Endotoxin exposure alters brain and liver effects of fumonisin B sub(1) in BALB/c mice: Implication of blood brain barrier

Fumonisin B sub(1) (FB sub(1)), a mycotoxin produced by Fusarium verticillioides, causes equine leukoencephalomalacia and hepatotoxicity. We studied the modulation of FB sub(1) toxicity in brain and liver of female BALB/c mice after endotoxin administration to compromise the blood-brain barrier (BBB) integrity. Mice were injected intraperitoneally with saline or 3 mg/kg of lipopolysaccharide (LPS) followed 2 h later by either a single or three daily subcutaneous doses of 2.25 mg/kg of FB sub(1). After 4 h of a single FB sub(1) injection the inhibition of sphingolipid biosynthesis occurred in liver. Circulating alanine aminotransferase increased by LPS alone at this time. In brain LPS triggered inflammation increasing the expression of tumor necrosis factor (TNF) alpha , interferon (IFN) gamma , interleukin (IL)-1 beta , IL-6, and IL-12; no effect of FB sub(1) was observed. In liver LPS + FB sub(1) attenuated the expression TNF alpha and IFN gamma compared to LPS alone. One day after the 3-day FB sub(1) treatment the biosynthesis of sphingolipids was markedly reduced in brain and liver and it was further inhibited when LPS was given before FB sub(1). FB sub(1) induced hepatotoxicity, as measured by circulating liver enzymes, was reduced after the combined treatment with LPS + FB sub(1) compared to FB sub(1) alone. FB sub(1) decreased the LPS-induced brain expression of IFN gamma and IL-1 beta , whereas the expression of IL-6 and IL-12 was augmented. In liver FB sub(1) also reduced the expression of IL-1 beta and IFN gamma compared to LPS alone. Results indicated that endotoxemia concurrent with FB sub(1) intoxication facilitated the permeability of fumonisin in brain indicated by increased accumulation of sphinganine and endotoxin modified the effects of FB sub(1) in both brain and liver.