Explore the vast range of titles available.

Microcystins are ubiquitous toxins produced by photoautotrophic cyanobacteria. Human exposures to microcystins occur through the consumption of contaminated drinking water, fish and shellfish, vegetables, and algal dietary supplements and through recreational activities. Microcystin-leucine-arginine (MCLR) is the prototypical microcystin because it is reported to be the most common and toxic variant and is the only microcystin with an established tolerable daily intake of 0.04 µg/kg. Microcystin toxicokinetics is characterized by low intestinal absorption, rapid and specific distribution to the liver, moderate metabolism to glutathione and cysteinyl conjugates, and low urinary and fecal excretion. Molecular toxicology involves covalent binding to and inhibition of protein phosphatases, oxidative stress, cell death (autophagy, apoptosis, necrosis), and cytoskeleton disruption. These molecular and cellular effects are interconnected and are commonly observed together. The main target organs for microcystin toxicity are the intestine, liver, and kidney. Preclinical data indicate microcystins may also have nervous, pulmonary, cardiac, and reproductive system toxicities. Recent evidence suggests that exposure to other hepatotoxic insults could potentiate microcystin toxicity and increase the risk for chronic diseases. This review summarizes the current knowledge for microcystin toxicokinetics, molecular toxicology, and pathophysiology in preclinical rodent models and humans. More research is needed to better understand human toxicokinetics and how multifactorial exposures contribute to disease pathogenesis and progression.

Microcystin-LR (MCLR) is a hepatotoxic cyanotoxin reported to cause a phenotype similar to nonalcoholic steatohepatitis (NASH). NASH is a common progressive liver disease that advances in severity due to exogenous stressors such as poor diet and toxicant exposure. Our objective was to determine how sub-chronic MCLR toxicity affects preexisting diet-induced NASH. Sprague-Dawley rats were fed one of three diets for 10 weeks: control, methionine and choline deficient (MCD), or high fat/high cholesterol (HFHC). After six weeks of diet, animals received vehicle, 10 µg/kg, or 30 µg/kg MCLR via intraperitoneal injection every other day for the final 4 weeks. Incidence and severity scoring of histopathology endpoints suggested that MCLR toxicity drove NASH to a less fatty and more fibrotic state. In general, expression of genes involved in de novo lipogenesis and fatty acid esterification were altered in favor of decreased steatosis. The higher MCLR dose increased expression of genes involved in fibrosis and inflammation in the control and HFHC groups. These data suggest MCLR toxicity in the context of preexisting NASH may drive the liver to a more severe phenotype that resembles burnt-out NASH.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the United States. Up to 54% of patients with a severe form of NAFLD, called nonalcoholic steatohepatitis (NASH), also have chronic kidney disease (CKD). NAFLD encompasses a spectrum of liver pathologies including steatosis, inflammation, fibrosis, hepatocellular ballooning, and is a risk factor for hepatocellular carcinoma. CKD is defined by proteinuria and reduced glomerular filtration rate. NAFLD and CKD share multiple risk factors including obesity, hyperlipidemia, insulin resistance, and hypertension. In addition, various environmental toxicants are implicated in pathogenesis and progression of NAFLD and CKD. This dissertation presents work on the role of microcystin-LR (MCLR) in the pathogenesis of NAFLD and CKD. Microcystin-LR is produced by blue-green algae that is found in surface water, and it is a well-known liver and kidney toxin. The central hypothesis defended in this dissertation is that MCLR irreversibly exacerbates the hepatic and renal manifestations of NASH. Exacerbation (Specific Aim 1) and irreversibility (Specific Aim 2) of the NASH phenotype by MCLR were tested in a diet-induced rodent NASH model. It was found that sub-chronic MCLR exposure induced a burnt-out NASH hepatic phenotype, characterized by loss of steatosis and increased fibrosis. It was also found that MCLR increased proteinuria and renal tubule cast formation in the rodent NASH model. Burnt-out NASH is a risk factor for mortality in NAFLD patients, and our findings suggest that MCLR exacerbates liver disease and increases the risk of death in NASH patients and be a risk factor for CKD in humans. Reversibility of MCLR toxicity was examined next. In NASH animals, MCLR-induced fibrosis persisted at least 4 weeks after toxin exposure discontinuation. Gene expression profiling (RNA-seq) further showed persistent overexpression of cancer-related genes 4 weeks post exposure. The data suggest the toxin has a long-lasting impact on the liver, that has the potential to increase the risk for hepato-cellular carcinoma in NASH patients. Collectively, the studies confirmed that MCLR exacerbates hepatic and renal pathology in NASH and confirmed partial irreversibility of the toxin action and the potential for short-term exposure to increase the risk for long-term adverse consequences.