Microcystin-LR-induced ultrastructural changes in rats

The ultrastructure of hepatic, pulmonary, and renal lesions was evaluated in rats injected intraperitoneally with a lethal dose of microcystin-LR (MCLR, 160 micrograms/kg), a cyclic heptapeptide hepatotoxin produced by the blue-green algae, Microcystis aeruginosa. Hepatic lesions were first seen at 10 minutes post-dosing and consisted of mild widening of hepatocyte intercellular spaces centrilobularly. At 20 minutes post-dosing, hepatocyte plasma membrane alterations were more pronounced, consisting of plasma membrane invagination with formation of variably sized and shaped intracytoplasmic vacuoles, loss of microvilli along the sinusoidal face, and widespread, pronounced hepatocyte separation. By 30 minutes, the space of Disse was markedly widened. At 60 minutes post-dosing, centrilobular areas contained necrotic cells and apparently intact, isolated, organelles intermingled with erythrocytes and platelets. In less severely affected regions there was prominent hepatocyte rounding, and erythrocytes and platelets were present in the widened space of Disse. Large amounts of hepatocellular debris and intact hepatocytes were present in the pulmonary vasculature, while smaller amounts of debris were also seen in the glomerular and peritubular capillaries of the renal cortex. This study shows that initial lesions are confined to shape changes in the plasma membrane of hepatocytes. These changes are consistent with the hypothesis that microcystin-LR induces alterations in the hepatocyte cytoskeleton. Later changes consist of hepatocyte disassociation and necrosis, as well as endothelial damage, which allow release of hepatocytes and debris into the circulation with microembolism in lungs and kidneys.