediated the toxic damage process caused by Ti(3)C(2) nanosheet exposure. CONCLUSION: Ti(3)C(2) nanosheet-induced disruption of proliferation and apoptosis of spermatogonia perturbed normal spermatogenic function that was mediated by ATM/p53 signaling pathway. Our findings shed more light on the mechanisms of male reproductive toxicity induced by Ti(3)C(2) nanosheets. GRAPHICAL ABSTRACT: [Image: see text]