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Toxins, Mycotoxins, Endotoxins, Fusariotoxin


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Information on Toxins Mycotoxins Endotoxins Fusariotoxin

Fungi are ubiquitous to the environment and primarily saprophytic, using nonliving organic material as a nutrient source for growth and reproduction. Many of these saprophytes can colonize organic water-damaged building materials. During the digestion process fungi secrete enzymes into the nutrient source to break down complex compounds into simpler compounds, which are taken up by the fungi and digested. The digested nutrients are classified into two categories, primary and secondary metabolites. The primary metabolites consist of cellulose and other compounds that are used for energy to grow and reproduce. The secondary metabolites, called mycotoxins, are produced to give fungi a competitive edge against other microorganisms, including other fungi. There are over 200 recognized mycotoxins, however, the study of mycotoxins and their health effects on humans is in its infancy and many more are waiting to be discovered. Many mycotoxins are harmful to humans and animals when inhaled, ingested or brought into contact with human skin. Mycotoxins can cause a variety of short term as well as long-term health effects, ranging from immediate toxic response to potential long-term carcinogenic and teratogenic effects. Symptoms due to exposure to mycotoxins include dermatitis, cold and flu symptoms, sore throat, headache, fatigue, diarrhea, and impaired or altered immune function, which may lead to opportunistic infection. Historically, mycotoxins have been a persistent problem to farmers and the animal husbandry industry in Eastern Europe and developing countries. Recently, however, research has implicated many toxin-producing fungi, such as Stachybotrys, Penicillium, Aspergillus and Fusarium species, to indoor air quality problems and building related illnesses. Inhalation of mycotoxin producing fungi in contaminated buildings is the most significant exposure, however, dermal contact from handling contaminated materials and the chance of ingesting toxin containing spores through eating, drinking and smoking is likely to increase exposure in a contaminated environment. Recent advances in technology have given laboratories the ability to test for specific mycotoxins without employing cost-prohibitive gas chromatography or high performance liquid chromatography techniques. Currently, surface, bulk, food and feeds, and air samples can be analyzed relatively inexpensively for the following mycotoxins:

Mold growth on walls and under carpet.

Aflatoxin

Aflatoxin is one of the most potent carcinogens known to man and has been linked to a wide variety of human health problems. The FDA has established maximum allowable levels of total aflatoxin in food commodities at 20 parts per billion. The maximum level for milk products is even lower at 0.5 parts per billion. Primarily Aspergillus species fungi produce aflatoxin.

Ochratoxin

Ochratoxin is primarily produced by species of Penicillium and Aspergillus. Ochratoxin is damaging to the kidneys and liver and is also a suspected carcinogen. There is also evidence that it impairs the immune system.

T-2 Toxin

T-2 Toxin is a tricothecene produced by species of Fusarium and is one of the more deadly toxins. If ingested in sufficient quantity, T-2 toxin can severely damage the entire digestive tract and cause rapid death due to internal hemorrhage. T-2 has been implicated in the human diseases alimentary toxic aleukia and pulmonary hemosiderosis. Damage caused by T-2 toxin is often permanent.

Fumonisin

Fumonisin is a toxin associated with species of Fusarium. Fumonisin is commonly found in corn and corn-based products, with recent outbreaks of veterinary mycotoxicosis occurring in Arizona, Indiana, Kentucky, North Carolina, South Carolina, Texas and Virginia. The animals most affected were horses and swine, resulting in dozens of deaths. Fumonisin toxin causes "crazy horse disease", or leukoencephalomalcia, a liquefaction of the brain. Symptoms include blindness, head butting and pressing, constant circling and ataxia, followed by death. Chronic low-level exposure in humans has been linked to esophageal cancer. The American Association of Veterinary Laboratory Diagnosticians (AAVLD) advisory levels for fumonisin in horse feed is 5 PPM.

Vomitoxin or Deoxynivalenol (DON)

Vomitoxin, chemically known as Deoxynivalenol, a tricothecene mycotoxin, is produced by several species of Fusarium. Vomitoxin has been associated with outbreaks of acute gastrointestinal illness in humans. The FDA advisory level for vomitoxin for human consumption is 1ppm.

