Fumonisins, mycotoxins of increasing importance: Their nature and their effects

Phurmucol. Ther. Vol. 70, No. 2, pp. 137-161, 1996 Copyright 0 1996 Elsev~er Science Inc.

ISSN 0163-7258196 $32.00 PII SO163-7258(96)00006-X ELSEVIER

Associate

Editor:

K. D.

Bhoola

Fumonisins, Mycotoxins of Increasing Importance: Their Nature and Their Effects Michael

E Dutton

DEPARTMENT

OF PHYSIOLOGY,FACULTYOF MEDICINE, UNIVERSITYOFNATAL,CONGELLA,DURBAN 4103,NATAL,SOUTH AFRICA ABSTRACT. The fumonisins (FBs) are a group of closely related mycotoxins that are prevalent in maize. They were isolated from strains of Fusariummoniliforme (Sheldon), which were implicated in the aetiology of human oesophageal cancer in the Transkei, South Africa. Their discovery explained the cause of equine encephalomalacia, or “hole in the head” syndrome, when it was found by feeding trials in horses that they elicited the disease. Subsequently, they were found to cause hepatic cancer in rats and pulmonary oedema in pigs, with most animal species tested showing liver and kidney damage. FBl is the most important of the group and, although poorly absorbed from the gastrointestinal tract, its action is at the cellular level, affecting sphingolipid metabolism. Ceramides derived from sphingosine metabolism are cell regulatory factors affecting, among other things, DNA synthesis. Because FBl has a close molecular resemblance to sphinganine, it interferes with ceramide biosynthesis and, hence, the processes that it regulates, which is thought to explain its carcinogenic properties. Studies on the FBs are still at a relatively early stage, but it is already clear that they play an important role in animal mycotoxicoses and, by implication, in human disease. A more positive aspect is that they will be used in elucidating the role of sphingolipids in cellular regulation. PHARMACOL. THER. 70(2): 137-161, 1996. KEY WORDS. metabolism.

Fusarium moniliforme. encephalomalacia, ,

Fumonisin,

ELEM,

liver cancer, maize, sphingolipid

CONTENTS 1. INTRODUCTION ................... 1.1. MYC~T~~INS AND

137

HUMANDISEASE .............. HISTORICALBACKGROUND ...... CHARACTERISTICS ............. DETECTION ANDQUANTITATION . . 1.4.1.ISOLATION ANDTHIN LAYERCHROMATOGRAPHY.. 1.4.2.HIGH PERFORMANCE LIQUIDCHROMATOGRAPHY 1.4.3.CAPILLARY ELECTROPHORESIS ....... 1.4.4.OTHERMETHODS ........ 1.5.OCCURRENCE ................ 1.6.PRODUCTION ................ 1.7.RELATEDMETABOLITES ......... 2. DISEASE AND EFFECTS.............. 2.1. EQWDAE .................... 2.1.1.HORSES ............... 2.1.2.DONKEYS .............. 2.1.3.PONIES ................

137

1.2. 1.3. 1.4.

ABBREVIATIONS. gastrointestinal tract;

1. 1.1.

138 138

139 139 140 140 140 140 142 142 143 143 143 144 144

AAL, Alternaria alternata; ELEM, equine leucoencephalomalacia; OC, oesophageal cancer; OPA, 0-phthaldialdehyde.

INTRODUCTION

Mycotoxins

Mycotoxins,

allowed

and Human Disease

the poisonous

humans

since

probable

that poisonings

products

the commencement occurred

have plagued

of agriculture. before

due to toadstools

and moulded

by the uninitiated.

The mass production

age, such as that described

fungi,

of fungi,

materials

in the Jewish

It is also

this development, being

consumed

of food and its storscriptures

by Joseph,

144 145 145 145 146 146 146 147 147 147 149 149 149 149 149 150 150 150 151 152

2.2. PIGS ..,................ 2.3. RODENTS . . . .. . . . .. . . . .. . 2.3.1.RATS.............. 2.3.2.OTHERRODENTS .. . . 2.4. OTHER SPECIESANDTISSUES . 2.4.1.POULTRY . . .. . . . .. . 2.4.2.OTHER ANIMALS . . .. 2.4.3.PLANTS . . . . .. . . . .. 2.4.4.TISSUES . . . . .. . . . .. 2.5. CELLCULTURES . . . .. . . . . .. 3. HUMAN INVOLVEMENT ........... 3.1. DISEASE .................... 3.1.1.OESOPHAGEALCANCER .. 3.1.2.PRIMATE STUDIES ....... 3.2. EXPOSURE .................. 3.3. CONTROL .................. 3.3.1.RISK ASSESSMENT ....... 3.3.2.LIMITINGCONTAMINATION 4. CONCLUSION .................... REFERENCES .......................

for

together

the problem, mycotoxicoses often

infection

production

food staples. ods,

the

not

The

FB, fumonisin;

of

of mycotoxins, development

with

recognised

of acute

(Campbell,

by in meth-

has exacerbated diseases

1974) and also chronic

as such

The effects of mycotoxins

produce distribution

agricultural

processing,

in outbreaks

(Newberne,

stored

and their

of modern

large-scale

resulting

the

GIT,

termed

conditions,

1990).

have been documented

through-

M. E Dutton

138 out history;

there

is possibly

is an Assyrian

ergot

throughout

(Berry,

the middle

until the beginning recognised sudden

of

in 1961 and

were

literature

the

for

toxic

evidence yielded

approaches

metabolites

and Cox,

1981). At this stage,

fruit,

and

a problem

by their

and

that

those

more

to be understood

by vigilant

screening

As is the

have a habit discovery

and legislative

case

in the

of resurfacing,

of the

if not unrelated

of a specific

species

son et al., earlier

1983).

was

because

ing,

are more

rather

both

the

The

origin

Marasas’

workers (1983),

toxins,

for

observed

associated

at least

members

of the

malacia lomalacia

feed.

have been: mouldy From

the work

from

described

(Thigpen ct al.,

FB

as being implicated

et aI.,

1990),

1993b).

et al.,

1972;

produces

moniliformin, It is not

a range and

easy to define

when the diagnosis of species,

fusarin

rather

depends than

fungus

is maize,

to Ft*saritlm

grass

in laboratory

and

of toxins

strain

(Abbas

was implicated 1971),

because including

this fusaric

et ul.,

a mycotoxicosis, upon mycological

the mycotoxin

feed

of Fusaritlm

Maronpot,

C (Bruckner

cer-

in New

animal

from jimsonweed

observation,

infec-

other

e.g., oats (Wilson

E moniliforme

Wilson

was not a very useful

(Wilson

in forage

was isolated

In particular,

the causative

although

in ELEM, found

1992b),

cerebritis.

Fusarium

of the

susceptible

Voss,

has been

(Sheldon)

the condition

others,

of the genus source

et al., 1990a;

with

for most of this century

et ul., 1992), and a FB-producing

(Kellerman species

and many

The

was

corn stalk disease, and

itself.

such

but

however,

isolates,

from toxigenic

strains

of E moniliforme

and given the trivial

macrofusine

by Laurent

related

forme

and Altemuriu

areas

these,

A differwith

(Marasas

E moniliforme,

to rats (Gelderblom carcinogenic

fractions

were detected

(Bezui-

two toxic metabolites

names,

of

Transkei

compared

in particular

the rat, various

purified

prevalence of the

was observed

Using

et al., 1988). From

and cardiac

was being studied.

and carcinogenic

denhout

acute

line of investi-

high areas

in OC

et ul., 1988a,b).

other

cirrhosis

the

in the region

to be toxic

caused

1995) of severe nephro-

in certain

seaboard)

areas

and of E

fed to pigs; this also

an additional

flora

this

1981).

where

(OC)

et al., 1979, 1980). Fungat were found

et al.,

the fungal

nonOC

when

and hepatic

pursued

on the eastern

between

with

a strain

as E moniliformr) (Tibor,

et al. agent

FBl

(isolated

were

and called

et al., 198913) and FB2. Subsequently,

compounds

were isolated

spp. (Cawood

from

et al.,

both

E monili-

1991; Chen

et al.,

1992). Feeding

trials

on two horses,

purified

FBI,

necrotic

brain lesions

on other cancer

elicited

species

typical

using ELEM

(Kellerman

revealed

Osweiler none

et al.,

of the

species

tested

(Fincham

FBs

1992). have

Despite been

caused,

extensive

studies

in addition,

liver

et ul., 1992;

studies,

to produce

and

including

in pigs (Haschek

shown

(Diaz and Boermans,

purified

et al., 1990). Further

that FBl

in rats and lung ocdema

partially symptoms,

however, OC

1994), including

in any primates

et ul., 1992).

fungal acid,

1989). as ELEM,

identification Confusion

(a region ence

Gelderblom

the causative

is when

oedema

in rats (Kriek

cancer

1989). Several

to be involved

example

in sheep,

been

e.g.,

to isolate

known

(now

oesophageal

similar

leucoencepha-

in a test animal

disease,

decade,

An

Africa,

in 1988, discov-

diseases.

had

when,

et al., 1988; Anon,

to have a long history

of the disease

leucoencephalitis,

species

1971).

