fumonisin-b1 and Inflammation

Currently, due to the actual contamination levels of multiple mycotoxins, the limits for a single mycotoxin may be no longer applicable. Deoxynivalenol (DON) and Fumonisin B

Topics: Animals; Caspases; Inflammation; Interleukin-18; Mice; Mycotoxins; NLR Family, Pyrin Domain-Containing 3 Protein; Pyroptosis

Obesity, which is a worldwide public health issue, is associated with chronic inflammation that contribute to long-term complications, including insulin resistance, type 2 diabetes and non-alcoholic fatty liver disease. We hypothesized that obesity may also influence the sensitivity to food contaminants, such as fumonisin B1 (FB1), a mycotoxin produced mainly by the Fusarium verticillioides. FB1, a common contaminant of corn, is the most abundant and best characterized member of the fumonisins family. We investigated whether diet-induced obesity could modulate the sensitivity to oral FB1 exposure, with emphasis on gut health and hepatotoxicity. Thus, metabolic effects of FB1 were assessed in obese and non-obese male C57BL/6J mice. Mice received a high-fat diet (HFD) or normal chow diet (CHOW) for 15 weeks. Then, during the last three weeks, mice were exposed to these diets in combination or not with FB1 (10 mg/kg body weight/day) through drinking water. As expected, HFD feeding induced significant body weight gain, increased fasting glycemia, and hepatic steatosis. Combined exposure to HFD and FB1 resulted in body weight loss and a decrease in fasting blood glucose level. This co-exposition also induces gut dysbiosis, an increase in plasma FB1 level, a decrease in liver weight and hepatic steatosis. Moreover, plasma transaminase levels were significantly increased and associated with liver inflammation in HFD/FB1-treated mice. Liver gene expression analysis revealed that the combined exposure to HFD and FB1 was associated with reduced expression of genes involved in lipogenesis and increased expression of immune response and cell cycle-associated genes. These results suggest that, in the context of obesity, FB1 exposure promotes gut dysbiosis and severe liver inflammation. To our knowledge, this study provides the first example of obesity-induced hepatitis in response to a food contaminant.

Topics: Animals; Chemical and Drug Induced Liver Injury; Diabetes Mellitus, Type 2; Dysbiosis; Fumonisins; Inflammation; Liver; Male; Mice; Mice, Inbred C57BL; Obesity

Fumonisin B

Topics: Autophagy; Fumonisins; Humans; Inflammasomes; Inflammation; NLR Family, Pyrin Domain-Containing 3 Protein; Pyroptosis; TOR Serine-Threonine Kinases

Ceramide is a major proapoptotic mediator released in response to numerous stimuli, including oxidative stress and cytokines. The role of ceramide in the pathophysiology of inflammation is just emerging, and the potential relevance of this pathway in nonseptic shock is not known. The aim of this study was to investigate the effects of fumonisin B1 (FB1), a specific inhibitor of ceramide synthase, on the development of nonseptic shock in mice caused by zymosan. CD1 mice received either zymosan (500 mg/kg, administered i.p. as a suspension in saline) or vehicle (0.25 mL per mouse saline). Fumonisin B1 (3 mg/kg, i.p.) was administered 1 and 6 h after zymosan administration. Organ failure and systemic inflammation in mice were assessed 18 h after administration of zymosan and/or FB1. Treatment of mice with FB1 attenuated peritoneal exudate formation and the migration of polymorphonuclear cells caused by zymosan. Fumonisin B1 also attenuated plasma markers of lung, liver and pancreatic injury, and renal dysfunction caused by zymosan and the increase in myeloperoxidase activity in the intestine caused by zymosan. Immunohistochemical analyses for the presence of ceramide and nitrotyrosine revealed positive staining in intestinal tissue obtained from zymosan-injected mice. The degree of staining for ceramide and nitrotyrosine was markedly reduced in tissue sections obtained from zymosan-injected mice that had received FB1. In addition, administration of zymosan caused a severe illness in the mice characterized by a systemic toxicity, significant loss of body weight, and 80% mortality within 12 days. Treatment with FB1 significantly reduced systemic toxicity, weight loss, and mortality caused by zymosan. This study provides evidence that FB1 attenuates the degree of zymosan-induced nonseptic shock in mice.

Topics: Animals; Cytokines; Fumonisins; Immunohistochemistry; Inflammation; Male; Mice; Multiple Organ Failure; Nitric Oxide; Peritonitis; Peroxidase; Shock; Time Factors; Treatment Outcome; Zymosan

