Howard P C, Warbritton A, Voss K A, Lorentzen R J, Thurman J D, Kovach R M, Bucci T J
National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, Arkansas, USA.
Environ Health Perspect. 2001 May;109 Suppl 2(Suppl 2):309-14. doi: 10.1289/ehp.01109s2309.
Fumonisin B1(FB1) is a fungal metabolite of Fusarium verticillioides (= F. moniliforme), a fungus that grows on many crops worldwide. Previous studies demonstrated that male BD IX rats consuming diets containing 50 ppm fumonisin B1 developed hepatocellular carcinomas. In our recent studies, diets containing FB1 at 50 ppm or higher concentrations induced renal tubule carcinomas in male F344/N/Nctr BR rats and hepatocellular carcinomas in female B6C3F1/Nctr BR mice. The carcinogenicity of FB1 in rats and mice is not due to DNA damage, as several laboratories have demonstrated that FB1 is not a genotoxin. FB1 induces apoptosis in cells in vitro. Including FB1 in the diets of rats results in increased hepatocellular and renal tubule epithelial cell apoptosis. In studies with F344/N/Nctr BR rats consuming diets containing up to 484 ppm FB1 for 28 days, female rats demonstrated more sensitivity than male rats in the induction of hepatocellular apoptosis and mitosis. Conversely, induction of renal tubule apoptosis and regeneration were more pronounced in male than in female rats. Induction of renal tubule apoptosis and hyperplasia correlated with the incidence of renal tubule carcinomas that developed in the 2-year feeding study with FB1 in the F344/N/Nctr BR rats. The data are consistent with the hypothesis that the induction of renal tubule carcinomas in male rats could be partly due to the continuous compensatory regeneration of renal tubule epithelial cells in response to the induction of apoptosis by fumonisin B1.
伏马菌素B1（FB1）是轮枝镰孢菌（=串珠镰孢菌）的一种真菌代谢产物，该真菌在全球许多农作物上生长。先前的研究表明，食用含50 ppm伏马菌素B1饲料的雄性BD IX大鼠会发生肝细胞癌。在我们最近的研究中，含50 ppm或更高浓度FB1的饲料可诱导雄性F344/N/Nctr BR大鼠发生肾小管癌，以及雌性B6C3F1/Nctr BR小鼠发生肝细胞癌。FB1对大鼠和小鼠的致癌性并非由于DNA损伤，因为多个实验室已证明FB1不是基因毒素。FB1在体外可诱导细胞凋亡。在大鼠饲料中添加FB1会导致肝细胞和肾小管上皮细胞凋亡增加。在对食用含高达484 ppm FB1饲料28天的F344/N/Nctr BR大鼠的研究中，雌性大鼠在诱导肝细胞凋亡和有丝分裂方面比雄性大鼠更敏感。相反，雄性大鼠肾小管凋亡和再生的诱导比雌性大鼠更明显。在对F344/N/Nctr BR大鼠进行的为期2年的FB1喂养研究中，肾小管凋亡和增生的诱导与所发生的肾小管癌的发生率相关。这些数据与以下假设一致，即雄性大鼠肾小管癌的诱导可能部分归因于肾小管上皮细胞因伏马菌素B1诱导凋亡而持续进行的代偿性再生。
