Endotoxin exposure alters brain and liver effects of fumonisin B1 in BALB/c mice: implication of blood brain barrier.
Fumonisin B(1) (FB(1)), a mycotoxin produced by Fusarium verticillioides, causes equine leukoencephalomalacia and hepatotoxicity. We studied the modulation of FB(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(1). After 4h of a single FB(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)-1beta, IL-6, and IL-12; no effect of FB(1) was observed. In liver LPS+FB(1) attenuated the expression TNFalpha and IFNgamma compared to LPS alone. One day after the 3-day FB(1) treatment the biosynthesis of sphingolipids was markedly reduced in brain and liver and it was further inhibited when LPS was given before FB(1). FB(1) induced hepatotoxicity, as measured by circulating liver enzymes, was reduced after the combined treatment with LPS+FB(1) compared to FB(1) alone. FB(1) decreased the LPS-induced brain expression of IFNgamma and IL-1beta, whereas the expression of IL-6 and IL-12 was augmented. In liver FB(1) also reduced the expression of IL-1beta and IFNgamma compared to LPS alone. Results indicated that endotoxemia concurrent with FB(1) intoxication facilitated the permeability of fumonisin in brain indicated by increased accumulation of sphinganine and endotoxin modified the effects of FB(1) in both brain and liver.
Osuchowski
Marcin F
MF
Department of Physiology and Pharmacology, College of Veterinary Medicine, The University of Georgia, Athens, GA 30602-7389, USA.
He
Quanren
Q
Sharma
Raghubir P
RP
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects*; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D017931:DNA Primers / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004731:Endotoxins / Q000633:toxicity*; D005260:Female; D037341:Fumonisins / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009929:Organ Size / Q000187:drug effects; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D013107:Sphingolipids / Q000378:metabolism
D016207:Cytokines; D017931:DNA Primers; D004731:Endotoxins; D037341:Fumonisins; D008070:Lipopolysaccharides; D013107:Sphingolipids; C056933:fumonisin B1; D012313:RNA