Zearalenone

Zearalenone is also a mycotoxin produced by Fusarium molds. Zearalenone toxin is similar in chemical structure to the female sex hormone estrogen and targets the reproductive organs.


Other mycotoxins of clinical significance are as follows:


Citrinin

Citrinin is a nephrotoxin produced by Penicillium and Aspergillus species. Renal damage, vasodilatation, and bronchial constriction are some of the health effects associated with this toxin.

Alternariol

Alternariol cytotoxic compound derived from Alternaria alternata

Satratoxin H

Satratoxin H is a macrocyclic tricothecene produced by Stachybotrys chartarum, Trichoderma viridi and other fungi. High doses or chronic low doses are lethal. This toxin is abortogenic in animals and is believed to alter immune system function and makes affected individuals more susceptible to opportunistic infection.

Gliotoxin

Gliotoxin is an immunosuppressive toxin produced by species of Alternaria, Penicillium and Aspergillus.

Patulin

Patulin is a mycotoxin produced by Penicillium, Aspergillus and a number of other genera of fungi. It is believed to cause hemorrhaging in the brain and lungs and is usually associated with apple and grape spoilage.

Sterigmatocystin

Sterigmatocystin is a nephrotoxin and a hepatotoxin produced by Aspergillus versicolor. This toxin is also considered to be carcinogenic. Other mycotoxins include - Penicillic acid, roquefortine, cyclopiazonic acid, verrucosidin, rubratoxins A and B, PR toxin, luteoskyrin, cychlochlorotine, rugulosin, erythroskyrine, secalonic acid D, viridicatumtoxin, kojic acid, xanthomegnin, viomellein, chaetoglobosin C, echinulin, flavoglaucin, versicolorin A, austamide, maltoyzine, aspergillic acid, paspaline, aflatrem, fumagillin nigragillin chlamydosporol, isotrichodermin and many more. As discussed there are many mycotoxins that can cause adverse health effects and even death in humans. The synergistic effect of exposure to multiple mycotoxins simultaneously is very poorly understood. Even more poorly understood are the by-products of mycotoxin degradation, particularly under the influence of strong oxidizing agents such as sodium hypochlorite and/or ozone, agents frequently used or misused by remediation personnel in the industry. More research is required in this field to better understand the relationship of fungal contamination, mycotoxin production on building substrates and building related disease.

Endotoxins

Endotoxin is the name given to a group of heat stabile lipopolysaccharide molecules present in the cell walls of gram-negative bacteria that have a certain characteristic toxic effect. The lipid portion of each molecule is responsible for its toxicity and can vary between bacterial species and even from cell to cell. When inhaled, endotoxin creates an inflammatory response in humans that may result in fever, malaise, alterations in white blood cell counts, headache, respiratory distress and even death. It is common to the environment due to the ubiquitous nature of Gram-negative bacteria. Exposure to elevated levels of endotoxin primarily occurs through exposure to aerosols from specific reservoirs such as cotton mills, wastewater treatment facilities, air washers, humidifiers and any other occupational settings where Gram-negative bacteria can flourish.

Mycotoxins

In addition to their roles as irritants and allergens, many fungi produce toxic chemical constituents (Kendrick, 1992; Miller, 1992; Wyllie and Morehouse, 1977). Samson and co-workers (1996) defined mycotoxins as "fungal secondary metabolites that in small concentrations are toxic to vertebrates and other animals when introduced via anatural route". These compounds are non-volatile and may be sequestered in spores and vegetative mycelium or secreted into the growth substrate. The mechanism of toxicity of many mycotoxins involves interference with various aspects of cell metabolism, producing neurotoxic, carcinogenic or teratogenic effects (Rylander, 1999). Other toxic fungal metabolites such as the cyclosporins exert potent and specific toxicity on the cellular immune system (Hawksworth et al., 1995); however, most mycotoxins are known to possess immunosuppressant properties that vary according to the compound (Flannigan and Miller, 1994). Indeed, the toxicity of certain fungal metabolites such as aflatoxin, ranks them among the most potently toxic, immunosuppressive and carcinogenic substances known (ibid.). There is unambiguous evidence that ingestion exposure as well as exposures by the inhalation pathway have been correlated with outbreaks of human and animal mycotoxicoses (Abdel-Hafez and Shoreit, 1985; Burg et al., 1982; Croft et al., 1986; Hintikka, 1978; Jarvis, 1986; Norbäck et al., 1990; Sorenson et al., 1987; Schiefer, 1986). Several common mycotoxigenic indoor fungi and their respective toxins are listed.

