Fumonisins

3.3.1 General Considerations

Structure Fumonisins
Figure 3 Chemical structures of different classes of fumonisins. The R residue is 3-hydroxypidinium in fumonisins, B1-B3 while the others are tricarballyl esters.

Fumonisins (Fm) are a group of toxic metabolites produced primarily by F. verticillioides, F. proliferatum and other related species readily colonize corn all over the world (Dutton 1996; Jackson et al. 1996; Marasas 2001). Although F. anthophilum, F. nupiforme, and F. nygamai are capable of producing Fms, they are not commonly isolated from food and feed. Other related fusaria, including F. subglutinans, F. annulatum, F. succisae, and F. beomiforme, are not Fm producers (Nelson et al. 1993). More than 11 structurally related Fms (B1, B2, B3, B4, C1, C4, A1, A2, etc.), have been found since the discovery of FmB1 (diester of propane-1,2,3-tricarboxylic acid of 2 amino-12, 16-dimethyl-3,5,10,14,15-pentahydroxyicosane) in 1987 (Figure 3) [reviewed in Bhatnagar et al. (2002); Chu (2002)]. Several hydrolyzed derivatives of Fms, resulting from removal of the tricarballylic acid and other ester groups, have also been found in nature. Fumonisins are chemically similar in structure to toxins (AAL) produced by A. alternata. Production of furnonisins by Alternaria has also been reported, and some fumonisin-producing Fusaria have been known to produce AAL toxins.

Fumonisins are most frequently found in corn, corn-based foods, and other grains (such as sorghum and rice) but peanuts and soybeans are poor substrate. The level of contamination varies considerably with different regions and year, ranging from negligible to more than 100 ppm; but is generally reported to be between 1 and 2 ppm. FmB1 is the most common Fm in naturally contaminated samples; FmB2 generally accounts for 1/3 or less of the total. Although production of the toxin generally occurs in the field, continued production of toxin during postharvest storage also contributes to the overall levels. (Chu 2001; 2002; 2001 May issues of Environmental Health Prospective, Vol. 109).

The biosynthesis of the 20-carbon chain backbone of Fms resembles those for fatty acids and linear polyketides [reviewed in Desjardins et al. 1996; Proctor 2000). Five loci (designated as fum 1, fum 2, fum 3, and fum 4 and fum 5) have been identified by classical genetic analyses utilizing Gibberella fuijikuroi, the sexual stage of F. monififorme (Proctor 2000). At least 15 genes are associated with the fumonisin production and these genes are clustered together on chromosone "1" (Proctor 2000; Xu and Leslie 1996) including apolyketide synthase gene (fum5). Gene Fum2 and Fum3 are associated with the interconversion of different fumonisins (Proctor 2000).

3.3.2 Toxicologic Effects

Fumonisin B1 is primarily a hepatotoxin and carcinogen in rats (Class 2B carcinogen). Feeding culture material from

F. verticillioides or pure FmB1 to rats resulted in cirrhosis and hepatic nodules, adenofibrosis, hepatocellular carcinoma-ductular carcinoma, and cholangiocarcinoma (Gelderblom et al. 2001; Haschek et al. 2001). Kidney is also a target organ, and tubular nephrosis was found both in rats and in horses of field cases associated with equine leukoencephalomalacia (ELEM). In addition to FmB1, which was originally found to be a potent cancer-causing agent, FmB2 and FmB3 have also been found to be carcinogens and have cancer initiation and promoting activities in rats. The effective dose of FmB1 for cancer initiation in rat liver depends both on the levels and on the duration of exposure. In cell culture systems, FmB1 has been demonstrated to be mitogenic and cytotoxic, without genotoxic effects (Gelderblom et al. 2001). Kidney cells have also been shown to be targeted by these toxins.