(Mirocha

moniliforme

this

with

fungi

was solved

Experi-

appears

been

1994),

Africa,

with pulmonary

have

et al.,

of the Aspergillus

in South

tlerticillioides

and related

(Bradburn

(PROMEC)]

toxicity

leucoencephalo-

used to describe

foraging

of Butler

also been

et ul., 1985~). Zealand

description

names

is well known (Rheeder

eals have

equine

was well understood

Maronpot,

which

effects

in horses

the symptoms

poisoning,

as feed infected

tions

called

early

staggers,

of ELEM

and

An

Other

blind

corn

their

in 1902, who called the disease

and produced

mouldy

century,

fatal condition

Equidae,

or ELEM.

given by Butler

agent

this

of this

acid poison-

and

Egmond,

to the myco-

is a case

symptoms

Mycotoxins

problems

gation addition

of different

on

attempting

sis and hepatosis

recent

disease

over the preceding

of ELEM

with the

the

from

a differ-

X” disease

by members

[Programme

had been

if not completely

Background

in a sporadic

of ELEM

group

could (Van

ELEM,

with cyclopiazonic

of aflatoxin

Carcinogenesis

to specific

of mankind,

that

(Nel-

clear

flaeaus group.

in infected be reduced

seems

produced

ered the FBs (Bezuidenhout

e.g.,

(FBs).

the FBs are a more

that

being

is truly

of “Turkey

consistent

than

toxins

In South Although

it now

difficult

always

or a combination

example

of related

the identification

is notoriously

the disease

as “mouldy

a range

it is not

altogether, The

thrombosis

1.2. Historical

whether

such

cover

Furthermore,

of Fusurium

ent mycotoxicosis

disease

ones.

could

Consequently,

literature

in point,

to a condition, that

nature,

and this has happened

fumonisins

fungi,

a label because

mental

control

affairs

cultures

feeling

toxins

and,

from the first world food chain,

and,

to have

cell

restricted

(AAL)

eliminated 1989).

by attaching poisoning,”

was over. Those

discovery

were

of myco-

the general

such as Alrernaria

were thought

animal

ubiquitous

past

results

were reported

animals

age of mycotoxin

range

and

Both

(Cole

aflatoxins,

cause,

a whole

metabolites,

towards

crops and regions,

X disease”

for documented

over 240 fungal

posed

for this

of its putative

of the a&toxins,

properties

that

reason

arise corn

mycotoxicoses.

toxic

the golden

were widely

The

1961).

screened

was scoured

that

but it was not

of “Turkey

discovery

et aI.,

and their effects.

by 1984,

of disease.

what

was reported

1979),

outbreak

after the discovery

fungi

toxins

causes

was the

(Sargeant

Soon

describing

ergotism

of the 1960s that mycotoxins

notoriety

a&toxin

and

ages (Robbers,

as potential

in Britain

bas-relief

1988),

can

1.3.

Characteristics

The

FBs are a group

isolated a review,

from

of related,

E moniliformr

see Scott,

1993).

polar

metabolites

(Bezuidenhout Their

structures

et ul.,

originally 1988;

are based

for on a

Fumonisins, Mycotoxins of Increasing Importance

139 activity, as chemically synthesized analogues of FBl with an extended chain were more toxic when evaluated by cell cultures (Kraus et al., 1992). Three-dimensional minimum energy conformations for all four FBs were calculated (Beier et al., 1995), and it was found that the amine and carboxylic

R = COCHZCH(COOH)CHzCOOH

FIGURE

1.

FBI:

R,

= OH.

R2 = OH

FB2.

R,

= OH.

R2 =

FB3:

R,

= H. Rz = OH

FB4:

R,

= H. R> = H

acid groups are spatially related, suggesting that they have chelating properties and, hence, could cause membrane ion leakage, as found in treated plants (Abbas et al., 1992a).

H

Structure of FBs.

long hydroxylated hydrocarbon chain (pentahydroxyeicosane) containing methyl and either amino (BI and B,) or acetyl amino groups (A, and AZ). Two hydroxyls are esterified to two propane-1,2,3-tricarboxylic acid molecules trivially named tricarballylic acid. FBl differs from FB2 in that it has a extra hydroxyl at position 10 (Fig. l), the backbone of the FBI molecule being chemically converted to FB2 by two methods (Badria et al. 1995). FB3 and FB4 were isolated later (Gelderblom et al., 1992a; Plattner et al., 1992), and lvere found to differ from the others in hydroxylation pattern (Fig. 1). A further addition was FBCl, which lacked the terminal methyl group adjacent to the amine (Branham and Plattner, 199313). The mass spectra of the FBs and associated metabolites was studied by Caldas et al. (1995) using electrospray injection, and agreed with the accepted structures. Because of the four free carboxyl groups and the amine group, the compounds are water soluble, but not soluble in nonpolar organic solvents. The lack of solvent solubility of the FBs explains, in part, the delay in their discovery, because isolation of most mycotoxins depends upon solvent extraction, which avoids contamination of extracts with materials such as carbohydrates and amino acids. Consequently, methods of purifving FBs are long and tedious (Cawood et al., 1991), often resulting in products that are not completely pure. The relative and absolute stereochemistry of FBl (ApSimon et al., 1994; Hoye et al., 1994; l’oche et al., 1994; Blackwell et al., 1995; Shier et al., 1995) and FB2 (Harmange et al., 1994) have been investigated using NMR spectroscopy. It was found that the C2 and C3 stereo configuration is threo and opposite to that of sphingosine. Overall, it is: 2S, 3S, iR, IOR, 12S, 14S, 15R, 16R, which is consistent with the stereo structure found for FB2. The absolute configuration of the chiral centres for the tricarballylic acid moieties of FB2 was found to be R (Boyle and Kishi, 1995a), which is in contradiction to that proposed for FBl and AAL toxin (Shier et al., 1995). This anomaly was studied further, and both FBl and AAL toxin TA were also found to be R (Boyle and Kishi, 1995b), although it was pointed out that different strains of fungi were used as a source of the toxins. The total stereochemical structure of the FBs is important to their biological effects, but it may not have optimal

1.4. Detection and Quantitation 1.4.1. Isolation and thin layer chromatography. After characterization had been achieved, methods of detection and quantitation for the FBs could be devised. Of these, TLC is the simplest but, like all other analytical procedures, depends upon their efficient extraction and “clean-up.” The lack of a suitable chromophore in the molecule means that the metabolites must be derivatised with reagents to allow detection. Extraction is achieved using aqueous methanol mixtures after acidification of the material (Cawood et al., 1991). Cleanup can be done with either reverse phase cartridges,

Cls

(Rottinghaus et ~2.) 1992), or ion-exchange cartridges (strong anionic exchanger) (Sydenham and Thiel, 1992*; StockenStrom et al., 1994), the latter authors claiming that ion exchange was superior to Cls. More recently, affinity columns have become available and have been evaluated (Ware et al., 1994). These are effective because of their high affinity for the test molecule; the only drawback seems to be that they become saturated at higher levels of FB concentrations,

which have to be diluted before use.

Cawood et al. (1991) used silica gel G plates with two developing solvents, chloroform/methanol/water/acetic acid (55:36:8:1) and chloroform/water/acetic

acid (6:3:1), FBs being

visualized with anisaldehyde spray reagent or ninhydrin (0.2 g in ethanol) after heat at 120°C. This system was used with effect to optimize the purification of the four FBs in their quantitative

isolation.

FBl gave an Rf value of 0.23 in the

first system and 0.15 in the second; FB2 gave one of 0.30 in the first and 0.2 in the second. Ackermann (1991) used chloroform/methanol/acetic acid (60:35:10) with silica gel G plates, which separated FBl from FB2 (Rf values of 0.32 and 0.52, respectively) and methanol/water

(8:2) using octa-

decyl silica plates (Rf values 0.61 and 0.47). Plattner et al. (1990) also used silica gel and chloroform/methanol/acetic acid (6:3:1), which gave an Rf value of 0.24. A reverse-phase Cl8 TLC

plate was used by Rottinghaus

et al. (1992), who

developed the plates with methanol:l% aqueous potassium chloride (3:2). The FBs were detected by spraying with fluorescamine solution and buffered acetonitrile, which gave a bright yellowish fluorescence under UV light at Rf values of FBl, 0.10 and FB2,0.50. Because of low solvent solubility, the preparation of standard FB solutions can be a problem, especially as methanolic solutions can generate the methyl * Sydenham, E. W. and Thiel, I? G. (1992) Training Course 2: Fumonisins. In: Eighth International IUPAC Symposium on Mycotoxins and Phycotoxins, Mexico City, 6-13 November 1992, pp. l-10.

M. F. Dutton

140 esters.*

Acetonitrile/water

mixtures

because

the FBs were found

to be stable

are

derivative

recommended,

in this solvent

for

atom

up to 6 months.

High-performance

1.4.2.

the FBs had been with respect Before

soon

after their from

column,

column, the

then

using

solvent.