Volatile Fungal Metabolites

During exponential growth, many fungi release low molecular weight, volatile organic compounds (VOCs) as products of secondary metabolism. These compounds comprise a great diversity of chemical structure, including ketones, aldehydes and alcohols as well as moderately to highly modified aromatics and aliphatics. Cultural studies of some common household molds suggest that the composition of VOCs remains qualitatively stable over a range of growth media and conditions (Sunesson et al., 1995). Furthermore, the presence of certain marker compounds common to multiple species, such as 3-methylfuran, may be monitored as a proxy for the presence of a fungal amplifier (Sunesson et al., 1995). This method has been suggested as a means of monitoring fungal contamination in grain storage facilities (Börjesson et al., 1989; 1990; 1992; 1993). Limited evidence suggests that exposure to low concentrations of VOCs may induce respiratory irritation independent of exposure to allergenic particulate (Koren et al., 1992). Volatile organic compounds may also arise through indirect metabolic effects. A well-known example of this is the fungal degradation of urea formaldehyde foam insulation. Fungal colonization of this material results in the cleavage of urea from the polymer, presumably to serve as a carbon or nitrogen source for primary metabolism. During this process formaldehyde is evolved as a derivative, contributing to a decline in IAQ (Bissett, 1987).

Objectives of the current study

The present study was conceived with two primary objectives. First, this investigation shall characterize the fungal biodiversity of house dust. This work shall investigate correlations between dustborne fungal species, and examine the ecological similar of positively associated taxa based on the hypothesis that positively associated dustborne fungi are likely to share habitat characteristics. From this, a second hypothesis follows that mechanisms that permit the entry or concentration a given species will tend to facilitate the entry of other positively correlated taxa. A second objective of this research if to assess the extent of genotypic variability in two dustborne Penicillia, P. brevicompactum and P. chrysogenum. The goal of this work shall be to examine the extent of clonality within these two species, and to determine if the observed patterns of genotypic variation support the current species concepts.

Mycotoxins of significance produced by indoor fungi

Mycotoxin Primary health effect Fungal producers

Aflatoxins Carcinogens, hepatotoxins Aspergillus flavus, As. parasiticus

Citrinin Nephrotoxin Penicillium citrinum, Pe. verrucosum

Cyclosporin Immunosuppressant Tolypocladium inflatum

Fumonisins Carcinogens, neurotoxins Fusarium moniliforme,

F. proliferatum

Ochratoxin A Carcinogen As. Ochraceus, Pe. verrucosum

Patulin Protein synthesis inhibitor, As. Terreus

nephrotoxin Paecilomyces variotii

Pe. expansum

Pe. griseofulvum

Pe. roquefortii

Sterigmatocystin Carcinogen, hepatotoxin As. nidulans

As versicolor

Chaetomium spp.

Trichothecenes Macrocyclic

Satratoxins Protein synthesis inhibitors Stachybotrys chartarum

Myrothecium spp.

Trichothecenes, Non-Macrocyclic

Deoxynivalenol Emetic F. cerealis

(vomitoxin) F. culmorum

F. graminearum

T-2 toxin Hemorrhagic, emetic F. sporotrichioides

carcinogen

Verrucosidin Neurotoxin Pe. aurantiogriseum group

Xanthomegnin Hepatotoxin, nephrotoxin As. ochraceus

Pe. aurantiogriseum group

Zeralenone Estrogenic Fusarium spp.

