In addition to the mycotoxins discussed above, a number of other mycotoxins occur naturally. The impacts of some of these mycotoxins on human and animal health are discussed in the following sections.
Sterigmatocystin (ST) is a naturally occurring hepatotoxic and carcinogenic mycotoxin produced by fungi in the genera Aspergillus, Bipolaris, and Chaetomium as well as P. luteum [see Bhatnagar et al. (2002)]. Structurally related to AFB1 (Figure 5), ST is known to be a precursor of AFB1 (Bhatnagar
Figure 5 Structure of sterigmatocystin. The bis-furanyl structure is similar to that of the aflatoxins except that the E-ring is a substituted phenol.
Figure 5 Structure of sterigmatocystin. The bis-furanyl structure is similar to that of the aflatoxins except that the E-ring is a substituted phenol.
et al. 2003). Although the carcinogenicity of ST is less (10-100 times) than that of AFB1 in test animals (van der Watt 1977), ST is a mutagen and genotoxin and has been found in cereal grains (barley, rice, and corn), coffee beans, and cheese (Chu 2002). A. terreus and several other fungi (e.g., A. flavus and A. fumigatus and some Penicillia) have been found to produce the tremorgenic toxins, territrems, aflatrem, and fumitremorgin. These mycotoxins contain both the indole ring of tryptophan and a dioxopiperazine ring formed by condensation of two amino acids. A. terreus, A. fumigatus, and Trichoderma viride also produce gliotoxin, an epipolythiopiperazines -3,6-diones-sulfur containing piperazine antibiotic, that may have immunosuppressive effects in animals (Waring and Beaver 1996). In addition, A. flavus, A. wentii, A. oryzae, and P. atraovenetum are capable of producing nitropropionic acid (NPA), a mycotoxin causing apnea, convulsions, congestion in lungs and subcutaneous vessels, and liver damage in test animals (Burdock et al. 2001). Production of NPA in sugarcanes by Arthrinium sacchari, Arth. saccharicola, and Arth. phaeo-spermum has been found to be involved in fatal food poisoning in humans (Liu et al. 1988).
Other than OA, Penicillia produce many mycotoxins with diverse toxic effects. Cyclochlorotine, luteoskyrin (LS), and rugulosin (RS) have long been considered to be possibly involved in the yellow rice disease during the Second World War. They are hepatotoxins and also produce hepatomas in test animals. However, incidents of food contamination with these toxins have not been well documented. Several other mycotoxins, including patulin (PT, Figure 6), penicillic acid (PA, Figure 7), citrinin (CT), cyclopiazonic acid (CPA, Figure 8), citreoviridin, and xanthomegnin, which are produced primarily by several species of Penicillia, have attracted some attention because of their frequent occurrence in foods. PT and PA are produced by many species in the genera Aspergillus and Penicillium. Byssochlamys nivea also produces PT (Tournas 1994). Both toxins are hepatotoxic and teratogenic. Patulin is frequently found in damaged apples, apple juice, apple cider and sometimes in other fruit juices and feed. PA has been detected in "blue eye corn" beans and meat. Due to its highly reactive double bonds that readily react with sulfhydryl groups in foods, patulin is not very stable in foods containing these groups (Scott 1975). As a hepatotoxin but not known as a carcinogen, PT is considered a health hazard to humans (CAST 2003).
Frequently associated with the natural occurrence of OA, citrinin, also a nephrotoxin, is produced by P. citrinum and several other penicillia, aspergilli (Cole and Cox 1981) and Monocuus ruber and M. purpureus (Pastrana et al. 1996). The presence of citrinin in the diet with low quality corn could lead to chronic, hard to diagnose kidney disease in susceptible individuals and animals (CAST 2003). One of the mycotoxins closely associated with the natural occurrence of AF in peanuts is CPA, which causes hyperesthesia and convulsions as well as liver, spleen, pancreas, kidney, salivary gland, and myocardial damage (CAST 2003). CPA inhibits the calcium-dependent ATPase (Chu 2002; Petr et al. 1999). The toxin is produced by several species of the genus Penicillium, including P. cyclopium, P. crustosum, P. griseofulvin, P. puberulum, P. camemberti, and Aspergilli including A. versicolor, A. flavus but not by A. parasiticus and A. tamarii [in Bhatnagar et al. (2002)]. Other than peanuts, CPA has been found in corn, cheese and fermented meat sausage, and sometimes along with aflatoxin (Fernandez-Pinto et al. 2001; Lopez-Diaz et al. 2001).