250 nm, whereas (RI detector)

the maleyl

heavily

the

ham et al.,

1990a),

found

reagent,

using

widely

lY92b;

system

allows

and Eppley,

levels

FB3

to be measured

FB2

measurements

reported

(Shephard

other

HPLC

arc all essentially agents, Lawrence, although

lY92);

but

has been

Visconti aspects,

such

have been using

developed.

different

derivatizing (Scott

(Holcomb criticised

et al.,

because

and

1993a),

it produces

was preferred

criticised

other

by Holcomb including

OPA,

naphthalene-2,3dicarboxyaldehyde 1994);

et ul.,

Other cal and

et ul. (1993b), because

who

of insta-

(Ware etu1.,

1993;

4-(N,N-dimethylaminosulpho-

nyl)-i-fluoro-2,1,~-henzoxadl~~zole) quez

as

They

(Ware et al., 1993); 9(fluorenylmethyl)chloro-

6-aminoqurnolyl

for

et al7

which

and Richard,

and

trial on this method

formate,

Bennett

This

reproducibility.

fluorescamine

derivatives,

et

FB2,

two derivatives

bility;

sub-

modified

4-fluoro-7-nitrobenzofurazan

this reagent

1993).

of FBl,

to certain

methods

the same,

including

et ai.,

et ul., 1995a).

attention

and

Sydenham

specifically

comparative

to optimise

purity,

Many

1992; Thiel

tissues.

(Akiyama

et ul., 1995); and

N-hydroxysuccinimidylcarbamate

(Velaz-

1995).

variations

on detecting

fluorescence

of the

the FBs were: electrochemi-

OPA/2-methyl-Z-propanethiol

scattering

correct

charge

pass

and opposite

tizing

(Plattner 1994)

et al.,

method it requires

expensive

treatment

(Shephard

A sensitive toxins

of an antibody clonal and

polyclonal

et ul., specific

(Shelby

An

than

trometry

Although

HPLC

of analyzing which

indicated

based

et ul.,

of FBl

required legislated

The total

of FB conanti-

and

and Peska based

aflatoxin

This

methods

as primary tolerances.

study

by this

an ELISA

against

used the

(1994)

FBI

devised

on monoclonal

antibody

was claimed

a multimyco-

to check

of

simultaneously.

a dipstick where

immo-

to he capable

rig/g of corn-based

cvill he useful

in

in Fttsurium

antibodies

RI, and zearalenone

screens

spec-

assay FB in food

A further

et ul. (lYY5) have developed these

1995).

on a polyclonal

to localise

FBI down to levels of 40-60

Clearly

lY92a; the FBs,

measure

level

that it could

methods.

study

on nitrocellulose.

Schneider detect

a higher

mono-

et ul., 1994)

et ul.,

et ul., 1995) compared

detection

Abouzied

FBl,

Both

against

(Chu

with

the quality

Fukuda

to effectively

giving

for myco-

upon

the mycotoxin.

of an ELISA

immunoblot

detecting

pre-

can he simple

(Azcona-Olivera

as the other

for the

biliscd

that

and a hydrolytic

antibodies

an immunocytochemical cultures.

this

disadvantage

et cd., 1994) vs. gas chromatography-mass

group (Tejada-Simon

toxin

the

199213).

was found

and HPLC,

as effectively

mass

the FBs

by TLC.

assessment (Pestka

with

chain.

have

et cd., 1992h;

antibodies

with

et ul., 1995).

et al., 1991a; Pestka et ul.,

it does depend

et al., lY94),

centration body

(Hints

used to quantitate long

against

antibody

used

and another

et al., 1994) have been developed

monoclonal

to

moment,

detection

chromatography

method

but

as well as anti-idiotype FBs

at the

also employs

method

Gas

(Azcona-Olivera

Usleber

seem

a deriva-

which

it does

raised

would

has the advantage

isothiocyanate,

1991; Thiel

equipment,

also

(1995)

instrumentation

and

but

has been

is the use of immunoassay,

less costly

groups,

although,

the de-esterified

is acceptable,

and

molecules

capillary,

as fluorescence

has been

1990,

buffer,

using this instrumentation

methods.

through

a high

a fused sil-

ionised

which

power

ms as the detection

detection

the

ionisahle

resolving

Other

1.4.4.

having

fluorescein

spectrometry

upon

down

due to an ion flow created

for this method,

by Maragos

electrospray

down

is not as good

reagent,

depends

applied

Not only

charge

A method

developed

capillary

1 pm, filled with a suitable

of the

FBs,

recently,

as a complementary

This

effects.

with HI’LC.

derivatizing

1990;

as low as 50 pg/kg

an inter-laboratory

and

was devised

et al.,

and has been

recommended

reagent

(OPA),

used (Shephard

Stack

fluids

a fluorescent

light

More

kV, being

heating

of detection.

for the lower

to HPLC.

diameter

high

enough

fast

spectrometry

for all four FBs (Wilkes

developed

to avoid

the sensitivity and

mass

evaporative

HPLC

cooled

of a very

i.e., levels > 10 mg/kg (Syden-

been

20-30

used a refractometer

physiological

O-phthaldialdehyde

sequently

and

and

a method

of analysis typically

suitable

of E moniliforme

in cultures

method voltage,

in the buffer.

was adequate

and

phase

electrophoresis. has

be highly

method

it was not sensitive

in foods

For this purpose,

means

Capillary

1.4.3.

electrophoresis

was used to make at

bombardment

et al., 1995).

uncharged

as the running

electrospray

1991);

after reverse

fast atom

et al., 1993a); thermospray,

and

et al.,

detection

by absorption

anhydride

et al. (1990)

(Korfmacher

1994);

(Holcomh

bombardment,

ica capillary,

on a reverse-phase

was detected

feedstuffs,

et

are extracted

buffer

derivatization

FBs

contaminated

HPLC

(Sydenham

by use of an Amberlite

by HPLC

maleic that

employing

Commodities

separated

Vesonder

for determining

levels

1993a).

and sen-

were needed

laboratory

as an alternative

Although

accurate

a method

methanol/phosphate

derivative

was aroused

and measurement

and cleaned

In this method,

maleyl

ul.,

et al.,

After

and occurrence.

be conducted,

discovery,

methanol

interest

to disease

the PROMEC

Alberts

with aqueous XAD2

could

of detection

was reported ul., lY90a;

worldwide

contribution

surveys

methods

and,

discovered,

to their

useful

sitive

liquid chromatography.

et al.,

(Holcomb

mass spectrometry

rapid

the safety

that

can

foods. tests

are

of food and

Fumonisins,

Mycotoxins

of Increasing

Importance

Occurrence

1.5. Many

mycotoxins

restricted perate

zones,

having and

have

because

found

in all parts

of the

regarded

as a global

E moniliforme er al.,

et al.,

population jardins

et al.,

(Nelson

1992,

were found

Norred, 1994),

1994,

maize,

et u2., 1994).

More

recently,

of E polyphialidicum, Because

E moniliforme

mating

seeds

is widely

strains

distributed

global

capable

reporting

of producing

to the

presence

1). In South

Africa,

Sydenham

conclusive

report

the Transkei.

of FBl

consumption,

the high mean

(595 pg/kg)

samples

that

Africa,

Peru,

were

that

removed

As in other

mycotoxin

low compared

by sieving

were found

grain,

it was suggested

bulk

(Sydenham

grain et al.,

would

(Murphy

to have

were found material.

in maize

and Illinois,

et al.,

FBI in United

1993)

States

meal, USA

up to 4140

USA

and

FB3.

at 37.9

programme showed corn,

dog,

examined

pg/kg

that

FBl/FBZ,

USA,

their

the

FB

1988-1989

(Binkerd The

et ~2.) 1993)

highest

mg/kg

in 1991

Food products,

and

1989

level of 12.1 mg/kg

and cat food

for FBs.

levels

in the

for mycotoxins

a mean

maize screenings.

canned were

FB2,

screenings

A surveillance

feed (Price ing maize

FBI,

“fines”

1994).

et ~2.) 1993) and Indiana,

was found

present, with other

lower

Some tortilla

includ-

purchased

of the foods and

Level &g/kg)’

Egypt France Honduras Hungary Italy Japan Korea Nepal Peru Poland Portugal Romania Sardinia South Africa Spain Switzerland United States Georgia Iowa

Zambia

Sydenham et al., 1993 Sydenham et al., 1992a Doko et al., 1995 Sydenham et al., 1991 Yoshizawa et al., 1994 Doko er al., 1995 Sydenham et al., 1991 Le Bars and Le Bars, 1995 Julian et al., 1995 Fazekas and Tothe, 1995 Doko et al., 1995 Ueno et al., 1993 So0 er al., 1994 Ueno et al., 1993 Sydenham et al., 1991 Doko et al., 1995 Doko et al., 1995 Doko et al., 1995 Bottalico et uI., 1995 Sydenham et u1., 1994 Rheeder et u1., 1995 Sanchis et ul., 1994 Pittet et al., 1992 Trucksess et al., 1995 Sydenham et ul., 1991 Chamberlain et al., 1993 Murphy et al., 1993 Hopmans and Murphy, 1993 Doko et al., 1995

