Bhandari N, He Q, Sharma R P
Department of Physiology and Pharmacology, College of Veterinary Medicine, The University of Georgia, Athens, GA 30602-7389, USA.
Toxicology. 2001 Aug 28;165(2-3):195-204. doi: 10.1016/s0300-483x(01)00449-8.
Fumonisin B1 (FB1), a potent mycotoxin prevalent in corn, is a carcinogen and causative agent of various animal diseases. Species and sex variations to chronic FB1 toxicity have been reported. Free sphingoid bases and cytokine levels are the two major biochemical alterations of FB1 in vivo and may explain any sex differences in FB1 toxicity. Male and female BALB/c mice (5/group) were injected subcutaneously with either saline vehicle or 2.25 mg/kg/day of FB1 for 5 days. One day after the last injection females showed a greater increase in circulating alanine aminotransferase and greater number of apoptotic cells in liver after FB1 treatment than males, indicating greater hepatotoxicity. Peripheral leukocytic counts, including neutrophils, were increased in females only after FB1 treatment. The increased toxicity in females correlated with a greater increase of sphinganine and sphingosine levels in liver after FB1 treatment compared to males. No sex differences in kidney sphinganine or sphingosine levels were observed after FB1 treatment. Previously we have shown the induction of tumor necrosis factor alpha (TNFalpha) in FB1-induced hepatotoxicity. While in males FB1 treatment caused increased expression of TNFalpha, interleukin (IL)-12 p40, interferon gamma (IFNgamma), IL-1beta, IL-6 and IL-10, females showed an increased expression of IL-6 only, and a downward modulation of IFNgamma, indicating gender differences in cytokine pathways in liver activated by FB1. The basal expression of TNFalpha, IL-12 p40, IL-1beta and IFNgamma in liver of females was higher compared to males. Gender differences in alterations of free sphingoid bases and cytokine modulation after FB1 treatment suggest their possible involvement in sex-dependent differential hepatotoxicity in mice.
伏马菌素B1（FB1）是一种在玉米中普遍存在的强效霉菌毒素，是一种致癌物和多种动物疾病的致病因子。已有报道称FB1慢性毒性存在物种和性别差异。游离鞘氨醇碱和细胞因子水平是FB1在体内的两种主要生化改变，可能解释了FB1毒性方面的任何性别差异。将雄性和雌性BALB/c小鼠（每组5只）皮下注射生理盐水或2.25毫克/千克/天的FB1，持续5天。最后一次注射后一天，FB1处理后，雌性小鼠循环中的丙氨酸转氨酶升高幅度更大，肝脏中的凋亡细胞数量也比雄性小鼠更多，表明雌性肝脏毒性更大。仅在FB1处理后，雌性小鼠的外周白细胞计数（包括中性粒细胞）增加。与雄性相比，FB1处理后雌性小鼠肝脏中鞘氨醇和鞘氨醇水平的升高幅度更大，这与雌性小鼠毒性增加相关。FB1处理后，未观察到肾脏中鞘氨醇或鞘氨醇水平存在性别差异。此前我们已经证明在FB1诱导的肝毒性中会诱导肿瘤坏死因子α（TNFα）。虽然在雄性小鼠中，FB1处理会导致TNFα、白细胞介素（IL）-12 p40、干扰素γ（IFNγ）、IL-1β、IL-6和IL-10的表达增加，但雌性小鼠仅表现出IL-6的表达增加，以及IFNγ的下调，表明FB1激活的肝脏中细胞因子途径存在性别差异。与雄性相比，雌性小鼠肝脏中TNFα、IL-12 p40、IL-1β和IFNγ的基础表达更高。FB1处理后游离鞘氨醇碱改变和细胞因子调节的性别差异表明它们可能参与了小鼠性别依赖性的肝毒性差异。
