Cultures on corn of Fusarium moniliforme MRC 826 are known to cause leukoencephalomalacia in horses and to be toxic and hepatocarcinogenic in rats. Culture material of this F. moniliforme isolate has also been shown to exhibit cancer-promoting activity in a short-term cancer initiation-promotion bioassay with diethylnitrosamine-initiated rats and the induction of gamma-glutamyl-transpeptidase-positive (GGT+) foci as an endpoint after 4 weeks of promotion. This bioassay was used as a monitoring system to isolate cancer-promoting compounds from cultures of F. moniliforme MRC 826. Culture material was successively extracted with ethyl acetate and CH30H-H20 (3:1). Most of the cancer-promoting activity was recovered in the CH30H-H20 extract and remained in the aqueous phase following partitioning of this extract between CH30H-H20 (1:3) and CHCl3. The CH30H-H20 fraction was chromatographed on an Amberlite XAD-2 column, and the active fraction was eluted with CH30H. This fraction was chromatographed on a silica gel column with CHCl3-CH30H-CH3COOH (6:3:1) as eluent and further purified on a C18 reverse-phase column. Two pure compounds were isolated, and these have been chemically characterized and given the trivial names fumonisin B1 and B2. At least 2 g of the major compound fumonisin B1 was purified from 1 kg of culture material. Fumonisin BI in the diet (0.1%) significantly (P < 0.001) induced the formation of GGT+ foci in the livers of initiated as well as noninitiated rats. The cancer-promoting effect of fumonisin B1 in rats was associated with a toxic effect, as evidenced by a significant (P < 0.0005) reduction in weight gain during the 4-week promoting treatment. The principal pathological change in rats treated with fumonisin B1 was an insidious and progressive toxic hepatitis similar to that induced by toxic culture material of F. moniliforme MRC 826. The toxicological effects of Fusarium moniliforme Sheldon in animals have been studied extensively (11). This fungus is known to cause leukoencephalomalacia (LEM) in horses (9) and to be highly toxic to a variety of experimental animals (5, 7, 8) and hepatocarcinogenic in rats (6, 10). Recently, corn samples naturally infected by F. moniliforme and implicated in field outbreaks of LEM in the United States have been reported to be hepatocarcinogenic in rats (14). These findings not only suggest that the LEM toxin and the hepatocarcinogen produced by F. moniliforme may be

Fumonisins are a family of toxic and carcinogenic mycotoxins produced by Fusarium verticillioides (formerly Fusarium moniliforme), a common fungal contaminant of maize. Fumonisins inhibit ceramide synthase, causing accumulation of bioactive intermediates of sphingolipid metabolism (sphinganine and other sphingoid bases and derivatives) as well as depletion of complex sphingolipids, which interferes with the function of some membrane proteins, including the folate-binding protein (human folate receptor alpha). Fumonisin causes neural tube and craniofacial defects in mouse embryos in culture. Many of these effects are prevented by supplemental folic acid. Recent studies in LMBc mice found that fumonisin exposure in utero increases the frequency of developmental defects and administration of folate or a complex sphingolipid is preventive. High incidences of neural tube defects (NTD) occur in some regions of the world where substantial consumption of fumonisins has been documented or plausibly suggested (Guatemala, South Africa, and China); furthermore, a recent study of NTD in border counties of Texas found a significant association between NTD and consumption of tortillas during the first trimester. Hence, we propose that fumonisins are potential risk factors for NTD, craniofacial anomalies, and other birth defects arising from neural crest cells because of their apparent interference with folate utilization.

The structures of the fumonisins, a family of structurally related mycotoxins isolated from cultures of Fusarium moniliforme, were elucidated by mass spectrometry and 1H and 13C n.m.r. spectroscopy as the diester of propane-lr2,3-tricarboxylic acid and either 2-acetylamino-or 2-amino-1 2,16-dimethyl-3,5,10,14,15-pentahydroxyicosane as well as in each case the C-10 deoxy analogue; in all cases both the C-14 and C-15 hydroxy groups are involved in ester formation with the terminal carboxy group of propane-I ,2,3-tricarboxylic acid.

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Contamination of corn with the fungus Fusarium moniliforme and its secondary metabolites, the fumonisins, has been associated with several human and animal diseases. This paper summarizes present knowledge and presents new data on the levels of fumonisins present in foods and feeds associated with these diseases as well as in commercial corn and corn-based products. The doses of fumonisins to which humans and animals consuming these products would be exposed are compared with those doses known to produce LEM in horses and hepatocarcinogenesis in rats. It is concluded that the known naturally occurring levels of fumonisins present a potential threat to human and animal health and realistic tolerance levels need to be set.

Fumonisins B1 (FBR) and B2 (FB2), two structurally related mycotoxins with cancer-promoting activity, were recently isolated from corn cultures of Fusarium moniliforme MRC 826. These toxins have been reported to be produced also by isolates of F. proliferatum. Contamination of foods and feeds by F. moniliforme has been associated with human esophageal cancer risk, and FB, has been shown to be the causative agent of the neurotoxic disease leukoencephalomalacia in horses. Because of the toxicological importance of the fumonisins, the potential to produce FBI and FB2 was determined in a study of 40 toxic Fusarium isolates representing 27 taxa in 9 of the 12 sections of Fusarium, as well as two recently described species not yet classified into sections. With the exception of one isolate of F. nygamai, fumonisin production was restricted to isolates of F. moniliforme and F. proliferatum, in the section Liseola. The F. nygamai isolate produced 605 ,ug of FB1 g1-and 530 ,ug of FB2 g-', and the identity of the toxins was confirmed by capillary gas chromatography-mass spectrometry. This is the first report of the production of the fumonisins by F. nygamai.