1710

20/20

’ Highest

Reference

2000 38,500 2310 50 1732 70 2380 50,000 6555 334,000 5310 2600 1327 4600 660 30 3450 30 250,000 1890 7100 80 790 350 1048 321 37,900 1410

16/17 20/21 9/ll l/2 5/20 1 l/19 2/2 95/100 24124 36/56 All 14/17 j/l2 12/24 l/4 2/7 9/9 3/6 6/6 lO/lO 187/249 B/50 44/120 35/97 25/26 ?3/28 44/160 15

concentration

in Maize in

recorded

of

to be relatively

significantly

Argentina Brazil Benin Canada China Croatia

of FBl

et al.,

“screenings”or

than

Maize from Iowa, Wisconsin,

had

Surveys

(Rheeder

grain

from

in Iowa,

South

from

from

and

and

came Canada.

studies,

Location

for human pg/kg)

Other

Africa*

main

was

maize meal.

in FBl

removal levels

was the

the levels were relatively

areas in the world. higher

and

that

(Sydenham

(2380

in Egyptian States,

FB

survey

levels of FBl

maize in South

et al. (1990a)

destined

to be positive

United

grown

showed

although

found

the

commercially 1995)

were found

of the toxins

in maize

In a further

et al., 1991) of maize and maize products

the

the FBs (Nel-

in addition

from

strobus

in the world,

surveys

(Table

obtained

in cultures

of Pinus

1991), first

that

(Desjardins

was detected

from

themselves the

Des-

populations

it was concluded

son et al., made

1992a,b;

of FB existed

FBl

to find

of fungal

Such

1995).

surprising

presence

and

E dlamini,

to the ‘A mating

et al.,

and

isolated

Ocamb,

(Thiel

Bullerman

(Leslie

1995).

for the production

it is not

E nygamui

E unthophilum,

fujikuroi

in Mexican

and

by memincluding

et al., 1992), E oxysporum vclr redolens

the potential

(Abbas

becoming

Liseola,

1993;

FBs,

1989).

also

are produced

and are also related

of Gibberella

et al.,

They

are

time

of the Occurrence

Number of samples (positive/ total)

toxins are one,

at some

Report,

maize,

in the section

1992;

1995c),

Alternaria

E proliferatum,

Nelson,

and E nupifonne (Abbas

problem.

Fusurium

Meireles

e.g.,

(CAST to

(Sheldon),

1991a;

Thai, 1994;

world

being

TABLE 1. Examples Different Countries

in tem-

the aflatoxins

food commodities

restricted

hers of the genus

either

e.g., citrinin

exceptions;

in most

mainly

distribution,

conditions,

of commodity,

are notable

been

although

limited

of climatic

or type

in fruit. There

FB2

141

canned

yellow

corn

Murphy,

had

hydrolysed

the presence a total

of both

of 28

recently,

FBl

pg/kg

Sydenham

States

with

ham

levels

(Sydenham

tina and found FB

levels

affecting

et al., 1992a).

Peruvian

maize

was found

pg/kg

respectively.

in 16 maize meal consumption

in

1048 pg/kg

samples

tested,

only

maize-based

feeds

asso-

horses, Levels

pigs, rabbits,

of FBI

pg/kg.

ranged

materials.

maize samples

that the bulk of them, of 2000

of 235

of FBI,

contaminated

also examined

in excess

35

of FBI.

in Brazilian

with mycotoxicoses

et al. (1993)

and FB2

for human

that

the United

corn,

Of the Canadian

detectable

0.2 to 38.5 mg/kg in naturally *Viljocn, J. H., Marasas, WI E 0. and Thiel, I? G. (1993) Fungal lnfectlon and rnv~~to~m contamination of commercial maize. In: Proceedings of the ICC lnternatmnalSymposium: Cereal Science and lkhnology; Impact on a Changing Africa, Pretoria, 9-13 May 1993, pp. 837X53, Taylor, J. R. N., Kandall, I? G. and Villoen, J. H. (eds.) CSIR, Pretoria.

levels

frozen

from More

for canned

found

all over

at mean concentrations

FBs were first found poultry

from

FBl

and

showed

1993).

devised

et al. (1995)

and

USA

in 23 samples

maximum

destined

601 pg/kg.

showed

ciated

(Hopmans

et al.,

method

taken

et al. (1991) found

the United and FB2,

HPLC

in canned

10 grit products

one

aflatoxin

Trucksess

samples

contained 350

and

present

(Chamberlain

sweet corn,

of 97 commercial and

FB and

analyzed

using a modified

and frozen States

FBl

1993). A survey of corn from Georgia,

from

and from

SydenArgen-

16 of 17, had combined One

to contain

of four

FBI

samples

of

at a level of 660

142

M. E Dutton

pg/kg

(Sydenham

et al.,

maize in Honduras (Julian

Preharvest

to be predominant,

24 samples

tested

third

and FBI

at levels

Of maize-based

and

had FBl

between

ranging

from

in Spain

were found

at a low level of a mean mainly

from European

Doko FB

rt al.,

levels

Zambia,

1995),

Romania,

showed

study on Italian

with

puffed

pg/kg* also

found

sample

but the

lower,

to be contaminated 33.4

of the

1995)

derived

tion

of several

lent,

at levels

Ninety-five

mg/kg

FBl

from

mycotoxins,

on maize

for human

of 80 pg/kg to contain

FBs,

talico

et al.,

FBI

another

et ul. (1995)

showed

that

strains

isolated

(Ueno

et ul.,

in Taiwan 1993)

all the

positive

for FBl.

only

Similar

Other

presence

gos and

were also

beauvericin

(Bot-

Richard,

feeds

dosed

et al.,

Asia

in milk

et al.,

for

Of the

in imported

were Chi-

also showed

1995).

of FR in milk was done (Maraof the

165 samples

mg/kg)

analyzed,

1.29 pg/L of FBl,

of raw milk is possible,

with FBI p.o. (1 and 5 mg/kg

and 0.20

FBI.

12 of 24 samples

in Southeast

at a low level,

or by i.v. (0.05

products

were positive

contained

were found

(Yamashita and

and maize

samples

in Nepal,

that contamination

(Scott

of maize

results

1994),

53 to 1327 pg/kg. FBs. A study

survey for the presence

dairy cattle

of

E moniliformr

studies

of FBs

one was positive

gesting

samples

all were found

of the

gluten-based

of maize originating

from

66%

8 of 9 maize

samples

One

8 of

a mean

were able to produce

was done

into Japan;

maize.

in Spain,

maize, and FBl was found

Tseng

nese

28

Because

of the perceived

effects,

methods

tities.

chemical eters

sug-

although

bodyweight)

had no detectable

residues

1994).

as substrate,

E moniliforme activities

dropped

from

lowering

cessation strain MRC was mainly

(Alberts was best

glucose

as the carbon

1990; Alberts

Most

on the

cultures, hone;

which

ul.

methyl

(1993b).

labelled

‘+C acetate

labelled with

“C-labelled

glutarate ketide

simpler

radiolabelled

FBs

to fungal

on the

FB hack-

method

with

was used

‘“C by Alberts

et al. (1994)

cultures

and

The

indicated

the backbone

biosynthesis apart

from

the

et

added

obtained

use of this

FBl

method

involvement

of the molecule

of the the

rest

of the

demonstration

of the nitrogen-containing to the way that serine

(Branham

and

Plattner,

into

FBl

in place

FB that

of

was poly-

molecule alanine

is not was the

end of the molecule, is incorporated

1993a).

ever, were not able to demonstrate

These

in sphingoworkers,

the incorporation

of palmitate

utilized

how-

of stearic

in sphinganine

biosynthesis.

1. i’. Related Meta bolites All mycotoxins

of maize *Doko, M. R. and Visconti, A. (1993) F umonlsin contamination hased foods in Italv. In: Proceedings of the United Kingdom Workshop on the Occurrence and Sigmficance of Mycotoxins, London, 21-23 April 1993, pp. 49-50, Skudamore, K. A. (ed.) MAFF, London.

with

et al., 1994).

groups

Blackwell

analogous

acid

pro-

compa-

into FBl using this method

precursor sine

has been yields

derived.

