MC-LR induces dysregulation of iron homeostasis by inhibiting hepcidin expression: A preliminary study

Abstract The liver is an important iron storage site and a primary MC-LR target. C57BL/6 and Hfe −/− mice were used to investigate effects and mechanisms of MC-LR on systematic iron homeostasis. Body weight, tissue iron content, hematological and serological indexes, and histopathological were evaluated. Ultrastructure and iron metabolism-related genes and proteins were analyzed. MC-LR induced dose-dependent increases in red blood cells, hemoglobin, and hematocrit. In contrast MC-LR-induced dose-dependent decreases in mean corpuscular volume, hemoglobin, and hemoglobin concentration were observed both C57BL/6 and Hfe −/− mice. In both mouse species, serological indexes increased. Aggravated liver and spleen iron were observed in C57BL/6 mice, consistent with Perls’ Prussian blue staining. However, an opposite trend was observed in Hfe −/− mice. C57BL/6 mice had lower Hamp1 ( Hepcidn ), Bmp6 , Il-6 , and Tmprss6 . Significant increased Hjv , Hif-1α and Hif-2α were observed in both C57BL/6 and Hfe −/− mice. MC-LR-induced pathological lesions were dose-dependent increase in C57BL/6 mice. More severe pathological injuries in MC-LR groups (25 μg/kg) were observed in Hfe −/− mice than in C57BL/6 mice. In Hfe −/− mice, upon exposure to 25 μg/kg MC-LR, mitochondrial membranes were damaged and mitochondrial counts increased with significant swelling. These results indicated that MC-LR can induce the accumulation of iron in C57BL/6 mice with the occurrence of anemia, similar to thalassemia. Moreover, dysregulation of iron homeostasis may be due to MC-LR-induced Hamp1 downregulation, possibly mediated by hypoxia or the IL6–STAT3 and BMP–SMAD signaling pathways.