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PubMed1996

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.

Administration, Oral↗

PubMedDate not supplied

Cytotoxic activity of fusaric acid on human adenocarcinoma cells in tissue culture.

When cultured human normal WI-38 fibroblasts were exposed to 500 microM fusaric acid (5-butylpicolinic acid), cell proliferation ceases. The majority of the WI-38 cells remained in a quiescent G1(G0) state and viable for approximately 30 to 48 h. The effect of fusaric acid on WI-38 cell growth was slowly reversible after removal of the agent from the culture media. In contrast, within 24 h of exposure to 500 microM fusaric acid, most of the human colon adenocarcinoma LoVo cells were blocked at random in the cell cycle and approximately 80% of the cells were dead after 30 h. Three additional human colorectal adenocarcinoma cell lines, denoted SW48, SW480, and SW742, were also sensitive to the inhibitory and cytotoxic effects of fusaric acid. Of all the cell lines tested, the human mammary adenocarcinoma cell line MDA-MB-468 was the most sensitive to the growth inhibitory and cytotoxic effects of fusaric acid. Further experiments with MDA-MB-468 cells demonstrated that fusaric acid is a potent inhibitor of DNA synthesis. Fusaric acid also inhibited the growth of human epidermoid carcinoma KB cells and showed cytotoxic actions for this cell line but its effects on cell viability were not as pronounced. The results presented here indicate that fusaric acid has potent anti-proliferative activity in vitro on various normal and cancer cell lines and suggest that it exhibits some cytotoxic specificity for growing and confluent colorectal adenocarcinoma and mammary adenocarcinoma cell lines.

Adenocarcinoma↗

PubMed1976

Time-course changes in blood pressure, urinary excretion of norepinephrine and dopamine after administration of fusaric acid in a single dose in elderly hypertensive patients.

Time-course changes in blood pressure, urinary norepinephrine and dopamine excretion after administration in a single dose of fusaric acid calcium salt were examined in 8 elderly hypertensive patients. Eight elderly hypertensive patients served as controls receiving placebo administration in a single dose. The dose of fusaric acid calcium salt ranged from 5.1 mg/Kg to 6.0 mg/Kg. The results obtained are as follows: 1) Both systolic and diastolic blood pressure showed a significant reduction in fusaric acid calcium salt group, the lowest value of systolic blood pressure being observed from 4 to 8 hrs. and that of diastolic blood pressure being observed from 4 to 6 hrs. after administration of this agent, respectively. Systolic blood pressure returned more slowly to the level before fusaric acid calcium salt administration than diatolic blood pressure did. In placebo group, however, no significant reduction of both systolic and diastolic blood pressures was noted. 2) In fusaric acid calcium salt group, norepinephrine excretion in the urine did not show a diurnal change. In placebo group, however, a tendency of diurnal change was noted. These results would suggest that noepinephrine synthesis might be inhibited temporalily by fusaric acid calcijm salt. 3) In fusaric acid calcium salt group, dopamine excretion in the urine did hardly show a diurnal change. In placebo group, however, a fairly evident diurnal change was observed. The interpretation of these results seems to be difficult in the present state of knowledge of the action of fusaric acid calcium salt in humans.

Aged↗

PubMed1976

Inhibition of mid-cycle gonadotrophin release in healthy women by pimozide and fusaric acid.

The effects of pimozide, a drug blocking dopamine receptors, and fusaric acid, an inhibitor of dopamine beta-hydroxylase, on mid-cycle release of FSH and LH were studied in 8 healthy women 20-25 years of age. None had used contraceptive drugs for the preceding 10 months. From the menstrual history and serum LH determinations during the normal cycle, mid-cycle gonadotrophin bursts were predicted for the following three cycles. Two days before and after the expected gonadotrophin surge were regarded as sufficient for the drug tests. Pimozide (initially 2 mg, then 1 mg/day) and fusaric acid (600 mg/day) were administered in a randomized cross-over study. The mid-cycle LH values were reduced from the control level of 56 +/- 10 mIU/ml (mean +/- SE) to 22 +/- 4 mIU/ml by pimozide (P less than 0.001) and to 17 +/- 5 mIU/ml by fusaric acid (P less than 0.001). The serum FSH level was 9 +/- 2 mIU/ml on the day of the LH surge and did not change significantly during treatment with either drug. The LH and FSH responses to synthetic LRF (100 mug iv) were not changed by pimozide or fusaric acid. The rise of basal temperature associated with ovulation was not affected by the drugs. These results suggest that suprapituitary noradrenergic and dopaminergic neurotransmitters are involved in the regulation of mid-cycle gonadotrophin secretion in women.

Adult↗

PubMed1995

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.

Animal Feed↗

PubMed2006

Early physiological responses of Arabidopsis thaliana cells to fusaric acid: toxic and signalling effects.