Penicillium rubrum and P. purpurogenum produce two highly toxic hepatotoxins (LD50, 3.0mg/kg mice, IP) called rubratoxins A (RA, minor) and B (RB, major), which are complex nonadrides fused with anhydrides and lactone rings. Rubratoxin B has synergistic effects with AFB1 (CAST 2003). In addition, penicillia produce many neurotoxic mycotoxins. In many cases these mycotoxins do not cause noticeable toxicity, but in some cases have strong tremorgenic activity. Animals will also refuse food, and will have lowered resistance to disease. For example, P. crustosum and P. cyclopium produce tremorgenic indolediterpenes called penitrems A-F. Penitrem A, the major toxin in this group, causes tremorgenic effects in mice. Roquefortines A-C (C is
most toxic), which are produced by P. roqueforti and several other penicillia, have neurotoxic effects in animals and have been found in cheese. Tremorgens in the paspalitrem group (paspalicine, paspalinine, paspalitrem A and B, paspaline and paxilline) are produced by C. paspali and some penicillia (Plumlee and Galey 1994; Steyn 1995; Yamaguchi et al. 1993).
Some fusaria are capable of producing mycotoxins other than TCTCs and Fm. Zearalenone (ZE) (Figure 9) [6-(10-hydroxy-6-oxo-trans-1-undecenyl)-b(beta)-resorcyclic acid lactone], a mycotoxin produced by the scabby wheat fungus, F. graminearum (roseum), is of most concern. Also called F-2, ZE is a phytoestrogen causing hyperestrogenic effects and reproductive problems such as premature onset of puberty in female animals, especially swine. ZE has been shown to bind with the estrogen and steroid receptors, and stimulates protein synthesis by mimicking hormonal action (Zepnik et al. 2001). Zearalenone can be toxic to plants; it can inhibit seed germination and embryo growth at low concentrations. Natural contamination with ZE primarily occurs in cereal grains such as corn and wheat. Contamination of feed with ZE
in conjunction with DON may result in severe economic losses to the swine industry.
Fusarium verticillioides and related species, in addition to Fms, also produce several other mycotoxins, including fusarins A-F, moniliformin, fusarioic, and fusaric acid, fusaproliferin and beauvericin (CAST 2003; Chu 2002). Although the impact of these mycotoxins on human health is still not known, fusarin C (FC) has been identified as a potent mutagen and is also produced by F. subglutinans, F. graminearium and several other Fusaria. Moniliformin, which causes cardiomyopathy in test animals, may be involved in the Keshan disease in humans in regions where dietary selenium deficiency is also a problem (Liu 1996). In comparing their ability to form DNA-adducts, beauvericin forms a more stable complex with DNA than fusaproliferin (Pocsfalvi et al. 2000). Among many fungi, F. verticilioides is also most capable of reducing nitrates to form potent carcinogenic nitrosamines. These observations further suggest that the contamination of foods with this fungus could be one of the etiological factors involved in human carcinogenesis in certain regions of the world.
Alternaria has been known for centuries to cause various plant diseases. Species of this fungus are widely distributed in soil and on aerial plant parts. More than 20 species of Alternaria are known to produce about 70 secondary metabolites belonging to a diverse chemical group, including dibenzo-[a]-pyrones, tetramic acids, lactones, quinones, cyclic peptides. However, only alternariol (Figure 10), tenuazonic acid, altertoxin-I, alternariol monomethyl ether (AME), altenuene are common contaminants in consumable items like fruits (apples), vegetables (tomato), cereals (sorghum, barely, oat), and other plant parts (such as leaves) (Jelinek et al. 1989). Natural occurrence of isoaltenuene, altenuisol, altertoxins II and III (also called stemphyltoxin) are less common. The most common species of Alternaria, A. alternata (formerly known as A. kikuchiana) produces all important Alternaria toxins including the five mentioned above and tentoxin, alteniusol, alternaric acid, altenusin, dehydroaltenusin (Bottalico and Logrieco 1998; Chelkowski
1992). As mentioned previously, A. alternata f sp. lycopersici produces a group of host-specific toxins named AAL toxins with structure and functions similar to Fms. Although most of the compounds produced by Alternaria are generally nontoxic, AME has been shown to be mutagenic in Ames test (Woody and Chu 1992). Tenuazonic acid is a protein synthesis inhibitor and is capable of chelating metal ions and forming nitrosamines. This mycotoxin is also produced by Phoma sorghina and Pyricularia oryzae and may be related to "Onyalai," a hematological disorder in humans living south of the Sahara in Africa.
Sporidesmines, a group of hepatotoxins discovered in the 1960s, are also worthy of mention. These mycotoxins, causing facial eczema in animals, are produced by Pithomyces chartarum and Sporidesmium chartarum and are very important economically to the sheep industry. Slaframine, a significant mycotoxin produced by Rhizoctonia leguminicola (in infested legume forage crops), causes excessive salivation or slobbering in ruminants as a result of blocking acetylcholine receptor sites (CAST 2003).
4 PREVENTIVE MEASURES
The economic implications of the mycotoxin problem and its potential health threat to humans have clearly created a need to eliminate or at least minimize mycotoxin contamination of food and feed. While an association between mycotoxin contamination and inadequate storage conditions has long been recognized, studies have revealed that seeds are contaminated with mycotoxins prior to harvest (Lisker and Lillehoj 1991). Therefore, management of mycotoxin contamination in commodities must include both pre- and postharvest control measures (CAST 2003).
