Effects Of Microcystin-leucine Arginine Research Articles

PI3K/AKT/mTOR pathway mediated-cell cycle dysregulation contribute to malignant proliferation of mouse spermatogonia induced by microcystin-leucine arginine.

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.

Protective effects of melatonin and N-acetyl cysteine against oxidative stress induced by microcystin-LR on cardiac muscle tissue

Microcystin Leucine-Arginine (MC-LR) is a toxin produced by the cyanobacteria Microcystis aeruginosa. It is the most encountered and toxic type of cyanotoxins. Oxidative stress was shown to play a role in the pathogenesis of microcystin LR by the induction of intracellular reactive oxygen species (ROS) formation that oxidize and damage cellular macromolecules. In the present study we examined the effect of acute MC-LR dose on the cardiac muscle of BALB/c mice. Afterwards, melatonin and N-acetyl cysteine (NAC) were assayed and evaluated as potential protective and antioxidant agents against damages generated by MC-LR. For this purpose, thirty mice were assigned into six groups of five mice each. The effect of MC-LR was first compared to the control group supplied with distilled water, then compared to the other groups supplied with melatonin and NAC. The experiment lasted 10 days after which animals were euthanized. Biomarkers of toxicity such as alkaline phosphatase activity, lipid peroxidation, protein carbonyl content, reduced glutathione content, serum lactate dehydrogenase and serum sorbitol dehydrogenase were assayed. Results showed that toxin treated mice have experienced significant oxidative damage in their myocardial tissue as revealed by noticeable levels of oxidative stress biomarkers and by the reduction in alkaline phosphatase activity. Whereas, melatonin and NAC treated mice manifested lesser oxidative damages. Our findings suggest a potential therapeutic use of melatonin and N-acetyl cysteine as antioxidant protective agents against oxidative damage induced by MC-LR.

Microcystin-leucine arginine (MC-LR) induces bone loss and impairs bone micro-architecture by modulating host immunity in mice: Implications for bone health

Osteoporosis or enhanced bone loss is one of the most commonly occurring bone conditions in the world, responsible for higher incidence of fractures leading to increased morbidity and mortality in adults. Bone loss is affected by various environmental factors including diet, age, drugs, toxins etc. Microcystins are toxins produced by cyanobacteria with microcystin-LR being the most abundantly found around the world effecting both human and animal health. The present study demonstrates that MC-LR treatment induces bone loss and impairs both trabecular and cortical bone microarchitecture along with decreasing the mineral density and heterogeneity of bones in mice. This effect of MC-LR was found due to its immunomodulatory effects on the host immune system, wherein MC-LR skews both T cell (CD4+ and CD8+ T cells) and B cell populations in various lymphoid tissues. MC-LR further was found to significantly enhance the levels of osteoclastogenic cytokines (IL-6, IL-17 and TNF-α) along with simultaneously decreasing the levels of anti-osteoclastogenic cytokines (IL-10 and IFN-γ). Taken together, our study for the first time establishes a direct link between MC-LR intake and enhanced bone loss thereby giving a strong impetus to the naïve field of “osteo-toxicology”, to delineate the effects of various toxins (including cyanotoxins) on bone health.