Toxicological Synergism between Fusarium Mycotoxins in Feeds

Mycotoxins are metabolites produced by molds (fungi) which are toxic when consumed in significant amounts by livestock. The resulting pathological syndromes are referred to as mycotoxicoses.

Mold growth on grains and subsequent mycotoxin synthesis is regulated by numerous factors of which moisture content is usually the most important. Toxigenic fungi generally grow best under humid, warm, aerobic conditions. High moisture grains are, therefore, particularly susceptible to infestation. Stored grains must contain less than 15% moisture to minimize mold growth. High moisture grains can be ensiled, however, to prevent mycotoxin accumulation.

Mold infestation usually begins pre-harvest. This is greatly influenced by weather conditions and is difficult to control. Improper grain storage postharvest can lead to further mold growth. Mycotoxins are produced at only certain stages of mold growth.

The presence of visible mold spores, therefore, does not always serve as a reliable guide to toxin content. Mycotoxin molecules are generally quite resistant to chemical or thermal treatments which destroy mold spores. The absence of visible mold, therefore, cannot be extrapolated to infer that grains are devoid of mycotoxins.

Ruminant animals are generally more tolerant of feed-borne mycotoxins than non-ruminant species due to the detoxifying capabilities of rumen microorganisms. Swine are generally the most sensitive species with poultry being somewhat intermediate. Residues of mycotoxins and metabolites have been reported in many animal food products including meat, milk and eggs.


Fusarium mycotoxins

Fusarium fungi are commonly found in temperate climates and Fusarium mycotoxins are likely the most economically significant grain mycotoxins on a global basis (Wood, 1992). The numerous Fusarium mycotoxins are very diverse in chemical structure and characteristic mycotoxicoses. They include the trichothecenes, the fumonisins, zearalenone, moniliformin and fusaric acid.


THE TRICHOTHECENES

About 150 different, but structurally related, trichothecenes have been chemically identified. The major physiological response to these compounds is a loss of appetite and these are considered to be feed refusal toxins. Most of the trichothecenes are found in very small amounts. The most commonly reported are deoxynivalenol (vomitoxin, DON; Figure 1) and T-2 toxin with deoxynivalenol likely being the major contributor to reduced animal performance.

Complete testing of suspect feeds for trichothecenes would be prohibitively expensive and not all of these compounds are available in pure form to serve as analytical standards.

Consumption of feed contaminated with trichothecenes is commonly associated with loss of appetite, vomiting, lesions of the intestinal tract, immunosuppression, lethargy and ataxia. Trichothecene toxicoses have been described in a wide range of domestic animals as well as humans.

Swine are the most sensitive species to feed-borne trichothecenes. Ruminants tend to be more resistant to trichothecenes because of the detoxifying action of rumen microorganisms. Overt toxicity such as vomiting in swine is rare. Economic losses are more likely due to non-specific symptoms such as reduced feed intake and immunosuppression caused by chronic consumption of low levels of toxin.

The trichothecenes inhibit, to varying degrees, cellular protein synthesis.

This property is likely the cause of many of the pathologies associated with trichothecene toxicoses. T-2 toxicosis results in hyperaminoacidemia (Wannemacher and Dinterman, 1983) and this is likely due to inhibition of hepatic protein synthesis (Meloche and Smith, 1995).

Subsequent elevations in blood tryptophan can result in increased concentrations of tryptophan in the brain. Tryptophan is the precursor of the neurotransmitter serotonin and the serotonergic neurons are thought to be important mediators of behaviors such as appetite, muscle coordination and sleep.

Serotonin synthesis in the brain is poorly regulated and can be promoted by increased concentrations of tryptophan (Leathwood, 1987). Increased amounts of brain serotonin are thought to cause a loss of appetite and cause sleepiness. Elevated brain tryptophan concentrations have been proposed as a common pathogenic mechanism for loss of appetite associated with many diseases (Rossi-Fanelli and Cangiano, 1991). Chung et al. (1991) reported that large excesses of dietary tryptophan could cause vomiting in swine.




Figure 1.Deoxynivalenol (DON, vomitoxin).


The neurochemical effects of trichothecenes were examined by MacDonald et al. (1988) and Cavan et al. (1988) who reported that acute doses of T-2 toxin caused sequential elevations in rat brain concentrations of tryptophan, serotonin and 5-hydroxyindoleacetic acid (5-HIAA). The latter compound is a metabolite of serotonin and is sometimes used as evidence of increased firing of serotonergic neurons. Boyd et al. (1988) reported similar findings in rats and chicks. Chick brains were less sensitive to T-2 toxin than rat brains and this is in agreement with earlier studies (Chi et al., 1981).

