Mycotoxins J. W. 1* and M. Klich2

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Clin Microbiol Rev. 2003 July; 16(3): 497–516.

doi: 10.1128/CMR.16.3.497-516.2003.

American Society for Microbiology

Mycotoxins

http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=164220

J. W. 1* and M. Klich2

Department of Cell and Molecular Biology, Tulane University, New

Orleans, Louisiana 70118,1 Agricultural Research Service, Southern

Regional Research Center, New Orleans, Louisiana 701242

*Corresponding author. Mailing address: Department of Cell and

Molecular Biology, Tulane University, New Orleans, LA 70118. Phone:

(504) 788-8101. Fax: (504) 788-8765. E-mail: jbennett@....

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Top Abstract

Mycotoxins are secondary metabolites produced by microfungi that are

capable of causing disease and death in humans and other animals.

Because of their pharmacological activity, some mycotoxins or

mycotoxin derivatives have found use as antibiotics, growth

promotants, and other kinds of drugs; still others have been

implicated as chemical warfare agents. This review focuses on the

most important ones associated with human and veterinary diseases,

including aflatoxin, citrinin, ergot akaloids, fumonisins,

ochratoxin A, patulin, trichothecenes, and zearalenone.

Mycoses and Mycotoxicoses

Fungi are major plant and insect pathogens, but they are not nearly

as important as agents of disease in vertebrates, i.e., the number

of medically important fungi is relatively low. growth of

fungi on animal hosts produces the diseases collectively called

mycoses, while dietary, respiratory, dermal, and other exposures to

toxic fungal metabolites produce the diseases collectively called

mycotoxicoses.

Mycoses range from merely annoying (e.g., athlete's foot) to life-

threatening (e.g., invasive aspergillosis). The fungi that cause

mycoses can be divided into two categories, primary pathogens (e.g.,

Coccidioides immitis and Histoplasma capsulatum) and opportunistic

pathogens (e.g., Aspergillus fumigatus and Candida albicans).

Primary pathogens affect otherwise healthy individuals with normal

immune systems. Opportunistic pathogens produce illness by taking

advantage of debilitated or immunocompromised hosts. The majority of

human mycoses are caused by opportunistic fungi (149, 172, 245,

265). The mechanisms of pathogenesis of both primary and

opportunistic fungi are complex, and medical mycologists have

devoted considerable research energy trying to identify the factors

that distinguish fungal pathogens from saprophytic and commensal

species (31, 66). Some infections remain localized, while others

progress to systemic infection. For many mycoses, the ordinary

portal of entry is through the pulmonary tract, but direct

inoculation through skin contact is not uncommon.

In contrast to mycoses, mycotoxicoses are examples of " poisoning by

natural means " and thus are analogous to the pathologies caused by

exposure to pesticides or heavy metal residues. The symptoms of a

mycotoxicosis depend on the type of mycotoxin; the amount and

duration of the exposure; the age, health, and sex of the exposed

individual; and many poorly understood synergistic effects involving

genetics, dietary status, and interactions with other toxic insults.

Thus, the severity of mycotoxin poisoning can be compounded by

factors such as vitamin deficiency, caloric deprivation, alcohol

abuse, and infectious disease status. In turn, mycotoxicoses can

heighten vulnerability to microbial diseases, worsen the effects of

malnutrition, and interact synergistically with other toxins.

The number of people affected by mycoses and mycotoxicoses is

unknown. Although the total number affected is believed to be

smaller than the number afflicted with bacterial, protozoan, and

viral infections, fungal diseases are nevertheless a serious

international health problem. Mycoses caused by opportunistic

pathogens are largely diseases of the developed world, usually

occurring in patients whose immune systems have been compromised by

advanced medical treatment. Mycotoxicoses, in contrast, are more

common in underdeveloped nations. One of the characteristics shared

by mycoses and mycotoxicoses is that neither category of illness is

generally communicable from person to person.

