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Title: LUPUS-PRONE NZBWF1/J MICE, DEFECTIVE IN CYTOKINE SIGNALING, ARE RESISTANT TO FUMONISIN HEPATOTOXICITY DESPITE ACCUMULATION OF LIVER SPHINGANINE

Author
item SHARMA, RAGHUBIR - VET.MED., U. OF GEORGIA
item HE, QUANREN - VET.MED., U. OF GEORGIA
item Riley, Ronald

Submitted to: Toxicology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/20/2005
Publication Date: 9/27/2005
Citation: Sharma, R.P., He, Q., Riley, R.T. 2005. Lupus-prone NZBWF1/J mice, defective in cytokine signaling, are resistant to fumonisin hepatotoxicity despite accumulation of liver sphinganine. Toxicology. 216:59-71.

Interpretive Summary: Fumonisins are toxic chemicals produced by molds that contaminate US corn. The presence of fumonisin in US corn can reduce the value of the corn. The Food and Drug Administration has published guidelines for fumonisins in corn and corn products. The guidelines are based on what is known about the levels of fumonisin in food that can cause harm to animals including liver cancer. Because fumonisins are potentially harmful to humans and because the level at which they are harmful to animals is used as the basis for setting guidelines by CODEX, the way in which fumonisins harm the liver must be established as accurately as possible. We have noticed that the toxicity in liver of mice is associated with the production of a chemical called “tumor necrosis factor”. The purpose of this study was to determine the role that “tumor necrosis factor” plays in the liver toxicity in mice that are predisposed to development of a disease known as Lupus and which are also defective in the expression of the tumor necrosis signaling pathway. We found that in mice lacking the ability to increase “tumor necrosis factor” expression in response to fumonisin, hepatotoxicity was reduced indicating that there are strain specific differences in response to both fumonisin-induced hepatoxicity and tumor necrosis factor expression. This is important because it provides another mouse model to study the genetic basis for the coupling of disrupted sphingolipid metabolism, tumor necrosis factor expression and hepatoxicity and may lead to a better understanding of the mechanism of fumonisin-induced heptocarcinogenesis.

Technical Abstract: Fumonisin B1 (FB1) is a mycotoxin produced by Fusarium verticillioides, commonly present in corn and other cereals. Exposure to FB1 causes organ-specific diseases in various species, e.g., equine leukoencephalomalacia and porcine pulmonary edema; in mice the response is hepatotoxicity. We earlier reported that ceramide synthase inhibition by FB1, the initial biochemical effect of this mycotoxin, results in modulation of cytokine network in response to accumulated free sphingoid bases. In the current study we used NZB/NZW-F1 (NZBW) mice that have modified cytokine expression and develop lupus beginning at five months of age. The NZBW and control C57BL/6J (CBL) mice were given five daily subcutaneous injections of either saline or 2.25 mg FB1/kg/day and euthanized one day after the last treatment. Peripheral leukocyte counts were higher after exposure to FB in CBL but not in NZBW. FB1 treatment caused increases of plasma alanine aminotransferase and aspartate aminotransferase activity in CBL mice indicating hepatotoxicity; no elevation of circulating liver enzymes was recorded in NZBW mice. Hepatotoxic responses were confirmed by microscopic evaluation of apoptotic cells. The FB1-induced proliferation of cells observed in CBL strain was abolished in NZBW animals. The sphinganine accumulation in liver after FB1 was equal in both strains of mice. The NZBW strain lacked the FB1-induced increases in the expression of liver tumor necrosis factor alpha, interferon gamma, receptor interacting protein (RIP), and tumor necrosis factor alpha-related apoptosis-inducing ligand (TRAIL), observed in CBL. Results confirmed our hypothesis that initial altered sphingolipid metabolism caused by FB1 leads to perturbation of liver cytokine network and ultimate cellular injury; the mice deficient in cytokine signaling are refractory to FB hepatotoxicity.