Osuchowski Marcin F, He Quanren, Sharma Raghubir P
Department of Physiology and Pharmacology, College of Veterinary Medicine, The University of Georgia, Athens, GA 30602-7389, USA.
Food Chem Toxicol. 2005 Sep;43(9):1389-97. doi: 10.1016/j.fct.2005.03.014.
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.
伏马菌素B(1)（FB(1)）是由轮枝镰孢菌产生的一种霉菌毒素，可导致马脑白质软化和肝毒性。我们研究了在内毒素给药以破坏血脑屏障（BBB）完整性后，雌性BALB/c小鼠脑和肝中FB(1)毒性的调节情况。小鼠腹腔注射生理盐水或3mg/kg脂多糖（LPS），2小时后，皮下单次或每日三次注射2.25mg/kg的FB(1)。单次注射FB(1)4小时后，肝脏中鞘脂生物合成受到抑制。此时，单独LPS可使循环丙氨酸转氨酶升高。在脑中，LPS引发炎症，增加肿瘤坏死因子（TNF）α、干扰素（IFN）γ、白细胞介素（IL）-1β、IL-6和IL-12的表达；未观察到FB(1)的作用。在肝脏中，与单独LPS相比，LPS+FB(1)减弱了TNFα和IFNγ的表达。在3天FB(1)治疗后一天，脑和肝中鞘脂的生物合成明显减少，当在FB(1)之前给予LPS时，其进一步受到抑制。与单独FB(1)相比，LPS+FB(1)联合治疗后，通过循环肝酶测量的FB(1)诱导的肝毒性降低。FB(1)降低了LPS诱导的脑中IFNγ和IL-1β的表达，而IL-6和IL-12的表达增加。在肝脏中，与单独LPS相比，FB(1)也降低了IL-1β和IFNγ的表达。结果表明，与FB(1)中毒同时发生的内毒素血症促进了伏马菌素在脑中的通透性，这表现为鞘氨醇积累增加，并且内毒素改变了FB(1)在脑和肝中的作用。