Mycotoxin contamination can be reduced somewhat by using of resistant varieties (most effective, but not all are successful) and earlier harvest varieties, crop rotation, adequate irrigation, control of insect pests, etc [reviewed in Bacon et al. (2001); Chen et al. (2002); Duvick (2001); Sinha and Bhatnagar (1998)]. Significant control of toxin contamination is expected to be dependent on a detailed understanding of the physiological and environmental factors that affect the biosynthesis of the toxin, the biology and ecology of the fungus, and the parameters of the host plant-fungal interactions. Efforts are underway to study these parameters primarily for the most agriculturally significant toxins, namely AFs, Fms, and TCTCs [reviewed in Brown et al. (1998); Duvick (2001); Sinha and Bhatnagar (1988)].
Use of atoxigenic biocompetitive, native A. flavus strains to out-compete the toxigenic isolates has been effective in significantly reducing preharvest contamination with afla-toxin in cotton and peanuts (Cotty and Bhatnagar 1994; Dorner et al. 1992). However, the aflatoxin contamination process is so complex (Payne 1998) that a combination of approaches will be required to eliminate or even control the preharvest toxin contamination problem (Bhatnagar et al. 1995).
After harvest, crop should not be allowed to overwinter in the field as well as subjected to bird and insect damage or mechanical damage. Grains should be cleaned and dried quickly to less than 10-13% moisture and stored in a clean area to avoid insect and rodent infestation (Trenholm et al. 1988). Postharvest mycotoxin contamination is prevalent in most tropical countries due to a hot, wet climate coupled with subadequate methods of harvesting, handling, and storage practices, which often lead to severe fungal growth and mycotoxin contamination of food and feed (Birzele et al. 2000; Phillips et al. 1994). Sometimes contaminated food has been diverted to animal feed to prevent economic losses and health concerns. However, this is not a solution to the contamination problem. Irradiation has been suggested as a possible means of controlling insect and microbial populations in stored food, and consequently, reducing the hazard of mycotoxin production under these conditions [reviewed in Sharma (1998)]. Significant emphasis has been placed on detoxification methods to eliminate the toxins from the contaminated lots or at least reduce the toxin hazards by bringing down the mycotoxin levels under the acceptable limits.
a. Removal or Elimination of Mycotoxins. Since most of the mycotoxin burden in contaminated commodities is localized to a relatively small number or seeds or kernels [reviewed in Dickens (1977)], removal of these contaminated seeds/kernels is effective in detoxifying the commodity. Methods currently used include: (a) physical separation by identification and removal of damaged seed; mechanical or electronic sorting; flotation and density separation of damaged or contaminated seed; physical screening and subsequent removal of damaged kernels by air blowing; washing with water or use of specific gravity methods have shown some effect for some mycotoxins, including DON, FmB, and AFB1 (Trenholm et al. 1992), (b) removal by filtration and adsorption onto filter pads, clays, activated charcoal, etc., (c) removal of the toxin by milling processes, (d) removal of the mycotoxin by solvent extraction (CAST 2003; DeVries et al. 2002).
b. Inactivation of Mycotoxins. When removal or elimination of mycotoxins is not possible, mycotoxins can be inactivated by (a) physical methods such as thermal inactivation, photochemical or gamma irradiation, (b)
chemical methods such a treatment of commodities with acids, alkalies, aldehydes, oxidizing agents, and gases like chlorine, sulfur dioxide, NaNO2, ozone and ammonia, (c) biological methods such as fermentations and enzymatic digestion that cause the breakdown of mycotoxins. The commercial application of some of these detoxifying mechanisms is not feasible because, in a number of cases, the methods will be limited by factors such as the toxicity of the detoxifying agent, nutritional or aesthetic losses of commodities during treatment, and the cost of the sophisticated treatment [reviewed in Sinha and Bhatnagar 1998]. Although several detoxification methods have been established for aflatoxins, only the ammoniation process is an effective and practical method (Piva et al. 1995). Other chemicals such as ozone, chlorine, and bisulfite have been tested and some effect for some mycotoxins was shown in it (Doyle et al. 1982). Solvent extractions have been shown to be effective but are not economically feasible.
c. Removal of Mycotoxins During Food Processing. While cooking generally does not destroy myco-toxins, some mycotoxins can be detoxified or removed by certain kinds of food processing. For example, extrusion cooking appears to be effective for detoxifying DON but not AFB. FmB1 can form Schiff's bases with reducing sugars such as fructose under certain conditions (Murphy et al. 1995) and lose its hepato-carcinogenicity (Liu et al. 2001); but the hydrolyzed FmB1 was found to be still toxic (Voss et al. 1996). Loss of FmB1 occurs during extrusion and baking of corn-base foods with sugars and nixtamalization (alkaline cooking) and rinsing in the preparation of tortilla chip and masa (Dombrink-Kurtzman et al. 2000; Voss et al. 2001). PT can be removed from apple juice by treatment with certain types of active carbons (Leggott et al. 2001). The effect of food processing on various mycotoxins has been recently reviewed by several authors in an ACS symposium (DeVries et al. 2002).
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