title: Fumonisin B1 hepatotoxicity in mice is attenuated by depletion of Kupffer cells by gadolinium chloride.
abstract: Fumonisin B1 (FB1) is a toxic and carcinogenic mycotoxin produced by Fusarium verticillioides found on corn worldwide. The biological effects of FB1 are attributed to sphingolipid metabolism disruption as a result of ceramide synthase inhibition. Tumor necrosis factor alpha (TNFalpha) is an important modulator of FB1 hepatotoxicity. Kupffer cells are major source of cytokine production in liver. In the present study we investigated the effects of Kupffer cell depletion by gadolinium on FB1 hepatotoxicity in female BALB/c mice. Mice were given saline or 50 mg/kg of gadolinium chloride once via the tail vein; 16 h later they were treated with subcutaneous injections of vehicle or 2.25 mg/kg/day FB1 in saline for three successive days. Gadolinium significantly attenuated FB1-induced increases in the activities of circulating alanine aminotransferase and aspartate aminotransferase and reduced the FB1-induced hepatocyte apoptosis and free sphinganine accumulation in liver. Both gadolinium and FB1 treatments individually increased the expression of selected cell signal factors; e.g., TNFalpha, TNF receptor 1, TNF-related apoptosis-inducing ligand, lymphotoxin beta, interferon gamma, and transforming growth factor beta1; gadolinium chloride did not alter FB1-induced expression of the above genes. Results indicated that Kupffer cells play a role in FB1 hepatotoxicity. Decreased FB1-induced sphinganine accumulation and increased protective TNFalpha signaling by gadolinium chloride may in part account for its ameliorating effect on FB1 liver damage.
authors.affiliation: Department of Physiology and Pharmacology, College of Veterinary Medicine, The University of Georgia, Athens, GA 30602-7389, USA.
authors.forename: Quanren
authors.initials: Q
authors.lastname: He
authors.forename: Jiyoung
authors.initials: J
authors.lastname: Kim
authors.forename: Raghubir P
authors.initials: RP
authors.lastname: Sharma
mesh_terms: D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001219:Aspartate Aminotransferases / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D037341:Fumonisins / Q000633:toxicity*; D005682:Gadolinium / Q000627:therapeutic use*; D015870:Gene Expression / Q000187:drug effects; D006520:Hepatitis, Animal / Q000209:etiology* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D007728:Kupffer Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018121:Receptors, Cytokine / Q000096:biosynthesis
chemical_list: D016207:Cytokines; D037341:Fumonisins; D018121:Receptors, Cytokine; C056933:fumonisin B1; D005682:Gadolinium; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; C038958:gadolinium chloride