Fusaric acid (FA) is a toxin produced by Fusarium species. Most studies on FA have reported toxic effects (for example, alteration of cell growth, mitochondrial activity and membrane permeability) at concentrations greater than 10(-5) m. FA participates in fungal pathogenicity by decreasing plant cell viability. However, FA is also produced by nonpathogenic Fusarii, potential biocontrol agents of vascular wilt fusaria. The aim of this study was to determine whether FA, at nontoxic concentrations, could induce plant defence responses. Nontoxic concentrations of FA were determined from cell-growth and O2-uptake measurements on suspensions of Arabidopsis thaliana cells. Ion flux variations were analysed from electrophysiological and pH measurements. H2O2 and cytosolic calcium were quantified by luminescence techniques. FA at nontoxic concentrations (i.e. below 10(-6) m) was able to induce the synthesis of phytoalexin, a classic delayed plant response to pathogen. FA could also induce rapid responses putatively involved in signal transduction, such as the production of reactive oxygen species, and an increase in cytosolic calcium and ion channel current modulations. FA can thus act as an elicitor at nanomolar concentrations.

Arabidopsis↗

PubMed1985

Isolation and characterization of two new fusaric acid analogs from Fusarium moniliforme NRRL 13,163.

Fusarium moniliforme NRRL 13,163 produced two new fusaric acid analogs, a 10,11-dihydroxyfusaric acid and a diacid of fusaric acid in which the C-11 methyl was oxidized to a carboxyl. Several hundred milligrams of the 10,11-dihydroxyfusaric acid were routinely recovered from a kilogram of corn grit medium. It crystallized as white, irregularly shaped rectangles that melted at 153 to 154 degrees C. The diacid analog of fusaric acid crystallized as white rods that melted at 210 to 211 degrees C. Unlike the consistent recovery experienced with the 10,11-dihydroxyfusaric acid, the diacid analog proved difficult to purify after the initial discovery and was detectable in subsequent fermentations only by mass spectrometry.

Chromatography, High Pressure Liquid↗

PubMed1976

Rapid GLC determination of fusaric acid in biological fluids.

A simple, sensitive GLC assay was developed for fusaric acid, the active metabolite of bupicomide, to follow the disposition of this investigational antihypertensive agent in patients undergoing therapy. Fusaric acid is efficiently extracted from biological samples, derivatized by on-column methylation, and chromatographed using flame-ionization detection. An internal standard is utilized to quantitate results. The procedure is rapid and specific for fusaric acid, and has a lower limit of sensitivity of 0.1 mug/ml. The method is suitable for supporting pharmacokinetic studies of bupicomide following therapeutic doses in animals and humans.

Body Fluids↗

PubMed1986

Chain elongation of fusaric acid and related compounds in rat liver.

Chain elongation of fusaric acid and related compounds in the presence of rat liver preparations was investigated by gas chromatography-mass spectrometry. The mitochondrial fraction catalyzed the elongation of the CoA esters of fusaric acid and 5-butyl-2-pyrimidinecarboxylic acid utilizing acetyl-CoA as a C2 donor. The microsomal fraction failed to afford elongation products. However, when the CoA ester of 3-(5-butyl-2-pyrimidinyl)-3-hydroxypropionic acid was incubated in the presence of the mitochondrial or the microsomal fraction, the corresponding alpha beta-unsaturated and saturated metabolites were identified in both cases, suggesting that the microsomal fraction could not catalyze the condensation or the keto-reduction of these heteroaromatic carboxylic acids.

Acetyl Coenzyme A↗

PubMed1991

Effect of fusaric acid on brain regional neurochemistry and vomiting behavior in swine.

Fusaric (5-butylpicolinic) acid is a phytotoxin produced especially by Fusarium moniliforme, a mold commonly found in Canadian-grown corn. Experiments were conducted to determine the effects of acute doses of fusaric acid on brain neurochemistry and behavior in swine. A total of 40 crossbred barrows (initial weight 10 kg) were orally dosed with 0 or 200 mg of fusaric acid/kg of BW and five animals from each treatment were killed 4.5, 9, 18, or 36 h after dosing. All brains were dissected, and concentrations of indoleamine and catecholamine neurotransmitters and metabolites were determined. Animals in the group killed 36 h after dosing were observed for behavioral changes. Vomiting was noted in 60% of the pigs dosed with fusaric acid. These pigs also seemed more lethargic than controls and appeared sedated. The major neurochemical changes due to exposure to fusaric acid were seen in the hypothalamus 18 h after dosing. Brain tryptophan, serotonin, and 5-hydroxyindoleacetic acid all tended to be elevated by the action of fusaric acid. Brain catecholamine concentrations were largely refractory to treatment. It was concluded that exposure to acute doses of fusaric acid can cause vomiting and neurochemical changes in swine. Fusaric acid may, therefore, be acting synergistically with trichothecene mycotoxins to cause vomiting and feed refusal in pigs consuming trichothecene-contaminated feedstuffs.

