cyanoginosin-lr and Carcinoma

Microcystin-LR (MCLR), a cyanotoxin widely present in freshwater, has been shown to have potent acute hepatotoxicity. However, the chronic toxicity of low-dose MCLR remains confusing by traditional measurements of toxicity. This has impeded understanding of the chronic liver damage of low-dose MCLR and corresponding safety risks of the human exposure guideline value. Here, iTRAQ-based proteomics and NMR-based metabonomics were used to decipher the molecular toxicological signatures of low doses of MCLR in mice exposed to this agent for 90 days. Low levels of MCLR, even under the reported no observed adverse effect level, significantly altered hepatic protein expression, especially of proteins associated with lipid metabolism, transport, immune and proteolysis. Coherently, MCLR induced marked perturbations in lipid metabolites in both liver and serum. Integrated analysis of proteomic, metabolic, histological and cytokine profiles revealed that MCLR significantly inhibited fatty acid β-oxidation and hepatic lipoprotein secretion and promoted hepatic inflammation, resulting in nonalcoholic steatohepatitis disease (NASH). These findings for the first time provide compelling evidence that chronic exposure to low-level MCLR can induce NASH. These results also indicate that current guidelines for MCs in drinking water may be inadequate and associated with risks to human health.

Topics: Administration, Oral; Animals; Bacterial Toxins; Carcinoma; Cytokines; Disease Progression; Dose-Response Relationship, Drug; Gene Expression Profiling; Gene Expression Regulation; Lipid Metabolism; Lipoproteins; Liver; Liver Neoplasms; Male; Marine Toxins; Mice, Inbred BALB C; Microcystins; Models, Biological; Non-alcoholic Fatty Liver Disease; Random Allocation; Specific Pathogen-Free Organisms; Toxicity Tests, Chronic

The increasing presence of toxic cyanobacteria in drinking and recreational water bodies, and their potential to impact on human and animal health is cause for concern. Recent work suggests that apoptosis plays a major role in the toxic effects induced by microcystin-LR (MCLR) in the gastrointestinal tract; however, the biochemical pathway remains elusive. Exposure of CaCo2, a human colon carcinoma cell line, and MCF-7, a cell line deficient in pro-caspase-3, cells to 50 microM MCLR induced similar reductions in cell viability as measured by MTT and LDH leakage. The role of MCLR induced oxidative stress in the initiation of apoptosis was investigated over a 2-hr period, and it was found that there was an increase in the release of H(2)O(2) in the first 30 min of exposure for both cell lines. Both cell lines exhibited a dose-dependent increase in both micro- and millicalpain after 24 h exposure to MCLR suggesting a role for protease activation in MCLR-induced apoptosis in non-hepatic human derived cell lines.

Topics: Apoptosis; Bacterial Toxins; Breast Neoplasms; Caco-2 Cells; Carcinoma; Caspases; Cyanobacteria; Enzyme Inhibitors; Humans; Hydrogen Peroxide; Marine Toxins; Microcystins; Oxidative Stress; Peptides, Cyclic; Reactive Oxygen Species; Tumor Cells, Cultured