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Environmental cyanotoxin exposure may be a trigger of testicular cancer. Activation of PI3K/AKT/mTOR signaling pathway is the critical molecular event in testicular carcinogenesis. As a widespread cyanotoxin, microcystin‐leucine arginine (MC‐LR) is known to induce cell malignant transformation and tumorigenesis. However, the effects of MC‐LR on the regulatory mechanism of PI3K/AKT/mTOR pathway in seminoma, the most common testicular tumor, are unknown. In this study, mouse spermatogonia cell line (GC‐1) and nude mice were used to investigate the effects and mechanisms of MC‐LR on the malignant transformation of spermatogonia by nude mouse tumorigenesis assay, cell migration invasion assay, western blot, and cell cycle assay, and so forth. The results showed that, after continuous exposure to environmentally relevant concentrations of MC‐LR (20 nM) for 35 generations, the proliferation, migration, and invasion abilities of GC‐1 cells were increased by 120%, 340%, and 370%, respectively. In nude mice, MC‐LR‐treated GC‐1 cells formed tumors with significantly greater volume (0.998 ± 0.768 cm3) and weight (0.637 ± 0.406 g) than the control group (0.067 ± 0.039 cm3; 0.094 ± 0.087 g) (P <.05). Furthermore, PI3K inhibitor Wortmannin inhibited the PI3K/AKT/mTOR pathway and its downstream proteins (c‐MYC, CDK4, CCND1, and MMP14) activated by MC‐LR. Blocking PI3K alleviated MC‐LR‐induced cell cycle disorder and malignant proliferation, migration and invasive of GC‐1 cells. Altogether, our findings suggest that MC‐LR can induce malignant transformation of mouse spermatogonia, and the PI3K/AKT/mTOR pathway‐mediated cell cycle dysregulation may be an important target for malignant proliferation. This study provides clues to further reveal the etiology and pathogenesis of seminoma. [ABSTRACT FROM AUTHOR]

Microcystin-leucine arginine (MC-LR), an important hepatoxin, has the effect of promoting hepatocarcinogenesis. MicroRNA-122 (miR-122), an important tumor suppressor in liver, plays an important role in promoting cell apoptosis. Previous studies found that the expression of miR-122 was reduced after MC-LR exposure in liver. In this study, C57BL/6 mice were exposed to saline, negative control agomir, and MC-LR with or without miR-122 agomir transfection. The results indicated that MC-LR promoted the expressions of tumor suppressor genes and decreased the expressions of anti-apoptotic proteins B cell lymphoma-2 (Bcl-2) and Bcl-2-like 2 (Bcl-w), causing hepatocyte apoptosis. Under MC-LR exposure, miR-122 agomir transfection could further increase the expressions of tumor suppressor genes and the release of cytochrome-c (Cyt-c) and decrease the expressions of Bcl-2 and Bcl-w. In conclusion, miR-122 reduction can mitigate MC-LR-induced apoptosis to a certain extent, which in turn, it is likely to have contributed to MC-LR-induced hepatocarcinogenesis. [ABSTRACT FROM AUTHOR]

Microcystin‐leucine arginine (MC‐LR) is a cyclic heptapeptide, produced by aquatic cyanobacteria such as microcystis, with strong reproductive toxicity which poses greater threat to the reproductive abilities of humans and animals. By exploring the role of trimethylation of histone H3 at lysine 4 (H3K4me3) and the role of oxidative stress in MC‐LR‐induced apoptosis in testicular Sertoli cells in Sprague‐Dawley (SD) rats, this study indicated that MC‐LR increased the expression levels of apoptosis‐related genes by raising the levels of H3K4me3. 5′‐Deoxy‐5′‐methylthioadenosine (MTA), the inhibitor of H3K4me3, reduced apoptosis, indicating for the first time that epigenetic modification is closely related to the testicular reproductive toxicity induced by MC‐LR. MC‐LR also induced oxidative stress by stimulating the generation of reactive oxygen species (ROS), and subsequently triggering mitochondria‐mediated apoptotic pathway by decreasing mitochondrial membrane potential and increasing the levels of Bax, Bcl‐2, Caspase‐3, and so on. MC‐LR‐induced apoptosis of testicular cells could be decreased after pretreatment with oxidative stress inhibitor N‐acetyl‐cysteine (NAC). Furthermore, the pathological damage to mitochondria and testes were observed in SD rats. These results show that MC‐LR can induce apoptosis by raising the levels of H3K4me3, and pretreatment with MTA can ameliorate the MC‐LR‐induced apoptosis of cocultured cells by lowering the levels of H3K4me3. Furthermore, NAC has a protective effect on MC‐LR‐induced apoptosis of testicular cells in SD rats by inhibiting the oxidative stress. [ABSTRACT FROM AUTHOR]

As a common pollutant in the water environment, microcystin leucine arginine (MC-LR) can enter semen and damage the sperm in animals. However, the mechanism by which MC-LR damages human sperm is unclear. Therefore, human sperm samples were obtained from the Henan Provincial Sperm Bank and exposed to different concentrations (0, 1, 10, and 100 μg/L) of MC-LR for 1, 2, 4, and 6 h, to invegest the effects and potential mechanism of MC-LR on sperm. The results showed that MC-LR mainly accumulated in the neck and flagellum of human sperm. Compared to the control group, the sperm capacitation rate and motility were significantly decreased in the 100 μg/L group. After exposure of 100 μg/L of MC-LR, the central microtubule and microtubule doublet of sperm flagellum were blurred, asymmetrical, or even lost. Furthermore, the expression levels of flagellin DNAH17, SPEF2, SPAG16, SPAG6, and CFAP44 in human sperm were reduced. Also, the phosphorylation levels of CaMKKβ and AMPK can be inhibited by MC-LR. These findings revealed that MC-LR can induce functional and structural damage in human sperm, and the Ca 2+ /CaMKKβ/AMPK pathway may be involved in this process. This study will provide a basis for prevention and treatment of male fertility declines caused by MC-LR., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)