Administration, Oral↗

PubMed1986

[Effect of fusaric acid on phosphoinositide metabolism in the erythrocyte membranes of rats with spontaneous hypertension].

2- and 4-month-old male spontaneously hypertensive rats (SHR) were injected fusaric acid at a dose of 50 mg/kg body weight. Fusaric acid increased diphosphoinositide (DPI) and triphosphoinositide (TPI) levels in erythrocyte membranes of 4-month-old SHR by 41% and 20%, respectively. 32P incorporation into TPI decreased by 24% in 2- and by 20% in 4-month-old SHR. Phosphatidylinositol metabolism remained unchanged. The results also suggest that fusaric acid normalized DPI and TPI metabolism in erythrocyte membranes of SHR.

Animals↗

PubMed2006

The effect of single agent oral fusaric acid (FA) on the growth of subcutaneously xenografted SCC-1 cells in a nude mouse model.

OBJECTIVE: To determine whether oral administration of fusaric acid (FA) inhibits tumor growth in an animal model of head and neck cancer (HNSCC). DESIGN: In vivo murine model, two arm controlled study. METHODS: Thirty-eight (38) 5-week-old athymic nude mice were randomly assigned to a fusaric acid treatment group (1 mg/mL) (n = 19) or a sterile saline group (n = 19). A left, lateral flank subcutaneous injection of 2.0 x 10(6) UM-SCC-1 cells were administered to all mice on day 1. Both groups were gavaged daily with either 0.25 mLs of oral FA or sterile saline throughout the experiment (32 days). Latency to a measurable tumor (> or =65 mm3), and tumor volumes were recorded after tumor xenografting. Tumor weights were recorded at the conclusion of the experiment. Tumor volume growth curves were modeled as polynomial functions of time with treatment interaction effects. Survivorship functions for time to measurable tumor were estimated using the Kaplan-Meier product limit estimator. RESULTS: Survival analysis showed mice treated with FA developed measurable tumors after a significantly longer interval post-xenografting than control mice (p = 0.00451). By Day 9, all mice in the control group had developed measurable tumors in comparison to only 78% of mice in the FA group. Likewise, estimated growth curves for both groups suggested that mice receiving FA demonstrated significantly slower tumor growth rates throughout the entire study period (p < 0.0001). At the conclusion of the experiment, tumor weights from both the control and FA groups were also significantly different (p = 0.0142). CONCLUSIONS: Single agent oral fusaric acid (1 mg/mL) is an inhibitor of UM-SCC-1 in a murine model. As an orally active agent, it may have a potential role in the treatment of human squamous cell carcinoma of the head and neck.

Administration, Oral↗

PubMed1999

Pharmacological activities of fusaric acid (5-butylpicolinic acid).

This review article aims at summarizing research findings on the various pharmacological activities of fusaric acid (5-butylpicolinic acid), a mycotoxin produced by several Fusarium species which commonly infect cereal grains and other agricultural commodities. The actions of the toxin on mammals, birds, arthropods, crustaceans and plants are covered. The effects on mammals are diverse and are apparent in the nervous, cardiovascular and immune systems. Fusaric acid is toxic to some mammalian tumor cell lines.

Animals↗

PubMed1977

Effect of fusaric acid on tardive dyskinesia and mental state in psychogeriatric patients. A pilot study.

The effect of fusaric acid 150-450 mg daily on tardive dyskinesia and mental state was studied in 15 chronic psychogeriatric patients. The patient's previous drug treatment was maintained unchanged during the experiment. Fusaric acid significantly relieved oro-facial dyskinesia, tremor, and rigidity, and it improved the mental state of the patients (BPRS). Akathisia was exacerbated, but this change was not significant. Akinesia and anxiety were not altered.

Aged↗

PubMed2004

Role of chemotaxis toward fusaric acid in colonization of hyphae of Fusarium oxysporum f. sp. radicis-lycopersici by Pseudomonas fluorescens WCS365.