Although mechanisms involved in the pathogenesis of asthma remain unclear, roles for oxidative/nitrosative stress, epithelial cell apoptosis, and airway inflammation have been documented. Ceramide is a sphingolipid with potent proinflammatory and proapoptotic properties. This study aimed at determining whether increased formation of ceramide contributes to the development of airway inflammation and hyper-responsiveness, using a well characterized in vivo model of allergic asthmatic response and airway inflammation in ovalbumin-sensitized guinea pigs. Aerosol administration of ovalbumin increased ceramide levels and ceramide synthase activity in the airway epithelium associated with respiratory abnormalities, such as cough, dyspnea, and severe bronchoconstriction. These abnormalities correlated with nitrotyrosine formation in the airway epithelium and oxidative/nitrosative stress, epithelial cell apoptosis, and airway inflammation evident by the infiltration of neutrophils and eosinophils in lung tissues, mast cell degranulation, and release of prostaglandin D(2) and proinflammatory cytokines. Inhibition of de novo ceramide synthesis with the competitive and reversible inhibitor of ceramide synthase fumonisin B1 (0.25, 0.5 and 1 mg/kg b.wt.), given i.p. daily for 4 days before allergen challenge, attenuated nitrotyrosine formation and oxidative/nitrosative stress, epithelial cell apoptosis, and airway inflammation while improving the respiratory and histopathological abnormalities. These results implicate ceramide in the development of allergic asthmatic response and airway inflammation. Strategies aimed at reducing the levels of ceramide and downstream events should yield promising novel anti-asthmatic agents.

Topics: Allergens; Animals; Asthma; Bronchoconstriction; Disease Models, Animal; Fumonisins; Guinea Pigs; Inflammation; Male; Sphingosine N-Acyltransferase

Fumonisin B1 (FB1), a mycotoxin produced by Fusarium verticillioides, causes equine leukoencephalomalacia, a condition not reproduced in any other species. We hypothesized that direct exposure of murine brain to FB1 will result in neurotoxicity, characterized by biochemical and pathological alterations. The present study compared the toxicity of FB1 in mouse brain after an intracerebroventricular (icv) or subcutaneous (sc) infusion. Female BALB/c mice (5/group) were infused (0.5 microl/h) with total doses of 0, 10 or 100 microg FB1 in saline over 7 days via osmotic pumps implanted either via icv cannulation of the ventricle or via the sc route. One day after the last day of treatment, brains were dissected either fresh or after intracardiac paraformaldehyde fixation. In mice given 100 microg of FB1 icv, FluoroJade B staining revealed neurodegeneration in the cortex, and anti-glial fibrillary acidic protein staining detected activated astrocytes in the hippocampus. High performance liquid chromatography indicated accumulation of free sphinganine in animals given FB1 icv in all brain regions and increased free sphingosine after the 100 microg FB1 in the cortex. The concentration of cortical sphingomyelin and complex sphingolipids remained unchanged. The icv administration of FB1 induced expression of tumor necrosis factor alpha, interleukin-1beta, interleukin-6 and interferon gamma after both doses, assayed by the real-time polymerase chain reaction. The sc administration of 100 microg FB1 caused slight sphinganine accumulation and increased IL-1beta expression in cortex only. Results indicated that icv injection of FB1 caused neurodegeneration with simultaneous inhibition of de novo ceramide synthesis, stimulation of astrocytes, and upregulation of pro-inflammatory cytokines in the murine brain. A relative lack of FB1 availability into the brain could be responsible for the absence of its neurotoxicity in mouse.

Topics: Animals; Brain; Female; Fumonisins; Inflammation; Injections, Intraventricular; Mice; Mice, Inbred BALB C; Neurodegenerative Diseases; Signal Transduction; Sphingolipids

Fumonisin B1, a common mycotoxin produced by Fusarium verticillioides found in corn, causes several fatal animal diseases. Liver and kidney are target organs of fumonisin B1 in laboratory animals, but primary rodent hepatocytes and liver slices were resistant to fumonisin B1-induced cytotoxic effects. We have shown that fumonisin B1 induces expression of tumor necrosis factor (TNF)alpha, interferon (IFN)gamma, and interleukine (IL) 12, in mouse liver. In various models of acute liver injury, a positive amplification loop involving TNFalpha, IFNgamma, and IL-12 has been implied that involves Kupffer cells (macrophages), hepatic lymphocytes and non-parenchymatous liver epithelial cells (NPECs). In the current study, cellular interactions in fumonisin B1-induced toxicity were investigated, using co-cultures of murine macrophages (J774A.1) and NPECs (NMuLi). Treatment of the co-cultures with fumonisin B1-produced cytotoxicity, whereas either J774A.1 or NMuLi cultures alone showed no response to the mycotoxin. Accumulation of sphinganine occurred to the similar extent in individual cultures as well as co-cultures. Expression of TNFalpha and IL-12 was increased in co-cultures but not in individual cultures. Transfer of conditioned medium from fumonisin B1-treated J774A.1 cells to NMuLi cultures produced an increase in IFNgamma expression in NMuLi cells. Results indicated that macrophages and liver epithelial cells interact in response to fumonisin B1 and potentiate the cytokines expression, which may have implications in making hepatocytes responsive to cytotoxicity of fumonisin B1.

Topics: Animals; Apoptosis; Carcinogens, Environmental; Cell Death; Cell Survival; Coculture Techniques; Culture Media; Cytokines; Epithelial Cells; Fumonisins; Immunohistochemistry; Inflammation; Interferon-gamma; L-Lactate Dehydrogenase; Liver; Macrophages; Mice; Receptor Cross-Talk; RNA, Messenger; Tumor Necrosis Factor-alpha