Department of Animal Science and Biotechnology, Kyungpook National University, Sangju, Gyeongsangbuk-do 37224, Republic of Korea.
Department of Animal Biotechnology, Kyungpook National University, Sangju, Gyeongsangbuk-do 37224, Republic of Korea.
Toxicol In Vitro. 2024 Aug;99:105848. doi: 10.1016/j.tiv.2024.105848. Epub 2024 May 19.
Nirmatrelvir (NMV) is a recently developed selective inhibitor of the main protease of Sars-Cov-2 that reduces the severity of infection. Despite its widespread use and various side effects, NMV's effect on male fertility is still unclear. This study was thus established to investigate how NMV affects male fertility. For experiments, Duroc spermatozoa were incubated with various concentrations of NMV (0, 0.1, 1, 10, 50, and 100 μM). Then, sperm motility, motion kinematics, capacitation status, intracellular ATP level, and cell viability were evaluated. In addition, the expression levels of phospho-PKA substrates, tyrosine-phosphorylated proteins, and PI3K/PDK1/AKT signaling pathway-related proteins were measured by western blotting. Our results showed that sperm motility, motion kinematics, proportion of capacitated spermatozoa, and intracellular ATP level were significantly decreased by NMV in a dose-dependent manner. Moreover, PKA activation was significantly suppressed by NMV, and expression levels of PI3K, phospho-PDK1, AKT, and phospho-AKT (Thr and Ser) were significantly increased in a dose-dependent manner. Combining these findings, it is suggested that NMV has detrimental effects on sperm function by inducing abnormal changes in the PI3K/PDK1/AKT signaling pathway, resulting in PKA deactivation. Therefore, there is a need to pay particular attention to its male reproductive toxicity when NMV is administered.
尼马瑞韦（NMV）是一种最近开发的 SARS-CoV-2 主蛋白酶选择性抑制剂，可降低感染的严重程度。尽管广泛使用并具有各种副作用，但 NMV 对男性生育力的影响仍不清楚。因此，本研究旨在调查 NMV 如何影响男性生育力。在实验中，用不同浓度的 NMV（0、0.1、1、10、50 和 100 μM）孵育杜洛克精子。然后，评估精子的运动能力、运动动力学、获能状态、细胞内 ATP 水平和细胞活力。此外，通过 Western blot 测量磷酸化-PKA 底物、酪氨酸磷酸化蛋白和 PI3K/PDK1/AKT 信号通路相关蛋白的表达水平。我们的结果表明，NMV 以剂量依赖性方式显著降低精子的运动能力、运动动力学、获能精子的比例和细胞内 ATP 水平。此外，NMV 显著抑制 PKA 的激活，并且 PI3K、磷酸-PDK1、AKT 和磷酸化-AKT（Thr 和 Ser）的表达水平也呈剂量依赖性显著增加。综合这些发现表明，NMV 通过诱导 PI3K/PDK1/AKT 信号通路的异常变化，导致 PKA 失活，对精子功能产生有害影响。因此，在给予 NMV 时，需要特别注意其对男性生殖毒性。