The clear,

FBl

methionine

labelled

additives

and Bennett,

where (Miller

the molecule.

and that

dish pro-

produce

to liquid

throughout

with

in a petri

1992). A similar

recently,

medium

of maize

recently,

methyl

of 16.5

medium

were claimed

to

groups

More

defined

cultures,

incubation

maize

g/kg (Jackson

was introduced

and Shackelford,

that

a solid

of labelled the

Focus

of FBs by liquid

of a “patty”

More

made

labels

deuterium

to introduce

but

procedures

addition

Africa.

on moist

Production

cultures

cleanup

approaches

depend

it was found

liquid

substrate

and

and this is the basis for

a yield

at l-3

et al., 1994).

to solid

extraction

at aw 0.85.

used the E moniliforme

a chemically

in 10-L stirred

loss of

and, in an early investigation

source,

yields

remained

with total

of the FBs in South

in the form

the highest

in

production.

a 20-fold

activity

gave

with

flour with water

rate

metabolic

et ~11.) 1990).

culture

duced

growth

drop in FBl

group preferentially

11 weeks

water

is critical

production,

of temperature,

for

g/kg FBI

duced

5%,

on solid substrates

of the effects

and

the water activity

loss of FBl

production

The

on param-

which

When

826 in their investigations,

the commercial

at 25’C

and

tedious.

aeration,

of 5% (aw 0.9) caused

of growth

The PROMEC

and

1995),

was a 3-fold

rate and 300-fold

quanas total

on maize grain at different

et al., by

and their

spp. depends

temperature,

1.0

FBs

purified

is necessary,

costly

was grown

but there

A further

rable

be too

of most mycotoxins.

unchanged, growth

material

(Cahagnier

the formation was

would

of the

to prepare

of the FBs by Fusarium

such

activity. water

of natural

synthesis

production

importance

were developed

Production

(Plattner Korean ranging

the

after

In a study

at low levels,

toxin,

levels

1995). at levels

and

prevaisolated

maize

and 4 of these

Fusurium

in 5 of 12 samples,

FBI,

et

produc-

showed

1995).

in Sardinia,

up to 250 mg/kg,

Soo et al. (1994) analysed

imported

the

et al., 1994). Of 6 selected

maize ear rot collected

to contain

on sterile

consumption

preharvest found

1995).

(Logrieco

the most

and Le Bars,

to contain

(Sanchis

being

was

a mouldy

and Tothe,

in France

grown

(Le Bars

were found

with

of E moniliforme

by hand

and over, when destined

at 6100

mg/kg.

days of incubation 50 samples

results,

maize

revealed

FBl

and

pg/kg).

of FBl

FBs,

maize

of the strains

from maize seeds harvested of 5 mg/kg

(<70

gave similar

(Fazekas

with

of up to 2250 percent

levels

of E proliferutum

Italian

Portugal,

Poland,

Hungarian

with

toxigenicity

Italy,

level

1994).

1994;

with high

Croatia,

highest

Visconti,

albeit

and Doko,

being:

group,

et

con-

of samples,

of countries

corn products

having

and

having

A study al.,

corn

(Doko

(Visconti these

positive,

(Pittet

for human

A survey

a group

second

An earlier

about

to be contaminated,

pg/kg), The

&kg.

in Switzerland,

destined

countries

(1710-3310 and Benin.

were

in all of the

68-6555

of 80 /&kg.

discerned

E subglutinans

55 to 790 pg/kg

ul., 1992). Eight out of 50 samples sumption

and mycotoxins

was found

food and feed bought

1.6. Production

and farm-stored

for fungi

et al., 1995). E moniliforme

found

one

1991).

was examined

secondary that

belong

metabolites.

are essential

to a group These

of compounds

differ

for the functioning

mal living cell, and are characterised

from

the

known

as

compounds

and growth by their exclusive

of a nornature.

Fumonisins, Mycotoxins of Increasing Importance

dH$R R

=

FIGURE

CH3

HO

COCHZCH(COOH)CH2COOH 2. General structure of AAL

toxin.

This explains why various fungal species tend to produce specific mycotoxins and no others. If one looks at secondary metabolite production in general, however, the ideal criterion is not met, in that several species of a genus might produce the same toxins. Often these are closely related, e.g., Aspergillus j&us and Aspergillus parasiticus both producing aflatoxin B,. In some cases, they may not be closely related,

FIGURE 3. Brain lesion in a horse suffering from ELEM (T. S. Kellerman, personal communication).

e.g., cyclopiazonic acid produced by members of the Aspergillus and Penicillium genera. There are several explanations

spring (Buck et al., 1979). This latter observation

for this phenomenon,

be rationalised

including convergent evolution, direct

can now

on the basis of the fungus having had time

transfer of genetic information between organisms, and taxonomical classification based on morphology rather than

to grow on feedstuffs and to produce a toxin during this period. The literature on ELEM can be divided into phases,

genetic principles. Whatever the reason for lack of strict exclusivity, the FBs are no exception to this, and members of the genus A&maria produce compounds very similar to the FBs

i.e., where it was understood that ELEM was caused by the contamination of feedstuffs with certain toxigenic strains of E moniliforme, and where it was known that the causative

and, in at least one case, actually produce FB itself (Chen

agent was, in fact, FB, produced

et al., 1992). Four compounds were isolated from cell-free filtrates of Alternuriu ulternutu f.sp. lycopersici and were found to cause necrotic symptoms in tomatoes characteristic of the produc-

the fungus. In earlier accepted cases of ELEM*

as a toxic metabolite

of

(Wilson and Maronpot,

1971; Kellerman et al., 1972; Marasas et al., 1976; Buck et al., 1979; Pienaar et al., 1981; Wilson et al., 1985b; Domenech

ing fungus (Bottini et al., 1981). These compounds were isolated and found to be two pairs of structural isomers with

et al., 1984a,b), common elements are observed as follows:

a tricarballylic

contaminated feed; (2) becomes lethargic; and (3) as neurotoxic effects become apparent, develops uncoordinated movement and aimless walking with blindness and violent

acid esterified at either the Cl3 or Cl1 of an

amino polyol chain, and were named AAL toxins (see Fig. 2 for general structure), TAI, TA2, TBl, and TB2 (Bottini and Gilchrist, 1981; Bottini et al., 1981). Thus, they have a structural relationship to the FBs, exhibit similar biological activities (Mirocha

et al., 1992a), and have the same stereochem-

the animal (1) develops inappetence

after a period of eating

blunderings into the front of stalls and walls. In general, the animal will become difficult to handle and ill-tempered. In some cases, death can occur without any nervous symp-

istry, i.e., 2S, 4S, 5R, llS, 13S, 14R, and 15R (Oikawa et al., 1994). Subsequently, strains of Alternariu ulternutu were found to produce three new sets of stereoisomers designated AAL

toms and, in others, liver-related

toxins TC, TD, and TE (Caldas et al., 1995) and FBl (Chen

Two main types of histopathological signs are found on autopsy. The first being those involving the brain, where oedema in the form of an accumulation of clear fluid under

et al., 1992). Aspergillus fumigutus

was found to produce

a group of

symptoms are seen, such

as swelling of the lips and nose, severe icterus, petechial haemorrhages

in the mucous membranes,

metabolites named sphingofungins because of their structural similarity to sphingosine and, hence, the FBs, but without esterified tricarballylic acid moieties (Van Middlesworth

the meninges

et al., 1992). These compounds

the lobe. In severe cases, there may be a large liquified cavity within the white matter of the right cerebral hemisphere, with the cerebrum posterior to the cavity enlarged, oede-

were shown to have limited

antifungal properties. It is probable that further related metabolites will be isolated as investigations proceed. 2.

DISEASE

2.1.

AND

EFFECTS

Equidae

Horses. The earlier documented symptoms of ELEM in horses are variable and, in more temperate climates, such as those found in the United States, the disease tends to be seasonal, being most prevalent from late autumn to early

is seen and liquefaction

and cyanosis.

of areas within the

cerebral hemispheres is found, causing lesions that might range in size from microscopic to one occupying most of

matous with congested blood vessels (Fig. 3). The other organ affected is the liver, which often shows a mild swelling with a colour change to yellow-brown. In

2.1.1.

*Kriek, N. l? J., Marasas, W. F. 0. and Kellerman, T S. (1981) Aspects of equme leukoencephalomalacia. In: Proceedings of the Veterinary Pathology Group of the South African Veterinary Association, Pretoria, 1980, p. 75, South African Veterinary Association.

M. E Dutton

144 more severe cases, gross liver lesions of the

centrilobular

fibrotic

area

These

area.

have

large

observations,

breaks

of ELEM

(Pellegrin

fatty

1990;

FBs

Wilkins

FBs in added

cultured

material

et al., 1994), or administered et al.,

1988b;

Laurent

In addition in duodenitis

and et al.,

condition, juice,

which

did not

proximal

to FBl ingestion.

Plumlee

and Galey

symptoms

diagnosis, tified

the specific

from

2.1.2.

the

with

man

1 donkey autopsy

of ELEM)

on 3 horses

observed

were found. studies

other With

than

studies,

ELEM

in varying

2.1.3.

Ponies.

icterus,

and

a transient on being

and liver dam-

small perivascular

haemor-

it seems very likely that

feeding

of Fusurium toxins.

donkeys

with

et ul. (1968), Wilson

the

Keller-

horse

and Maron-

and Haliburton

animals

infected

et al. (1979).

were found

to develop

degrees. Ponies

were given

(Brownie

and

one developed

was found

sine

their

Cullen, clinical

metabolism

ponies

appeared

rapidly,

could

FB. Similar

symptoms

lesions

Of

Another mine

of 4 animals group

study

the minimum

FBs

2.5),

Wang FBI.

and

FBI

thoracic

cavities

toxic

alter

8 mg/kg.

they

markers

of FBl

with One

having liver

of ponies

autopsy

and

showed

revealed

isolated,

leading

involved.

Four

with various

mild

and

by foetal mortality and was referred

et cd., 1992; Osweiler USA,

in Illinois

and

found The

be positive. Several nary al.,

FBl

studies

oedema 1990,

diseases

had

and Harrison,

by Ross et al. (1993)

1-22

of FBI

exception from

died

geal

porcine

accepted

to

pulmo(Ross

that

et

the two

i.e., FBs. FBs

Haschek

1990).