Fitzpatrick et al. (1988) have demonstrated that deoxynivalenol alters rat brain neurochemistry in a similar manner and Prelusky et al. (1992) have reported that swine fed vomitoxin also have elevated brain serotonin and 5-HIAA. Prelusky (1993) subsequently demonstrated that even low doses of deoxynivalenol cause increased brain levels of 5-HIAA in swine.

Despite the large number of individual trichothecenes and the unlimited potential for toxicological synergism between these, it has not been possible to show such synergism using a chick embryo assay (Rotter et al., 1991) or growing swine (Rotter et al., 1992).


THE FUMONISINS

The fumonisins are a group of recently identified Fusarium mycotoxins (Gelderblom et al., 1988) which are produced mainly by Fusarium moniliforme, a Fusarium species commonly found in grains grown in North America (Neish et al., 1983).

It has been proposed that the fumonisins may play an important role in the etiology of Fusarium mycotoxicoses in livestock (Norred et al., 1991). Diseases associated with fumonisin consumption include equine leukoencephalomalacia (Marasas et al., 1988) and porcine pulmonary edema (Haschek et al., 1992).

It has been shown that the biochemical mode of action of the fumonisins is due to their chemical structure (Figure 2). They act as inhibitors of sphingolipid biosynthesis (Wang et al., 1991).

The feeding of corn contaminated with F. moniliforme and containing high concentrations of fumonisin B1 caused elevated rat brain serotonin and 5-HIAA concentrations (Porter et al., 1990). This is similar to the effect of feeding trichothecenes. The fusaric acid content of the corn, however, was not reported.

The same authors repeated the study feeding purified fumonisin, but failed to show the neurochemical changes (Porter et al., 1993). Attempts to demonstrate toxicological synergism between fumonisin and trichothecenes in turkey poults have not been successful (Kubena et al., 1995). Such synergism was also not seen when fumonisin and moniliformin were fed to broiler chicks (Ledoux et al., 1994).

It can be concluded that fumonisins have a specific toxicological mode of action related to their chemical structures. It is unlikely, therefore, that they would contribute to Fusarium trichothecene mycotoxicoses.




Figure 2.Fumonisin B1.


ZEARALENONE

Like the trichothecenes, zearalenone is produced by Fusarium fungi. It is, however, chemically unrelated (Figure 3). Zearalenone has estrogenic properties although it is not chemically an estrogen and zearalenone toxicity is more readily recognized than trichothecene toxicity because the symptoms are more specific.

The consumption of feeds contaminated with zearalenone causes hyperestrogenism and impaired reproduction in many species. Swine are particularly susceptible and suffer swollen, red vulvae which can lead to rectal and vaginal prolapse. Uterine enlargement is common and atrophy of the ovaries is seen.

Zearalenone has not been seen to contribute to the reduced feed intake characteristic of trichothecene toxicosis (Smith, 1980). It has also not been possible to show any toxicological synergism between zearalenone and deoxynivalenol in experiments with mice (Forsell et al., 1986) or swine (Cote et al., 1985).

Although zearalenone is sometimes found together with trichothecenes in feeds, the toxicological mechanism of action clearly differs and the potential for toxicological synergism is correspondingly small.




Figure 3.Zearalenone.


MONILIFORMIN

Moniliformin is produced mainly by F. moniliforme. It acts as an inhibitor of the tricarboxylic acid cycle in intermediary metabolism. This again differs from the mode of action of the trichothecenes.

Chicks are quite tolerant of purified moniliformin at dietary concentrations of up to 64 μg/g of feed (Allen et al., 1981). Engelhardt et al. (1989), however, reported that the feeding of 144 μg/g moniliformin from Fusarium isolate was lethal to chicks.

Little survey data are available for moniliformin. Reported concentrations, however, are much lower than toxic levels (Thiel et al., 1982, 1986).


FUSARIC ACID

It has been proposed that the Fusarium phytotoxin fusaric acid (Figure 4) may act synergistically with the trichothecenes to reduce feed intake and cause lethargy in sensitive species (Smith, 1992). Fusaric acid, like the fumonisins and moniliformin, is produced mainly by F. moniliforme (Burmeister et al., 1985).

More recently, Bacon et al. (1996) surveyed 78 different stains of Fusarium fungi and reported that all the cultures tested produced fusaric acid. These authors suggested that since the production of fusaric acid is so widespread, this compound should be used as a marker toxin for Fusarium contamination.

Fusaric acid has pharmacological activity and has the physiological effect of lowering blood pressure (Hidaka et al., 1969). This response is thought to be due to alterations in brain neurochemistry (Nagatsu et al., 1970).

