Meng Xiannan, Zhang Ling, Chen Xiang, Xiang Zou, Li Dongmei, Han Xiaodong
Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, 22 Hankou Road, Nanjing 210093, Jiangsu, China.
Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, 22 Hankou Road, Nanjing 210093, Jiangsu, China.
Toxins (Basel). 2016 Sep 6;8(9):260. doi: 10.3390/toxins8090260.
Microcystin-leucine arginine (MC-LR) is a harmful cyanotoxin produced by cyanobacteria. MC-LR can exert endocrine-disrupting activities in many organisms. We have previously demonstrated that MC-LR exerts both acute and chronic reproductive toxicity in male mice, resulting in a decline in sperm quality and damage to testicular structure. Moreover, we also observed extensive alterations in a panel of microRNAs in spermatogonial cells after exposure to MC-LR. In this study, we have confirmed that miR-541 was significantly increased both in GC-1 cells (in vitro) and in mouse testes (in vivo) after exposure to MC-LR. Our data support that p15 was the target gene of miR-541. Increase in miR-541 led to a reduction of p15 and murine double minute2 (MDM2), promoting the activation of p53 signaling and MC-LR-mediated cell apoptosis. Moreover, cells responded to MC-LR with reduced viability and increased apoptosis. Consistently, inhibiting miR-541 could upregulate the expression of p15 and MDM2, resulting in the downregulation of phospho-p53. Downregulation of miR-541 promoted cell viability by reducing MC-LR-induced cell apoptosis. In conclusion, we demonstrate here a crucial role for miR-541 in MC-LR-induced toxic effects on the reproductive system, in an attempt to provide a rational strategy for the diagnosis and treatment of MC-LR-induced impairment in the reproductive system.
微囊藻毒素 - 亮氨酸精氨酸（MC-LR）是一种由蓝藻产生的有害蓝藻毒素。MC-LR可在许多生物体中发挥内分泌干扰活性。我们之前已经证明，MC-LR对雄性小鼠具有急性和慢性生殖毒性，导致精子质量下降和睾丸结构受损。此外，我们还观察到暴露于MC-LR后精原细胞中一组微小RNA发生了广泛变化。在本研究中，我们证实暴露于MC-LR后，miR-541在GC-1细胞（体外）和小鼠睾丸（体内）中均显著增加。我们的数据支持p15是miR-541的靶基因。miR-541的增加导致p15和鼠双微体2（MDM2）减少，促进p53信号通路的激活和MC-LR介导的细胞凋亡。此外，细胞对MC-LR的反应是活力降低和凋亡增加。一致地，抑制miR-541可上调p15和MDM2的表达，导致磷酸化p53的下调。miR-541的下调通过减少MC-LR诱导的细胞凋亡来促进细胞活力。总之，我们在此证明了miR-541在MC-LR诱导的生殖系统毒性作用中的关键作用，试图为MC-LR诱导的生殖系统损伤的诊断和治疗提供合理策略。