FBs used either at known

et al.,

1992;

levels

Motelin

et

These

between

an intriguing

between

and a second

Feeding

in the first group

and there

acid FBl

other (Bacon

to lactating

was no evidence

both

in their

when

distal

Certainly,

mycotoxins,

nodular oesopha-

be explained that

other

One

feed ranging

by the however,

FB is some-

administered with

were those

lesions.

poisonings;

is the possibility

material.

whereas

and developed

could

sur-

pure toxin

pigs were given

and chronic

or in combination

contaminated

fusaric

variations acute

and those

oedema,

feed had

et

fed high

hepatotoxicosis.

receiving

FBI content,

in its action

form

are known

animals

3 young

alternative

different

with

oedema,

pulmonary

contaminated

FB (Haschek animals

of subacute

of the liver and changes

mucosa.

purified

of purified In general,

pulmonary

evidence,

100 to 190 mg/kg

differences how

with

to develop

hyperplasia

on ponies. mg/kg

and found

of ELEM

of pig with

quantities

et al.,

was where

et al. (1992) to deter-

pony

called

with

lower levels had evidence

naturally A group

1994;

with

1992; Harrison

naturally

to

cause,

the dosing

from outbreaks

et al., 1992; Ross et al., 1991b, 1992; Colvin 1992; Colvin et al., 1993; Harrison etal., 1990)

given

that such meafor exposure

of the outbreak

20 to 330 mg/kg.

outbreaks became

in older

al., 1994; Osweiler

likely

that

disorders

from

has been with

in pigs

was char-

swine disease”(Bane

for FB,

to range

and it soon

1993,

lesions

States

which

In light

analyzed

contamination

et al.,

in the United

1992).

USA,

a common

naturally

cava, a total

similar

of feed were taken

what

involving

(Casteel

et al.,

syndrome

1991a),

Studies feed

link

was

vena

for 4 days,

and respiratory

was found

From the limited

latter

weight

to as “mystery

samples

Iowa,

more

gave

a mycotoxicosis

in the cranial

1989 was also reported,

acterized

in Georgia,

prob-

field outbreak.

of disease

animals,

and,

to liver

that

body

in the

outbreak

1988

The

of FBI and FB2. The one that received

0.4 mg/kg

pigs involved

during

the

with the

liquid.

of 11.3 mg, died on the fifth day and exhibited to the

in 1989

autopsy,

and E moniliforme was

screenings,

to the suspicion

dose,

USA On

and hydrothorax,

pigs were injected

amounts

the highest

et ~2. (1990).

filled with a yellow

to maize

with

sphingo-

et al. (1992)

death,

by Wilson dose

group

in pigs in Georgia, oedema

being

lem was traced

viving

five

in 4 ponies.

was done

with

and

by Harrison

had pulmonary

levels

In addition

were also observed

with

can

were elevated.

as early

were fed rations

of 5 animals,

of disease

animals

an out-

consistent

and it was suggested

be used

trial

outbreak

the

with

1987).

mg/kg

and sphinganine

surements in a feeding

15-44

encephalopathy,

free sphingosine effects

that

(see Section

feed containing

cytotoxicity,

An

was investigated

al.,

signs of toxicity

to have brain

observation

associated

Pigs

a maize

feed containing

ELEM. Following

last 22 days

animals

second

signs,

(the

the other

mainly

The

clinical

or by injection

of E moniliform associated

of a strain of ELEM ponies,

One

the gross lesions

hindsight,

et al. (1973)

from

3 donkeys,

by a combination

involving

Wilson

inocu-

died. Observations

oedema,

were done by Badiali

on autopsy,

and iden-

developed

were similar,

these effects were caused

treated

for a correct

of maize

results.

animals

lesions,

break

that,

and

varying

and the remaining

age. No brain

culture

be related

that cause neuro-

the effects

1 donkey

In all of these

this

reflux of gastric might

has to be isolated

were unaffected,

pot (1971),

that

of E moniliforme (derived

strain

haemorrhages,

material

was studied

2.2.

Another

of the animals

Other

1990).

(1994) have also reviewed

concluded

mycotoxin

severe cardiac rhages,

and

mycotoxins

In examining

et al. (1972)

pruritus,

and

a toxigenic

an outbreak

lesions.

feed.

Donkeys.

lated

transient

(Marasas

it was thought

cause

the effects of FBl and four other toxicological

mild brain

using

et al.,

by a copious

a bacterial

of lesions

hemispheres.

feed

1988; Ross

compounds

in horses

because

is characterized

have

et al.,

Kellerman

jejunitis

1995)

225 days of feeding 22 mg/kg),

et al., 1991; Caramelli

(Kellerman 1989a;

after

degrees

et al.,

in the

the role of E moniliforme cultures

to ELEM,

(Schumacher

cerebral

Thiel

ELEM

of the diet contained

by field out-

or by experiments

as purified

et al.,

died with various

determined

et al., 1990a,b;

1994)

of the

cytoplasm.

in their

1992; Wilson

et al.,

edge

are supported

were

Wilson

1991b; Ross et al., 1991a,b,

et al., 1993;

on the

globules

in general,

where

er al.,

may be seen with fibrosis

Hepatocytes

either

in a

metabolites

synergistic including

in

effects

FBI

itself

suckling

pigs

et u1., 1995). sows did not affect of the toxin

present

in the milk

Fumonisins, Mycotoxins of Increasing Importance

145

(Becker et al., 1995). This agrees with other studies on cows’ milk (Scott et al., 1994).

Other work reported by the PROMEC group shows that the FBs are hepatotoxins and carcinogens in the rat. Cul-

As with other animal studies, the uptake of *4C-labelled FBl administered intragastrically to pigs was poor, 3-6% and, in that given i.p., elimination was rapid, 80% of the dose

ture material from E moniliforme fed to rats produced microand macronodular cirrhosis in animals that died, cholan-

being recovered within 3 days in the excreta, with the remainder being associated with liver and kidney tissue (Prelusky et al., 1994). Riley et al. (1993a) found alterations in sphinganine-to-sphingosine ratios in pigs fed diets containing FBl and FB2, and suggested this as an early biomarker for exposure to the toxin. 2.3. Rodents 2.3.1. Rat. Prior to the discovery of the FBs, several trials had been done where rats were dosed with feed infected with E moniliforme related to outbreaks of ELEM (Wilson et al., 1985a; Voss et al., 1989) or to OC (Marasas et al., 1984; Jaskiewicz et al., 1987b,c,d; Gelderblom et al., 1988a). In general, these studies indicated the presence of a hepatocarcinogen in these cultures with the development of hepatic nodules, adenofibrosis, hepatocellular carcinoma-ductular carcinoma, and cholangiocarcinoma. The rat was used as a model to explore the carcinogenic potential of FB, in light of its connection with OC. Several studies on rats were conducted by the workers at PROMEC (Gelderblom et al., 1991, 1992b; Shephard et al., 1992a,b; Gelderblom et al., 1994; Shephard et al., 1994a) and FB2

giofibrosis and primary hepatocellular carcinomas (Gelderblom et al., 1988b, 1991), and adenofibrosis (Wilson et al., 1985a). These effects were investigated further using purified FBl and FB2 (Gelderblom et al., 1992b), and with a comprehensive study into the cancer-initiating capability of FBl, FB2, and FB3 (Gelderblom et al., 1993, 1994). Investigations by other groups broadly support these observations (Voss et al., 1990, 1993; Bondy et al., 1995) but, interestingly, in addition to hepatic effects, tubular nephrosis was found in the renal cortex of animals fed material infected with E moniliforme associated with outbreaks of ELEM (Voss et al., 1989) and inhibition of protein synthesis in hepatocytes (Norred et al., 1990). Both these materials to contain FBs, but they were not quantitated. where purified FBl was fed to rats, showed that metabolism in the kidney is more susceptible

were shown Later work, sphingolipid to the toxin

than in the liver (Riley et al., 1994). More recent work also showed that the kidney was more susceptible to p.o. doses of FBI (Voss et al., 1995a,b), and various markers of nephrotoxicity were measured in rats dosed with FBI (Suzuki et al., 1995). The use of I‘C-labelled FBI as a single dose to rats killed at time intervals gave recoveries of the label in faeces and urine of over 80% (Norred et al., 1993). The bal-

(Shephard et al., 199513). These took two forms, those explor-

ance, however, remained in the blood, liver, and kidney for

ing the absorption and excretion of FBs and those examining its effect on the animal. An initial experiment on clearance was done by dosing

the duration of the experiment,

rats, both by i.p. injection and by gavage, with FBI (Shephard et al., 1992a). The injected doses were rapidly absorbed and reached a maximum in 20 min. Injected FBI was cleared with a half-life of 18 min, 16% of the total dose being recovered from the urine in an unchanged form. In the case of administration by gavage, only 0.4% of the dose was recovered in the urine. Two points were raised by these results: where had the rest of the i.p. dose gone, and why was there such a low excretion from dosage by the p.o. route. Radiolabelled FBl was used to explore this problem (Shephard et al., 1992~) and, from i.p. administration of ‘4C-FBl, 66% was found in the faeces, 32% in the urine, 1% in the liver, and traces in other tissues such as kidney. Of the material given p.o., 101% was found in the faeces. A further study (Shephard

et al., 1994a) clarified how FBl ended up in the

faeces of animals dosed i.p., because 67% of the dose in this latter study was found in the bile. In the animals dosed by gavage, only 0.2% ended there. Evidently, only a small portion of the doses (5 mg/kg to produce symptoms in animals, but it also indicates that the FBs must be highly active once internalised.