Mycoses are frequently acquired via inhalation of spores from an

environmental reservoir or by unusual growth of a commensal species

that is normally resident on human skin or the gastrointestinal

tract. These commensal species become pathogenic in the presence of

antibacterial, chemotherapeutic, or immunosuppressant drugs, human

immunodeficiency virus infection, in-dwelling catheters, and other

predisposing factors (31, 66). The majority of mycotoxicoses, on the

other hand, result from eating contaminated foods. Skin contact with

mold-infested substrates and inhalation of spore-borne toxins are

also important sources of exposure. Except for supportive therapy

(e.g., diet, hydration), there are almost no treatments for

mycotoxin exposure, although Fink-Gremmels (80) described a few

methods for veterinary management of mycotoxicoses, and there is

some evidence that some strains of Lactobacillus effectively bind

dietary mycotoxins (72, 73). Oltipraz, a drug originally used to

treat schistosomiasis, has been tested in Chinese populations

environmentally exposed to aflatoxin (111).

In plant pathology, many secondary metabolites produced by bacteria

and fungi are pathogenicity or virulence factors, i.e., they play a

role in causing or exacerbating the plant disease. The phytotoxins

made by fungal pathogens of Cochliobolus (Helminthosporium) and

Alternaria, for example, have well-established roles in disease

development (287), and several mycotoxins made by Fusarium species

are important in plant pathogenesis (62). On the other hand, there

is relatively little evidence that mycotoxins enhance the ability of

fungi to grow in vertebrate hosts. Aspergillus fumigatus is case in

point. It is the major species associated with aspergillosis and

produces gliotoxins (inhibitors of T-cell activation and

proliferation as well as macrophage phagocytosis). However,

gliotoxin is not known to be produced in significant amounts by

Aspergillus fumigatus during human disease (265). On the other hand,

there are reports that gliotoxin has been associated with infections

by Candida albicans (230, 231). The ability to grow at human body

temperature (37°C) is clearly an important requirement for systemic

mycotic infection, but the optimum temperature for the biosynthesis

of most mycotoxins is within a more mesophilic range (20 to 30°C).

For this and other reasons, the current view is that while some

mycotoxins are known pathogenicity factors in plants, their

significance in human mycoses is not yet clear.

Definitions, Etymology, and General Principles

It is difficult to define mycotoxin in a few words. All mycotoxins

are low-molecular-weight natural products (i.e., small molecules)

produced as secondary metabolites by filamentous fungi. These

metabolites constitute a toxigenically and chemically heterogeneous

assemblage that are grouped together only because the members can

cause disease and death in human beings and other vertebrates. Not

surprisingly, many mycotoxins display overlapping toxicities to

invertebrates, plants, and microorganisms (10).

The term mycotoxin was coined in 1962 in the aftermath of an unusual

veterinary crisis near London, England, during which approximately

100,000 turkey poults died (22, 82). When this mysterious turkey X

disease was linked to a peanut (groundnut) meal contaminated with

secondary metabolites from Aspergillus flavus (aflatoxins), it

sensitized scientists to the possibility that other occult mold

metabolites might be deadly. Soon, the mycotoxin rubric was extended

to include a number of previously known fungal toxins (e.g., the

ergot alkaloids), some compounds that had originally been isolated

as antibiotics (e.g., patulin), and a number of new secondary

metabolites revealed in screens targeted at mycotoxin discovery

(e.g., ochratoxin A).

The period between 1960 and 1975 has been termed the mycotoxin gold

rush (157) because so many scientists joined the well-funded search

for these toxigenic agents. Depending on the definition used, and

recognizing that most fungal toxins occur in families of chemically

related metabolites,. some 300 to 400 compounds are now recognized

as mycotoxins, of which approximately a dozen groups regularly

receive attention as threats to human and animal health (49).

Mycotoxicoses are the animal diseases caused by mycotoxins;

mycotoxicology is the study of mycotoxins (84).

While all mycotoxins are of fungal origin, not all toxic compounds

produced by fungi are called mycotoxins. The target and the

concentration of the metabolite are both important. Fungal products

that are mainly toxic to bacteria (such as penicillin) are usually

called antibiotics. Fungal products that are toxic to plants are

called phytotoxins by plant pathologists (confusingly, the term

phytotoxin can also refer to toxins made by plants; see Graniti [93]

for a cogent discussion of the etymology of phytotoxin and its use

in plant pathology). Mycotoxins are made by fungi and are toxic to

vertebrates and other animal groups in low concentrations. Other low-

molecular-weight fungal metabolites such as ethanol that are toxic

only in high concentrations are not considered mycotoxins (10).

Finally, although mushroom poisons are definitely fungal metabolites

that can cause disease and death in humans and other animals, they

are rather arbitrarily excluded from discussions of mycotoxicology.