The acute toxicity of fusaric acid is low compared to other Fusarium metabolites. It does, however, elevate brain concentrations of tryptophan and serotonin as has been shown for the trichothecenes (Chaouloff et al., 1986).

The biochemical mechanism by which fusaric acid elevates brain serotonin has been shown to differ from that of the trichothecenes. Fusaric acid is derived from tryptophan. Tryptophan is carried in blood mainly bound to albumin. Only free tryptophan can cross the blood-brain barrier; and the free and proteinbound forms exist in equilibrium in blood.

Fusaric acid competes with tryptophan for albumin binding sites and displaces tryptophan that would normally be in bound form (Chaouloff et al., 1986). This elevates free blood tryptophan, brain uptake of tryptophan, and serotonin synthesis.

Trichothecene mycotoxins do not alter the ratio of free to protein-bound tryptophan (Cavan et al., 1988), although they do increase total tryptophan concentrations in blood as described above. This explains how fusaric acid and deoxynivalenol could produce the same neurochemical and behavioral effects, albeit through different mechanisms.




Figure 4.Fusaric acid (5-butylpicolinic acid).


Acute doses of fusaric acid have been shown to cause vomiting and lethargy in swine (Smith and MacDonald, 1991), but the feeding of high doses to broilers had little effect (Chu et al., 1993). In vitro studies support the concept of a toxicological synergism between fusaric acid and the trichothecenes (Dowd, 1988) and Bacon et al. (1995) reported an interaction between fusaric acid and fumonisin B1.

There is little survey information regarding the fusaric acid content of feedstuffs (Smith and Sousadias, 1993; Porter et al., 1995). Fusaric acid has been shown to be present in whole swine feeds and cereal grains in concentrations greatly exceeding those of deoxynivalenol and zearalenone (Table 1).

Whole feeds had a higher average fusaric acid concentration than contaminated grains. This may implicate soybean meal as a source of fusaric acid. Fusaric acid has been shown to be toxic to soybean plants (Matsui and Watanabe, 1988).

Bacon et al. (1995) have stressed that given the numerous common Fusarium species that produce fusaric acid, the natural occurrence of this compound should be considered commonplace.


Determining the potential hazard posed by feeds contaminated with Fusarium mycotoxins

The non-specific symptoms of reduced feed consumption and growth due to trichothecene contamination of feeds makes this one of the most difficult mycotoxin-related problems to positively identify.

Chemical analysis of suspect feeds often indicates much lower concentrations of deoxynivalenol than would be expected based on the toxicity seen.Williams et al. (1992) described vomiting and a generalized muscle tremor in swine fed corn contaminated with F. moniliforme.

Upon analysis the corn was found to be devoid of aflatoxin, ochratoxin A, sterigmatocystin, zearalenone, T-2 toxin, deoxynivalenol, nivalenol, diacetoxyscirpenol and moniliformin. The symptoms are typical of acute fusaric acid poisoning in swine. Fusaric acid content, however, was not reported.

Trenholm et al. (1983) described a severe outbreak of what appeared to be trichothecene toxicosis in a swine herd in Quebec. The outbreak was characterized by vomiting, feed refusal and death.

Analysis of the feed indicated only 0.14 μg/g deoxynivalenol. This concentration would not normally be considered to be even minimally toxic based on studies using purified deoxynivalenol.

Purified deoxynivalenol has been shown to be less toxic to swine than deoxynivalenol from naturally contaminated feedstuffs when equivalent amounts are fed (Forsyth et al., 1977; Friend et al., 1986).


Table 1.Fusaric acid content of cereal grains and whole swine feeds.*


*Smith and Sousadias, 1993.


Such findings are usually attributed to the presence of unknown mycotoxins, or due to toxicological synergism between different mycotoxins. Trenholm et al. (1994) made one of the most heroic efforts to date to identify unrecognized toxins.

Fusarium-contaminated wheat was analyzed for deoxynivalenol, 3-acetyldeoxynivalenol, 15-acetyldeoxynivalenol, diacetyldeoxynivalenol, T-2 toxin, HT-2 toxin, apotrichothecene, culmorin, hydroxyclumorin, culmorone, zearalenone, sambucinol, deoxysambucinol and sambucinone.

Only deoxynivalenol was identified as a contaminant (fusaric acid was not tested for); however, the naturally contaminated wheat still proved more toxic to swine than equivalent amounts of purified compound.

Bacon et al. (1996) have proposed that studies “that attribute observed toxicities to a single compound when the test animals consumed contaminated feed may need to be re-examined” in light of the potential interactions with fusaric acid.

Smith et al. (1997) conducted several experiments with starter pigs to determine the effect of feeding diets containing blends of contaminated grains containing combinations of deoxynivalenol and fusaric acid (Table 2).