i.e., up to 96 hr, which does

not quite agree with the PROMEC

results, in that larger

quantities remained bound in the animal. Other workers using rats provided additional

data on

organs other than the liver. Porter and co-workers (1990, 1993) investigated the effect of FBl on neurotransmitters in the brain. The point of this investigation was to see if the imbalances in rat brain 5-hydroxytryptamine and 5hydroxyindoleacetic acid, induced by feeding with E moniliforme, was due to FB. Although changes in norepinephrineto-dihydrophenylacetic acid(s) ratios were disturbed in rats fed 150 ppb FBI for 4 weeks, nothing corresponding to the changes in 5-hydroxytryptamine/5-hydroxyindoleacetic acid ratios were observed, and it was concluded that other compounds in E moniliforme cultures were responsible effect.

for the

Lebepe-Mazur et al. (1995a,b) showed that FBl effected the foetus in pregnant rats, causing low litter weights and foetal bone development, as compared with untreated controls, and found that placental glutathione S-transferase was a more useful marker of y-glutamyl transferase in detecting hepatic cancer foci. 2.3.2. Other rodents. Pregnant mice fed culture material containing known amounts of FB were shown to have lowered body weights, increased morbidity and mortality in a dose-response way (Gross et al., 1994). Other observations were liver damage and ascites and a reduction in the number of live offspring.

M. E Dutton

146

Similar results were found in another

investigation

that

indicated that FBI fed at <81 ppm to female mice caused hepatotoxicity, and doses at 27 ppm or less had no effect, which is in contrast to the rat where nephrosis was observed at 9 ppm (Voss et al., 1995a). FBl fed to Syrian hamsters at a rate of 18 ppm also resulted in increased foetal death, but without evidence of maternal intoxication (Floss et al., 1994a,b). It may be that the rat is a better model for investigating the effects of the FB because of greater sensitivity compared with mice, which is the case for the aflatoxins. 2.4. Other Species and Tissues 2.4.1. Poultry. Considering the economic

importance

of

chickens and their dependence on maize-based feeds, which are often contaminated with E moniliforme (Bragulat et al., 1995a,b), investigations using FBs only began in 1992, although earlier trials had been done with maize infected with E moniliforme (Bryden et al., 1987). Day-old broiler chicks were fed doses of FBl ranging from 0 to 400 mg/kg for 21 days and 300 mg/kg for 2 weeks (Brown et ul., 1992; Ledoux

et al., 1992). Body weight gain was greatly reduced; hepatic necrosis, biliary hyperplasia, and thymic cortical atrophy were noted, along with diarrhoea and rickets. A further investigation (Weibking et al., 1993a) revealed increased sphinganine and sphinganine:sphingosine ratios in young chicks treated with culture material containing

FBl.

Another study where broiler chicks were fed with FBI and FB2 in conjunction with moniliformin showed abnor-

a test animal to investigate material from an OC area and ELEM outbreak, respectively. Some of the isolates of E mondiforme, when grown and incorporated into feed, caused 100% mortality. These birds had slightly swollen and reddened livers, with low body fat and loss in weight compared with controls. An outbreak of paralysis in quail was linked to the presence of 17.7 mg/kg FBl in their feed, but this could not reproduce the symptoms in a further feeding trial (Grimes et al., 1993). Turkey poults were fed culture material at different levels of FBI from three E moniliforme strains that produced various amounts of the toxin (Weibking et al., 1993b, 1995). Variations in body and organ weight were observed, depending upon the treatment, with ratios of serum sphinganineto-sphingosine hepatocellular

increased in most birds, and generalized hyperplasia in all the treated poults. Biliary

hyperplasia was found in turkeys fed FBl, 150-300 mg/kg body weight, and FB was implicated in cases of turkey cerebral encephalomalacia (Ficken et al., 1993). An investigation into the combined effects of aflatoxin and FB fed to turkey poults was done by Weibking et af. (1994) and Kubena et al. (19958). There was variation in body and organ weights with increased sphinganine/sphingosine ratios, but no evidence of synergistic activity between the toxins, which, at best, gave additive effects. A study with T-2 toxin in place of aflatoxin showed similar results (Kubena et al., 1995b), although some of the various parameters measured were affected by the combination of toxin alone. It was concluded

mal erythrocyte formation and lymphocyte cytotoxic effects Uaved et al., 1993a; Dombrink-Kurtzman et al., 1993). Chicken embryos exposed to FBl showed a mortality of 100%

that a combination of toxins poses a greater problem to the poultry industry than either of the toxins individually.

when dosed at 100 PM. Pathological changes were found in liver, kidney, heart, lungs, musculoskeletal system, intestines, testes, and brain (Javed et al., 1993b). Work by Espada et al. (1994) showed that pure FBl fed at a rate of 10 mg/kg

2.4.2.

Other animals.

Less work has been done on other

animals, presumably because of lack of exposure and lack of intoxication in animals, such as ruminants. One case of ELEM symptoms in white-tailed deer has been described

feed for 6 days was toxic to young chicks. A single dose of

in the United

“C-labelled FBl given to a laying hen (Vudathala et al., 1994) gave similar results to those in the rat, with poor p.o.

to have been caused by the animal finding a source of infected maize. Calves given feed containing FBI, up to 148 mg/kg, were unaffected in terms of feed intake or weight gain, although certain blood enzymes were elevated along with

uptake and rapid excretion of the i.p. dose, although no FBI residues were found in the eggs. Chatterjee and co-workers (Chatterjee and Mukherjee, 1994; Chatterjee et ul., 1995) examined the effects of FBl on chicken peritoneal macrophages, which exhibited breakdown of the nucleus with increasing numbers in a dose-

States (Howerth

et al., 1989), which seems

cholesterol (Osweiler et al., 1993). Those fed at the highest levels showed mild microscopic liver lesions, and it was concluded that cattle are less susceptible to FBI than other animals. Lambs were dosed intraruminally with FB-containing FBl and showed evidence of liver and kidney damage and, in

response manner (6-18 pg/mL). This suggests impaired disease immunity in chickens exposed to FBl, which is in agreement with other work where extracts of three isolates of E moniliforme were immunosuppressive (Marijanovic et al., 1991) and organs involved in immunocompetence were affected (Martinova et al., 1995). Vitamin A, an important factor in maintaining disease resistance in poultry, was depleted in the serum of broiler chicks fed both culture material containing FBl and FBl itself (Hall et al., 1995). Prior to the discovery of the FBs, cultured material from strains of E moniliforme were fed to ducklings and 24 of 25 were found to be toxigenic (Jeschke et al., 1987). Ducklings

those receiving 44.5 mg/kg total FB, death (Edrington et al., 1995). Liver and kidney damage were also observed in mink given chronic doses of FBs (Restum et al., 1995). Studies were done on catfish fed with cultured material containing FBs, and it was concluded that levels of 20 mg/kg or above are toxic to both i- and 2-year-old fish (Brown et cti., 1994; Lumlertdacha et al., 1995). FBl was used by Strum et ~1. (1995) to investigate the role of ceramide in the meiotic cell cycle of Xenopus luevis oocytes. The results indicated the potential use of FBI in regulatory studies involving

were used by Marasas (1982) and Vesonder

sphingolipids.

et al. (1989) as

Fumonisins, TABLE

2.

Mycotoxins Effects

of Increasing

of FBl

Importance

147

on Various Species Dose: route

Species exposed Calf Catfish Chicken Deer (Whitetail) Donkey Duckweed (Lemnu minor)

148 mg/kg body weight: 20 mg/kg feed: p.o. 300 mg/kg body weight: Unknown: p.o. Unknown: p.o. 10 pg/mL medium

Horse Jimsonweed (Dururu stramonium) Lamb Monkey (vervet) blouse Pig Pony Knt Turkey Yeast (Saccharomyces and Pichia spp.)

29.7 mg/kg body weight 0.05 pg: leaf surface

p.o. p.o.