SOURCES: Burge and Ammann (1999); Rodricks et al. (1977); Samson et al. (1996)

Fusarium Mycotoxins

"The genus Fusarium contains important mycotoxin-producing species that have been implicated in human diseases, such as alimentary toxic aleukia, Urov or Kashin-Beck disease, Akakabi-byo or scabby grain intoxication, and esophageal cancer. Many of these mycotoxin-producing species have also been implicated in several animal diseases, including hemorrhagic, estrogenic, emetic, and feed refusal syndromes, fescue foot, degnala disease, moldy sweet potato toxicosis, bean hulls poisoning, and equine leukoencephalomalacia. The interest in toxigenic Fusarium species is increasing world-wide due to the discovery of a growing number of naturally occurring Fusarium mycotoxins that have practical importance as threats to human and animal health," from Toxigenic Fusarium Species by Marasas et alia, Penn State U, 1984. Chemical Names of Fusarium Mycotoxins from Marasas et al. and other sources (Toxigenic Fusarium Species by Marasas et alia, Penn State U, 1984). Some of the names are redundant, and some are the result of research in different countries where two or more names have been given to the same compound, a common phenomenon in science.

4-Acetoxyscirpenediol

monodeacetylanguidin.

3-Acetyldeoxynivalenol

8-Acetylneosolaniol

4- or 15-Acetylscirpentriol

Acetyl T-2 toxin

Anguidin.

Avenacein +1

Beauvericin +2

Butenolide

Calonectrin

15-Deacetylcalonectrin

Deoxynivalenol

Deoxynivalenol diacetate

Deoxynivalenol monoacetate

Diacetoxyscirpendiol

Diacetoxyscirpenol

Diacetoxyscerpentriol

Diacetyldeoxynivalenol

Diacetylnivalenol

Dihydroxydiacetoxyscirpenol

Enniatins+1

Fructigenin +1

Fusarenon.

Fusarenon-X

Fusaric acid

Fusarinic acid

F-2. See Zearalenone

HT-2 toxin.

7"-Hydroxydiacetoxyscirpenol

1,4-Ipomeadiol

Ipomeanine

1-Ipomeanol

4-lpomeanol

Lateritin +1

Lycomarasmin +1

Moniliformin

Monoacetoxyscirpenol

Monoacetylnivalenol X

Monodeacetylanguidin.

Neosolaniol

Neosolaniolacetate

Neosolaniol monoacetate.

Nivalenol

Nivalenol diacetate

Nivalenol monoacetate

NT-1 toxin

NT-2 toxin

Rd toxin

Sambucynin +1

Scirpentriol

Solaniol

T-1 toxin

T-2 toxin

Triacetoxyscirpendiol

Triacetoxyscirpenol

Vomitoxin

Yavanicin +1

Zearalenol

Zearalenone

Mycotoxins reported from Fusarium oxysporum:

Diacetoxyscirpenol

Diacetylnivalenol

Fumonisin B1

Fusarenon-X

Fusaric acid

Moniliformin

Neosolaniol

T-2 Toxin

Zearalenone

Additional Mycotoxins

Fusarium Mycotoxins

Fusarium oxyspurum mycotoxins

Chemistry & Toxicology of the Fusarium mycotoxins

Mycotoxins in general

Mycotoxins are the toxic chemicals produced by fungi for a variety of reasons. These include to attack or gain access to hosts by helping to dissolve cell membranes, or as protective measures against encroaching organisms. The production of mycotoxins within the fungus depends on food sources and the particular enzymes of the fungus and other environmental factors. Mycotoxins are usually not found in spores, but are generally produced in the next stage, that of mycelium. Many mycotoxins, such as Mycotoxin T2 (Fusariotoxin) or the Amanita-toxins can be lethal to animals. Others, such as Psilocybin, are entheogenic, producing altered states of consciousness that are usually associated with shamanism/religion. Others, such as the ergot derivatives are used for migraine and post-partum hemorrhage. Still others, such as penicillin, Fusaric acid, and Wortmannin have antibiotic effects, and Zearalenone with anabolic effects, but which may or may not be beneficial to the host organism depending on the mode of administration and dose. By definition, only mycotoxin-producing fungi can be used as mycoherbicides to attack, colonize and kill plants.

