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

The cancer initiating potential of fusarin C, a mutagen produced by Fusarium moniliforme strain MRC 826 was investigated on mouse skin using 12-O-tetradecanoylphorbol-13-acetate as promoter. In neither of these models did fusarin C act as a cancer initiator. Culture material of strain MRC 826, which previously was found to be hepatocarcinogenic in rats, exhibited cancer promoting activity in rat liver using diethylnitrosamine (DEN) as initiator and the induction of gamma glutamyltranspeptidase (GGT)-positive foci as end-point. The culture material of this fungus could also induce the formation of GGT positive foci without DEN initiation. These results seem to indicate that fusarin C is not involved in the hepatocarcinogenic activity of F. moniliforme strain MRC 826.

A short-term cancer initiation/promotion bioassay was established to screen 10 toxic strains of Fusarium moniliforme for their cancer promoting activity in rats. The assay consisted of a four week 'promoting' treatment, effected by incorporating culture material (5%) of each strain into the diet, commencing one week after an initiation treatment with diethylnitrosamine (DEN, 200 mg/kg). The appearance of gamma-glutamyltranspeptidase-positive (GGT+) foci was used as an indication of promoting activity. Three out of 10 strains of F. moniliforme obtained from corn from a high risk area for esophageal cancer in Transkei, southern Africa, had significant cancer promoting activity. A highly significant correlation was found between toxicity expressed as reduction in body weight gain and cancer promoting activity. This finding suggests that the compounds responsible for the hepatotoxicity and hepatocarcinogenicity of F. moniliforme could be identical.

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The current study tested the hypothesis that deficiencies of certain mineral elements are risk factors for esophageal cancer (EC). In rural blacks living in areas with moderate to high EC incidence rates in southern Africa, the whole blood selenium (Se) levels were found to be significantly (P less than 0.0005) lower (58 to 71 ng/ml) than those of rural and urban populations living in low EC rate areas (114 to 177 ng/ml). No significant differences were found in the plasma levels of the other mineral elements examined, including zinc, copper, and magnesium. Within a high EC rate area occupants of households with previously recorded EC cases had significantly (P less than 0.0025) lower levels of Se (64 ng/ml), but not of other mineral elements, than subjects from households without known cases (77 ng/ml). Mean Se levels of subjects with premalignant or malignant esophageal cytological changes (54 ng/ml) were significantly (P less than 0.0025) lower than those of subjects without such lesions (68 ng/ml). An inverse relationship was found between Se status and the degree of cytologic abnormality. These findings suggest that Se deficiency may play a role in the development of EC. The potential value of whole blood Se determinations and esophageal cytologic examinations in the early detection and of Se supplementation in the prevention of EC merits further investigation.

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