Fumonisin B1 was identified as an etiological agent responsible for ELEM in horses and other Equidae (donkeys and ponies) and for porcine pulmonary edema (PPE) [Jackson et al. 1996; reviewed in Summerell et al. (2001)]. ELEM is characterized primarily by neurotoxic effects, including uncoordinated movements and apparent blindness showing as violent blundering into stalls and walls. The levels of FmB1 and FmB2 in feeds associated with confirmed cases of ELEM ranged from 1.3 to 27 ppm. In pigs, PPE occurs only at high FmB levels (175 ppm), while liver damage occurs at much lower concentrations with a NOAEL of < 12 ppm. FmB1 resulting in left-sided heart failure alters cardiovascular function. In the cattle, renal injury, hepatic lesions, and alteration of sphingolipid in various organs was observed (Haschek et al. 2001). Similar to AAL toxin, Fms are also

•H

Trichothecenes

R1

R2

R3

R4

R5

Diacetoxyscirpenol

OH

OAc'

OAc

H

H

4-M o n oac eto xy s c írpen o 1

OH

OAc

OH

H

H

15-Monoacetoxyscirpenola

OH

OH

OAc

H

H

Scirperuriol

OH

OH

OH

H

H

Deoxymvalenol

OH

H

OH

OH

=0

Nivalenol

OH

OH

OH

OH

=0

Plisare non-x

OH

OAc

OH

OH

=0

T-2

OH

OAc

OAc

H

ISV2

HT-2

OH

OH

OAc

H

ISV

T-2 triol

OH

OH

OH

H

ISV

3-OH-T-2

OH

OAc

OAc

H

OH-ISV-

T-2 tetrao 1

OH

OH

OH

H

OH

Neosolaniol

OH

OAc

OAc

H

OH

Roridin A,B,E>H,J

H

MCa

MC

H

H

Roridin K

H

MC

MC

H

OH

Verrucarin A,B,J,K

H

MC

MC

H

H

Vemicarin L

H

MC

MC

H

OH

Satratoxin F,G,H

H

MC

MC

H

H

Verrucarol

H

OH

OH

H

H

Macrocytic OAc OCOCH, ISV

__ OCOCH2CH(CH3)2

3 OH-ISV OCOCH2C(OH)(CH3)2

Figure 4 Chemical structure of different trichothecenes. MC = Macrocyclic; ISV = isovalerate; OH-ISV = hydroxyisovalerate.

toxic to some plants such as, jimsonweed, black nightshade, duckweed, and tomatoes (Abbas and Riley 1996).

3.3.3 Mode of Action

Mechanistically, Fms are inhibitors of ceramide synthase (sphinganine/sphingosine N-acyltransferase), a key enzyme involved in the biosynthesis of sphingolipids, which are heavily involved in cellular regulation, including cell differentiation, mitogenesis and apoptosis (Merrill et al. 2001; Riley et al. 2001). The primary amino group of Fms is essential for its inhibitory and toxic effects (Norred et al. 2001). The inhibitory effect of Fms on ceramide synthase appears to be related to interference with sphingolipid biosynthesis in multiple organs, such as brain, lung, liver, and kidney of the susceptible animals (Garren et al. 2001). Increased lipid peroxidation has also been considered as a mode for its effect on initiation of cancer (Gelderblom et al. 2001). The mode of action of FmB becomes more clear from recent data of its effects on apoptosis (Zhang et al. 2001) and the tumor necrosis factor (TNF) pathway is important in inducing tumors (He et al. 2001; Zhang et al. 2001; Sharma et al. 2001), but the tumor suppressor gene p53 was not required (Jones et al. 2001). The ability of FmB1 to alter gene expression and signal transduction pathways are considered necessary for its carcinogenic and toxic effects. FmB1 is a good example of an apparently nongenotoxic (non-DNA reactive) agent producing tumors through the regulation of apoptosis (Dragan et al. 2001).

3.3.4 Impact on Human and Animal Health

While Fms are commonly detected in corn-based foods and feeds, the impact of low levels of Fms in human foods is not clear. Although several reports have indicated a possible role of FmB1 in the etiology of human esophageal cancer in the regions of South Africa, China, and northeastern Italy where Fusarium species are common contaminants, more data are necessary to sustain this hypothesis (Groves et al. 1999). The co-occurrence of Fms with carcinogenic mycoroxins such as AFB (da-Silva et al. 2000; Vargas et al. 2001) or nitrosamines may play an important role in carcinogenesis in humans. Current data suggest that Fms may have greater effect on the health of farm animals than on humans [Bhatnagar et al. (2002) for review].

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