The most-studied mycotoxins in Fusarium are toxic to both plants and animals. Some have antibiotic properties. The mycotoxins of Pleospora have yet to be identified, but we know from reports in the lab where it is being researched that it has toxic effects on humans. After over a decade of work on EN-4 (a "coca-killing" strain of Fusarium oxysporum forma specialis erythroxyli), the USDA has neglected to examine strain EN-4 mycotoxins. And by ignoring this research, an ARS spokesperson was still able to repeat the written USDA "talking points" mantra which state that EN-4 does not produce or contain mycotoxins dangerous to animals or humans to various members of the press. This claim is disavowed by her superiors, such as Eric Rosenquist, who candidly offers that the work on the safety of EN-4 as a mycoherbicide, including tests on its mycotoxins--have yet to be done.

In the absence of hard data on mycotoxins present in the Fusarium oxysporum and Pleospora papaveraceae strains being considered for use as mycoherbicides, we can only speculate on what these strains may contain. We also must caution the reader that fungi can produce different toxins and varying amounts of toxins depending on which media they are growing on, humidity, temperature, and light, among other variables. Even the USDA has published on this phenomenon: "Cultures of F. proliferatum established from these samples produced fumonisins when cultured on rice. They also produced other toxins, including moniliformin and beauvericin, which were not found in naturally-infected field samples of rice. It is not known why moniliformin and beauvericin were not found in field samples. There may be mechanisms by which viable rice kernels suppress synthesis of moniliformin and beauvericin by F. proliferatum, that are not operative in autoclaved rice cultures. A better understanding of the mechanisms by which mycotoxin production is controlled in Fusarium sp. may lead to methods to control these compounds in food and feed.". USDA has yet to persue this research.

However, here, for comparison's sake and taking the aforementioned caveats about the variability of Fusaria into consideration, we may examine the series of mycotoxins that have been already isolated from Fusarium oxysporum and other Fusarium species.

Chemistry and toxicology of the Fusaria mycotoxins:

The mycotoxins produced by Fusarium species are structurally quite varied. Often, there is a series of closely related compounds which can be identified as a group, such as the Trichothecenes which lack nitrogen in their structure and Fumonisins and Lycomarasmins, which posses amine functions. Rather than approach this field by chemical category or structure, we shall resort to an alphabetical listing of the compounds by their most-used common names, as registered in the Merck Index, Twelfth Edition, which we will quote extensively here.

Fusarium mycotoxins may leach into the soil, causing damage to plants and animals through leaching even after the fungus is no longer active. Indeed, a very real risk may be extrapolated for humans, also.

Trichothecene Mycotoxins

Trichothecene mycotoxins are produced by fungi (e.g., Fusaria, Trichoderma, Myrothecium, Stachybotrys); 60 are known. These were originally isolated as possible antifungal microbials or as antiplant agents. Analysis of trichothecene (and aflatoxin) exposures is complicated by their natural occurrence: Their presence alone does not prove a biological attack.

Iraq has admitted to possessing trichothecene mycotoxins and testing them in animals and has been accused of using them against Iran (UNSCOM, 1991, 1992, 1995; Zilinskas, 1997; Heyndrickx, 1984). The report of Iraqi possession of trichothecenes followed a considerable period of interest, attention, and controversy about their use in Southeast Asia (between 1974 and 1981, against Lao and Khmer populations by communist forces) and in Afghanistan (by Soviet forces) (Crocker, 1984; Haig, 1982; Schultz, 1982; Seagrave, 1981). Wannemacher and Wiener (1997), concluded that the Soviets and their clients have used trichothecenes, and the authors present a detailed review of the history of the subject and associated controversy. There may have been shortcomings in the epidemiological approaches (Hu et al., 1989). There were also many difficulties and inconsistencies in agent sampling, transport, and analysis.

