Lactational passage of fusaric acid from the feed of nursing dams to the neonate rat and effects on pineal neurochemistry in the F1 and F2 generations at weaning.

Fusaric acid is produced by several species of Fusarium and is found in corn, corn-based foods and feeds, wheat, barley, and other cereal grains. Given parenterally to rats, the mycotoxin affects neurochemical parameters in the pineal gland associated with growth and maturation. Since little information exists concerning the dietary effects of fusaric acid, the mycotoxin was mixed with feed at 10, 75, and 200 ppm and fed ad libitum to pregnant rats (F0 dams) from d 11-12 of gestation, through parturition and weaning (F1 generation). On d 4 postpartum, F1 pups were culled to 9-10 pups/litter; the stomach colostrum was collected from the culls and analyzed for fusaric acid. The mycotoxin in the colostrum (ng fusaric acid/100 mg colostrum) was directly related to the amount consumed by the nursing dams (i.e., 200 ppm pups, 3547 ng; 75 ppm pups, 1449 ng; 10 ppm pups, 80 ng; controls pups, 18 ng). All other animals survived, and appeared normal, healthy, and in good pelage. F0 dam feed consumption and dam and pup weights were not statistically different, but there was an inverse relation between pup average weight gain and amount of fusaric acid in the diets (i.e., weight gains: control pup > 10 ppm pup > 75 ppm pups > 200 ppm pups). At weaning, the F1 pups were randomly assigned to two groups per treatment: one group (F1A) for reproduction and fusaric acid effects on the F2 generation, and another group (F1B) for neurochemical comparisons. The F1A rats were maintained on their respective diets to age 13-14 wk; animals were bred (i.e., control males x control females, 10 ppm x 10 ppm, etc.) and the F1A dams and F2 pups were monitored as already described. Weight gains and fusaric acid in stomach colostrum from the F2-culls were analogous to the F1 generation. On d 5-6 and 7-8 postpartum, using litter weight gains as an indication of milk production in the F1A dams (controls vs. 200 ppm), the controls gained 32.5% (p < .01) and 13.3% (p < .02), respectively, more than 200 ppm F2 pups. At weaning, no differences were observed in neurochemicals in the pineal gland for the F1 generation. However, in the F2 200 ppm male and female weanlings, fusaric acid decreased pineal serotonin (males, p < or = .001; females, p < or = .15) and tyrosine (males, p < or = .04; females, p < or = .07). The results indicate fusaric acid in diets at < or = 0.3 ppm (i.e., background control diet) lactationally passes from nursing dams to the neonate; in weanlings, at 200 ppm, fusaric acid decreases pineal serotonin and tyrosine. The data also suggest limited neonate weight gains may be related to either decreased milk production in dams or mycotoxin effects on the neonate. This is the first report of fusaric acid's lactational passage from the feed of nursing dams to neonates and the oral suppression of pineal serotonin and tyrosine in offspring.

Fusaric acid in Fusarium moniliforme cultures, corn, and feeds toxic to livestock and the neurochemical effects in the brain and pineal gland of rats.

Fusaric acid is produced by several species of Fusarium, which commonly infect corn and other agricultural commodities. Since this mycotoxin may augment the effects of other Fusarium toxins, a gas chromatography/mass spectrometry method of analysis in feeds was developed. Fusaric acid was analyzed as the trimethylsilyl-ester from F. moniliforme-cultures, -contaminated corn screenings, and feeds toxic to livestock. The mycotoxin was found in all samples and ranged from 0.43 to 12.39 micrograms/g sample. Also, fusaric acid was tested for its neurochemical effects in the brain and pineal gland of rats. Animals were dosed intraperitoneally (100 mg/kg body weight) 30 min prior to the onset of the dark phase (lights out) and the effects were studied at 1.5, 3.5, and 5.5 h after treatment. Brain serotonin (5HT), 5-hydroxyindoleacetic acid (5HIAA), tyrosine (TYRO), and dopamine (DA) were increased (P < 0.05) by fusaric acid, and norepinephrine (NEpi) was decreased (P < 0.05). Analogously, DA in the pineal gland increased and NEpi decreased (P < 0.05). Pineal N-acetylserotonin (NAc5HT) was increased (P < 0.05), whereas pineal 5HT and its two major metabolites 5HIAA and 5-hydroxytryptophol (5HTOL) decreased (P < 0.05). Elevated brain TYRO and brain and pineal DA, with decreased NEpi, may be consistent with fusaric acid's partial inhibitory effect on tyrosine-hydroxylase and its inhibitory effect on dopamine-beta-hydroxylase, respectively. Elevated pineal Nac5HT is consistent with decreased pineal 5HT and the increased pineal DA, and support the dopaminergic stimulatory activity of the enzyme responsible for the conversion of 5HT to NAc5HT. This is the first report of fusaric acid's in vivo effect on pineal DA, NEpi, 5HT, and NAc5HT in rats, and a relation for the effects on TYRO, 5HT, and 5HIAA in brain tissue. The results indicate fusaric acid alters brain and pineal neurotransmitters and may contribute to the toxic effects of Fusarium-contaminated feeds.

Fumonisin- and AAL-Toxin-Induced Disruption of Sphingolipid Metabolism with Accumulation of Free Sphingoid Bases.

Fumonisins (FB) and AAL-toxin are sphingoid-like compounds produced by several species of fungi associated with plant diseases. In animal cells, both fumonisins produced by Fusarium moniliforme and AAL-toxin produced by Alternaria alternata f. sp. lycopersici inhibit ceramide synthesis, an early biochemical event in the animal diseases associated with consumption of F. moniliforme-contaminated corn. In duckweed (Lemna pausicostata Heglem. 6746), tomato plants (Lycopersicon esculentum Mill), and tobacco callus (Nicotiana tabacum cv Wisconsin), pure FB1 or AAL-toxin caused a marked elevation of phytosphingosine and sphinganine, sphingoid bases normally present in low concentrations. The relative increases were quite different in the three plant systems. Nonetheless, disruption of sphingolipid metabolism was clearly a common feature in plants exposed to FB1 or AAL-toxin. Resistant varieties of tomato (Asc/Asc) were much less sensitive to toxin-induced increases in free sphinganine. Because free sphingoid bases are precursors to plant "ceramides," their accumulation suggests that the primary biochemical lesion is inhibition of de novo ceramide synthesis and reacylation of free sphingoid bases. Thus, in plants the disease symptoms associated with A. alternata and F. moniliforme infection may be due to disruption of sphingolipid metabolism.