Pseudomonas fluorescens WCS365 is an excellent competitive colonizer of tomato root tips after bacterization of seed or seedlings. The strain controls tomato foot and root rot (TFRR) caused by the phytopathogenic fungus Fusarium oxysporum f. sp. radicis-lycopersici. Under biocontrol conditions, fungal hyphae were shown to be colonized by WCS365 bacteria. Because chemotaxis is required for root colonization by WCS365 cells, we studied whether chemotaxis also is required for hyphae colonization. To that end, an in vitro assay was developed to study hyphae colonization by bacteria. The results indicated that cells of the cheA mutant FAJ2060 colonize hyphae less efficiently than cells of wild-type strain WCS365, when single strains were analyzed as well as when both strains were applied together. Cells of WCS365 show a chemotactic response toward the spent growth medium of F. oxysporum f. sp. radicis-lycopersici, but those of its cheA mutant, FAJ2060, did not. Fusaric acid, a secondary metabolite secreted by Fusarium strains, appeared to be an excellent chemo-attractant. Supernatant fluids of a number of Fusarium strains secreting different levels of fusaric acid were tested as chemo-attractants. A positive correlation was found between chemo-attractant activity and fusaric acid level. No chemotactic response was observed toward the low fusaric acid-producer FO242. Nevertheless, the hyphae of FO242 still were colonized by WCS365, suggesting that other metabolites also play a role in this process. The possible function of hyphae colonization for the bacterium is discussed.

Chemotactic Factors↗

PubMed1985

Effect of fusaric acid (a dopamine beta-hydroxylase inhibitor) on phaeochromocytoma.

Fusaric acid, an inhibitor of dopamine beta-hydroxylase, which converts dopamine to noradrenaline, lowered the blood pressure and induced a subjective improvement in patients with phaeochromocytoma. These effects may be due either to an impairment of catecholamine biosynthesis or to a direct action on the blood vessels. The use of this drug in the treatment of patients with inoperable malignant phaeochromocytoma or neuroblastoma may improve symptoms and prolong survival.

Blood Pressure↗

PubMed1978

Effects of diethyldithiocarbamate and fusaric acid upon memory storage processes in rats.

Diethyldithiocarbamate (DDC) and fusaric acid (FA), administered immediately posttraining, disrupted retention performance of rats trained on a one-trial inhibitory avoidance task. Posttraining DDC disrupted retention performance if the treatment was delayed up to at least 24 h (but not 72 h) after training. A single DDC injection also disrupted retention performance if the treatment was administered up to 10 days prior to training. The effects of DDC and FA upon several neurobiological measures were also investigated. Amnestic doses of DDC influence brain and adrenal catecholamine levels, brain electrographic activity and hippocampal Timm's staining. On the other hand, amnestic doses of FA only affected catecholamine levels. The amnestic effects of DDC were dissociated from brain seizure activity produced by DDC. The effects of DDC and FA upon retention may have been related to the drugs' effects upon catecholamine systems, but the bleaching by DDC of Timm's staining could reflect additional processes involved in DDC's effects upon retention. As opposed to the more widespread effects of DDC, FA's relative lack of effect upon other neurobiological measures more strongly supports a catecholaminergic interpretation for its effect upon retention.

Animals↗

PubMed1997

Effect of feeding blends of Fusarium mycotoxin-contaminated grains containing deoxynivalenol and fusaric acid on growth and feed consumption of immature swine.

Experiments were conducted to determine the effect of feeding diets containing combinations of the Fusarium metabolites deoxynivalenol (DON) and fusaric acid (FA) to starter swine. In all experiments, pigs of approximately 8.2 kg initial weight were fed diets containing blends of mycotoxin-contaminated corn, wheat, and barley for 21 d with growth and feed consumption determined weekly. In the first experiment, diets were determined to contain 0 microgram DON/g + 58.9 micrograms FA/g (control), 4.4 micrograms DON/g + 57.1 micrograms FA/g, 6.0 micrograms DON/g + 48.6 micrograms FA/g, and 7.5 micrograms DON/g + 57.4 micrograms FA/g. The feeding of all diets containing DON caused significant linear depressions in growth and feed intake after only 1 wk. Lower concentrations of DON and FA were fed in the second experiment with diets containing 0 microgram DON/g + 16.3 micrograms FA/g (control), .5 microgram DON/g + 14.3 micrograms FA/g, 1.1 micrograms DON/g + 14.1 micrograms FA/g, and 1.9 micrograms DON/g + 13.6 micrograms FA/g. There was a significant linear reduction in feed intake after 1 wk with increasing levels of dietary DON. Weight gains declined significantly only after 3 wk. Increasing amounts of FA combined with relatively constant amounts of DON were fed in the third experiment. By analysis, diets contained .5 micrograms DON/g + 2.9 micrograms FA/g (control), 2.2 micrograms DON/g + 12.2 micrograms FA/g, 2.5 micrograms DON/g + 15.6 micrograms FA/g, and 2.4 micrograms DON/g + 15.9 micrograms FA/g. In the 1st wk, the feeding of increasing amounts of fusaric acid combined with a relatively constant amount of DON caused a significant linear depression in weight gain. We concluded that a toxicological synergism exists between DON and FA when fed to immature swine and that FA concentrations in feeds should be determined whenever DON analysis is conducted.

Aging↗