Molds (i.e., microfungi) make mycotoxins; mushrooms and other

macroscopic fungi make mushroom poisons. The distinction between a

mycotoxin and a mushroom poison is based not only on the size of the

producing fungus, but also on human intention. Mycotoxin exposure is

almost always accidental. In contrast, with the exception of the

victims of a few mycologically accomplished murderers, mushroom

poisons are usually ingested by amateur mushroom hunters who have

collected, cooked, and eaten what was misidentified as a delectable

species (184).

Mycotoxins are not only hard to define, they are also challenging to

classify. Due to their diverse chemical structures and biosynthetic

origins, their myriad biological effects, and their production by a

wide number of different fungal species, classification schemes tend

to reflect the training of the person doing the categorizing.

Clinicians often arrange them by the organ they affect. Thus,

mycotoxins can be classified as hepatotoxins, nephrotoxins,

neurotoxins, immunotoxins, and so forth. Cell biologists put them

into generic groups such as teratogens, mutagens, carcinogens, and

allergens. Organic chemists have attempted to classify them by their

chemical structures (e.g., lactones, coumarins); biochemists

according to their biosynthetic origins (polyketides, amino acid-

derived, etc.); physicians by the illnesses they cause (e.g., St.

's fire, stachybotryotoxicosis), and mycologists by the fungi

that produce them (e.g., Aspergillus toxins, Penicillium toxins).

None of these classifications is entirely satisfactory. Moreover, as

our anthropomorphic focus shifts attention, the same compound may

get placed in different cognitive cubbyholes. Aflatoxin, for

example, is a hepatotoxic, mutagenic, carcinogenic, difuran-

containing, polyketide-derived Aspergillus toxin. Zearalenone is a

Fusarium metabolite with potent estrogenic activity; hence, in

addition to being called (probably erroneously) a mycotoxin, it also

has been labeled a phytoestrogen, a mycoestrogen, and a growth

promotant. For this article, we will eschew classification and

simply list the major mycotoxins in alphabetical order by name.

Toxicology and Human Health

Toxicologists tend to concentrate their efforts on hazardous

chemicals such as polyaromatic hydrocarbons, heavy metals, and

organic pesticides. Because they have devoted less effort to natural

products, agriculturalists, chemists, microbiologists, and

veterinarians who are often unfamiliar with the basic principles of

toxicology have conducted most of the mycotoxin research. There has

been a lot of reinventing of the wheel and sometimes an imprecise

use of toxicology jargon.

For example, mycotoxicoses, like all toxicological syndromes, can be

categorized as acute or chronic. Acute toxicity generally has a

rapid onset and an obvious toxic response, while chronic toxicity is

characterized by low-dose exposure over a long time period,

resulting in cancers and other generally irreversible effects (128).

Accepting that it is often difficult to distinguish between acute

and chronic effects, many papers on mycotoxicoses blur this basic

dichotomy entirely, and it is not always easy to interpret the

published data on purported health effects. Almost certainly, the

main human and veterinary health burden of mycotoxin exposure is

related to chronic exposure (e.g., cancer induction, kidney

toxicity, immune suppression). However, the best-known mycotoxin

episodes are manifestations of acute effects (e.g., turkey X

syndrome, human ergotism, stachybotryotoxicosis).

In order to demonstrate that a disease is a mycotoxicosis, it is

necessary to show a dose-response relationship between the mycotoxin

and the disease. For human populations, this correlation requires

epidemiological studies. Supportive evidence is provided when the

characteristic symptoms of a suspected human mycotoxicosis are

evoked reproducibly in animal models by exposure to the mycotoxin in

question (121). Human exposure to mycotoxins is further determined

by environmental or biological monitoring. In environmental

monitoring, mycotoxins are measured in food, air, or other samples;

in biological monitoring, the presence of residues, adducts, and

metabolites is assayed directly in tissues, fluids, and excreta

(121).

In general, mycotoxin exposure is more likely to occur in parts of

the world where poor methods of food handling and storage are

common, where malnutrition is a problem, and where few regulations

exist to protect exposed populations. However, even in developed

countries, specific subgroups may be vulnerable to mycotoxin

exposure. In the United States, for example, Hispanic populations

consume more corn products than the rest of the population, and

inner city populations are more likely to.............