These toxins, until discovered in Southeast Asian attack environments, had not been on the usual lists of potential toxin weapons (SIPRI, 1973). Analysts recognized that the toxins could produce the injuries encountered (Watson, Mirocha, and Hayes, 1984). Subsequent research identified properties of military significance, e.g., skin injury from nanogram amounts; eye injuries from micrograms; and serious central nervous system, respiratory, gastrointestinal, and hematological toxicity via multiple routes of exposure (Watson, Mirocha, and Hayes, 1984; Bunner et al., 1985; and Wannemacher and Wiener, 1997).

History

These mycotoxins have been poisoning people and animals for a long time. They grow well at low temperatures and frequently contaminate grain and other foodstuffs. They have been implicated in foodborne illnesses on several continents (Ueno et al., 1984). A large disease outbreak in the Soviet Union during World War II, which involved thousands and had high mortality, was eventually traced to the consumption of grain contaminated by Fusaria molds, which had been left in the fields over the winter. The disease, alimentary toxic aleukia, resembled a severe radiation injury with nausea, vomiting, diarrhea, leukopenia, hemorrhagic diathesis, and sepsis.

These toxins are also hazardous via other routes. Domestic animals and farmers manifested skin and respiratory irritation and systemic malaise from exposure to contaminated dusts and hay. Human illnesses have arisen from trichothecene mycotoxin contamination of houses and ventilation systems, resulting in so-called "sick building" syndrome (Croft et al., 1986; Jarvis, 1985; Smoragiewicz et al., 1993). One family so exposed was affected with nonspecific symptoms whose cause was not identified for months (Myrothecium and Stachybotrys were identified). For a time, several trichothecene mycotoxins were tested as anticancer agents in clinical trials (Thigpen et al., 1981; Bukowski et al., 1982; Yap et al., 1979; Diggs et al., 1978; Murphy et al., 1978; Goodwin et al., 1981). Some laboratory accidents have added to experience with human exposure (Wannemacher and Wiener, 1997). In addition, there is considerable information on the effects of trichothecene mycotoxins on economically important animals (Ueno et al., 1984).

Reports of communist attacks on Lao tribal people, and later on the Khmer, began in 1974 with aircraft and helicopter delivery of colored smokes, dusts, and droplets. People near these attacks had signs and symptoms that did not resemble known chemical warfare agents. Later similar attacks were reported in Cambodia and Afghanistan. Symptoms included vomiting, dizziness, seizures, hematemesis, respiratory distress, hypotension, and blisters. Survivors were ill for a long time with rashes, joint pains, fatigue, and memory problems (Haig, 1982; Schultz, 1982; Crossland and Townsend, 1984).

Investigative teams in refugee camps were puzzled, identifying a toxic epidermolysis without other expected findings from known chemical agents (House, 1979), but intelligence analysts recognized the similarities to trichothecene intoxication. Later, clinical examinations, autopsies, laboratory tests, and tissue samples showed trichothecene mycotoxins (and a propylene-glycol carrier) together with tissue damage compatible with trichothecene effects (Crocker, 1984; Watson, Mirocha, and Hayes, 1984; Rosen and Rosen, 1982; Stahl et al., 1985).

Chinese analysts attributed a higher toxicity to trichothecene mycotoxins than to nerve agents. They alleged that, between 1975 and 1982, 6,000 Laotians; 1,000 Cambodians; and 3,000 Afghans had died from attacks with what came to be known as "yellow rain" (Fang, 1983).

During the Iran-Iraq War, especially in the fighting around Majoon Island, colored smokes and powders were used against Iranian forces, perhaps reflecting combinations of agents. Although controversial in the scientific community, Heyndrickx (1984) found trichothecene mycotoxins in Iranian casualties who appeared to have sustained mustard injuries. Although other laboratories did not confirm these findings from the same material, Professor Heyndrickx argued that biological tissues had degraded the toxin over time. [7]


 

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