Feed intake and growth were depressed with the feeding of as little as 1.1 μg/g feed deoxynivalenol when combined with about 50 μg/g feed fusaric acid.

Only fusaric acid and deoxynivalenol were found to be present. The blends were devoid of aflatoxins B1, B2, G1, and G2, ochratoxin A, citrinin, sterigmatoxystin; patulin, T-2 toxin, HT-2 toxin, diacetoxyscirpenol, neosolaniol, fusarenon-X, 3-acetyldeoxynivalenol, 15-acetyldeoxynivalenol, nivalenol, zearalenone, zearalenol and fumonisins B1 and B2.

The degree of growth depression and reduced feed intake contrasts with literature reports of similar studies. Prelusky et al. (1994) fed starter pigs diets containing 1 μg of deoxynivalenol/g from natural sources for 32 days (fusaric acid levels not reported) and observed an increase in rate of gain of 5.3%.

Rotter et al. (1994) fed starter pigs 0.95, 1.78 and 2.85 μg/g deoxynivalenol (fusaric acid levels not reported), also from natural sources, for 28 days and reported an increase in rate of gain of 3.1% at the lowest level of deoyxnivalenol and depressions of 3.1 and 3.1% at the higher levels, respectively.

The greater degree of impaired growth and reduced feed consumption observed by Smith et al. (1997) may have been due to the fusaric acid content of the diets. Caution must be exercised, however, as factors such as health status are important in determining the response of animals to contaminated diets.

When the same diets fed by Smith et al. (1997) were fed by Seddon et al. (1997, Table 3) at a different experimental location, no growth depression was seen.

Smith et al. (1997) also showed that the toxicity of a diet containing about 2.4 μg/g deoxynivalenol was increased with increasing levels of fusaric acid.

It was concluded that a toxicological synergism exists between fusaric acid and deoxynivalenol and that this explains the enhanced toxicity of a given concentration of deoxynivalenol when naturally contaminated grains are fed compared to an equivalent dose of purified toxin.


Table 2. Effect of feeding blends of Fusarium-contaminated grains on growth and feed intake of starter pigs.*



*From Smith et al., 1997.
†Values are means, n=36.
‡Values are means, n=12.
§mg compound/kg diet.
¶Standard deviation.
**Not significant, P>0.05.


Table 3.Effect of feeding blends of Fusarium-contaminated grains on growth and feed intake of starter pigs at the Arkell Research Station.*


*From Seddon et al., 1997.
†Values are means, n=24.
‡Values are means, n=6.
DON = deoxynivalenol.


New strategies for overcoming Fusarium mycotoxicoses

It is clear from the studies of Smith et al. (1997) and Bacon et al. (1996) that feeds suspected of contamination with Fusarium mycotoxins should be analyzed for fusaric acid in addition to more conventional metabolites.

The potential hazard posed by a given degree of deoxynivalenol contamination can only be accurately estimated if this information is available. Essential to our progress in this field will be the availability of rapid, accurate ELISA (enzyme-linked immunosorbent assay) tests similar to those now available for deoxynivalenol, T-2 toxin, fumonisin and zearalenone.

Dietary treatment of Fusarium mycotoxicoses has included the use of inorganic and organic polymers as inert binding agents to prevent intestinal absorption of mycotoxins. Silica-based polymers such as bentonite (Carson and Smith, 1983a) and even by-products such as spent canola oil bleaching clays (Smith, 1984) can effectively overcome trichothecene toxicoses in this manner.

Organic fibers such as those from alfalfa meal are equally efficacious (Carson and Smith, 1983b). The chemical structures of fusaric acid (Figure 4) and deoxynivalenol (Figure 1), however, differ greatly in their molecular weight and charge. It may be possible to design binding agents that are effective because they bind fusaric acid very efficiently while binding trichothecenes to a much lesser degree.

There are indications that this is possible in the report of Smith et al. (1997). This may reduce costs and levels of inclusion. New product development efforts need to be made in this direction.

Another potentially valuable dietary treatment may be based on the biochemical mechanism of action by which fusaric acid and deoxynivalenol elevate blood and brain tryptophan and subsequently brain serotonin.

One can reduce the mycotoxin-induced brain uptake of tryptophan by increasing blood concentrations of other large neutral amino acids that compete with tryptophan for active transport carriers across the blood-brain barrier (Cavan et al., 1988).

Feedstuffs rich in a combination of leucine, isoleucine, valine, tyrosine and phenylalanine are possibilities. Corn gluten meal and various blood products are examples. These possibilities should be tested, perhaps in combination with binding agents.

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