45 mg/kg: p.o. 3.3 mg/day: p.o. 81 pg/kg body weight: p.0. 11.3 mg: i.v. 22 mg/kg/day: p.o. Feed total 13 mg/kg body weight: p.o. Feed total 300 mg/kg body weight: p.o. 100 mg/L culture fluid

2.4.3. Plants. FB causes toxicity on contact with plant tissue and at sites removed from application, indicating mobility of the toxin within the plant xylem (for a review, see Abbas et al., 1993a; Kuti and Abbas, 1993). An isolate of E moniliforme found growing on jimsonweed Duturu strumonium, was shown to produce a water-soluble material that

Principal effect

Reference

Mild liver lesion Death, liver damage Liver damage Brain lesion ELEM Reduced growth and chlorophyll, death ELEM Electrolyte leakage from cells

Osweiler et al., 1993 Lumlertdacha et al., 1995 Ledoux et al., 1992 Howerth et al., 1989 Haliburton et al., 1979 Vesonder et al., 1992a

Death, liver and kidney damage Atherosclerotic response Liver damage Death, lung edema

Erdington et al., 1995 Fincham et al., 1992 Voss et al., 199513 Harrison et al., 1990 Wilson et al., 1992 Voss et al., 1993 Weibking ec al., 199313 Wu et al., 1995; Kaneshiro et al., 1992

ELEM Liver and kidney damage Liver and myocardium damage Sphingolipid metabolism affected

Kellerman et al., 1990 Abbas et al., 1992a

The effects of FBl on various species are summarized in Table 2. Tissues. Laurent and co-workers (198913, 1990) also isolated FBl and called it macrofusin. They investigated its

2.4.4.

ability to cause heart failure in rats and horses by treating

caused mosaic-like patterns on leaves and inhibited growth when sprayed on the leaves (Abbas et al., 1991, 1992a,b, 199313). The major toxic component was found to be FBI.

frog skeletal muscle with FBl (Laurent et al., 1989b), where it was found to cause a 50% reduction in sodium ion current at a concentration of 300 PM. It was suggested (Ecault et

Further trials were done to investigate the phytotoxicity of FBl and assess its potential as a weed control agent (Abbas

al., 1990) that the calcium current

and Boyette, 1992). A range of plants were shown to be sensitive, the minimum amount of FBl administered to excised leaves to cause damage being 0.05 pg. The mycotoxin produced various symptoms, including chlorosis, necrosis, tissue curling, stunting,

and defoliation.

Leaf discs from this

plant were further used in bioassay for the FBs and their metabolites (Abbas et al., 1993a), as were jimsonweed seedlings (Abbas et al., 1995a). As in other organisms, sphingolipid metabolism was affected (Abbas et al., 1994, 1995b). Vesonder and co-workers (1992a,b) examined the effect

was the main target in

frog heart, and this was shown to be the case because calcium flux was blocked (Sauviat et al., 1991), resulting in loss of heart muscle activity and a possible cause of reported heart failure in horses.

2.5.

Cell Cuhres

The FBs are cytotoxic (Norred et al., 1991a) and the effects of FBI and FB2 were tested on several mammalian cell lines, including rat hepatoma and dog kidney epithelial cells, which were found to be sensitive (Shier et al., 1991). In an experi-

of FBl on duckweed, Lemnu minor, vs. other mycotoxins, including moniliformin, butenolide, and AAL toxin. Of these, FBl was the most effective in reducing growth and

ment evaluating the genotoxicity of several toxins to rat hepatocytes, however, Norred et ~1. (1992a) found FBl at 0.5-250 pm to have no effect in the unscheduled DNA assay.

chlorophyll

Epidermal hepatocyte

biosynthesis,

making it a suitable organism for

bioassay (Tanaka et al., 1993). Other plants found to be affected by the FBs are maize, with inhibition of seedling emergence (Doehlert et al., 1994) and cell cultures (Van Asch et ul., 1992), and tomato, where leaf discs were affected in a similar manner to that promoted by AAL toxin (Gilchrist et cd., 1992). Excised shoots of certain cultivars of tomato were induced to produce roots earlier than controls, when treated with <0.5 mg/plant FBI, indicating that the toxin does affect differentiation of tissue, presumably via its interference with cellular control mechanisms (Bacon et al., 1994).

growth factor-induced DNA synthesis was inhibited 90% by FBl (Gelderblom

in rat et al.,

1995), which was reversed when the FBl was removed. Labelling studies indicated that inhibition was not due to blockage of the primary receptor binding site; consequently, FBl must interfere further down the cascade. In contrast, Vesonder et al. (1993) found that neither AAL toxin nor FBl were cytotoxic to 5 mammalian cell lines at the level of 100 pg/mL culture medium. On adding radiolabelled FBl and FB2 to rat hepatocytes, it was found that FB2 had a higher cytotoxicity and specific binding than FBl, although at the effective dose level they

148

M. E Dutton OH

&CHPH Sphinganine

I

CHZOH tiH

Fumonisin

Sphinganine

Inhibits

Fatty

Acid

(co-enzyme

A

Derivative)

CH 20H

OH OH

R

NH

R FIGURE

OH

NH2

4. Step of ceramide biosynthesis inhibited by FBl. FBI

showed similar cytotoxicity

(Cawood et&,

1994). Very little

of the FB bound to the hepatocytes (0.01%) and no catabolism of the molecule was detected, which agrees with in viwo rat experiments, where 67% of an i.p. administered dose of FBl was excreted via the bile (Shephard

et al., 1994a). FBI

was also found to inhibit protein synthesis (Norred et al., 1990) and inhibit the secretion of ceramide into very-lowdensity lipoprotein (Merrill et al., 1995a). An important investigation was that done by Wang et

al. (1991), who showed that FBl disrupted sphingolipid biosynthesis

in rat hepatocytes.

A further investigation

using

rat hepatocytes and pig kidney epithelial cells (Norred et uL., 199213; Yoo et al., 1992) confirmed that the FBs were potent inhibitors of sphingolipid biosynthesis in both types of cells, killing the renal cells after 3 days at a level of 70 PM of FBl. This effect was further studied in mouse cere-

FIGURE 5. Structure of sphinganine general structure of the FBs.

compared

with the

in the presence of insulin. These effects were paralleled by an increase in DNA synthesis. It was also shown that by using an inhibitor of sphingoid base biosynthesis, the increase in DNA synthesis is directly attributable to accumulation of sphinganine. This result is important, not only because it suggests the use of FBl as a tool to investigate the role of free sphingoid bases as mitogens, but also gives a lead to the mechanism of tumour promotion by FBI by stimulation cell proliferation. In addition, the possible influence of dietary sphingolipid

and FB on the role of fat in disease

has been reviewed by Merrill et al. (1995b). Chicken macrophages were exposed to up to IO pg/mL FBl, where cytotoxicity was observed (Qureshi and Hagler, 1992). The results implied that exposure of chickens to FBl increased their susceptibility to infection. Turkey Iympho-

bellar neurons (Merrill et al., 1993a,b) and neuroblastoma cells (Rother et al., 1992), where it was shown that FBI specifically inhibited the conversion of sphinganine to dihy-

cytes were used in an 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-

droceramides (Fig. 4). The inhibitory effect on neuron cultures of FBI was demonstrated when treated hippocam-

tetrazolium bromide-based cytotoxicity assay by DombrinkKurtzman et al. (1994), and the 50% inhibitory dose for FBl

pal neuron axonal growth was completely suppressed (Hare1 and Futerman, 1993), as was short-term axonal branching (Schwartz et al., 1995).

or FB2 was 0.4-0.5 pg/mL medium. Cells exposed to the toxins exhibited vacuolization and were unable to proliferate.

It was pointed out by Wang er al. (1991) that the structure of the backbone of the FB molecule was similar to the important phospholipid, sphingosine (Fig. 5) (Shier, 1992). Hence, it may exert its action by interfering with its metabolism and processes mediated by this type of molecule (Kim et al., 1991), e.g., inhibition of protein kinase C (Hannun et al., 1986) and via ceramides, regulation of cell growth, differentiation, and apoptosis (Huang et al., 1994, 1995). Recently, Ramasamy et al. (1995) have shown that FBl increases the rate of albumin transfer across endothelial cell monolayers derived from pulmonary artery, in addition to elevation of sphinganine levels, the latter possibly explaining the loss of endothelial barrier function. Schroeder et al. (1994) (also discussed by Wolf, 1994) investigated the effect of FBl on Swiss 3T3 fibroblasts and found that sphinganine

accumulated,

and was greatly promoted

Interestingly, FB2 was 3- to 4-fold more cytotoxic than FBI. Chicken chondrocytes in culture were exposed to FBl, which was inhibited by levels as low as 25 pm, although a parallel study on growing broilers indicated that FBl, by itself, was not sufficient to cause bone deformation (Wu, W. D. et ui., 1995). The yeasts Succharomvces cerevisiue (Wu, W. I. et al., 1995), Pichiu svdowiorum (Kaneshiro et ul., 1993), and Pichiu ciferri (Kaneshiro et al., 1992), when treated with FBl, developed abnormalities in their sphingolipid metabolism, showing that lower organisms are equally affected by the toxin. The bioluminescent genotaxicity test using Vibrio fscheri revealed that FBl was directly mutagenic without prior activation by liver S9 fraction (Sun and Stahr, 1993). This was in contrast to the Ames test, because FBl exhibited cytotoxicity but no mutagenicity, against Salmonella tester strains (Gelderblom and Snyman, 1991), despite the mutagenic activity of E moniiiforme isolates (Bjeldanes and Thomson, 1979).

149

Fumonisins, Mycotoxins of Increasing Importance Other investigations using cell cultures included the treat-

FB ranging from 784 to 3257 pg/vervet/day) and 310 to 748

ment of green monkey kidney cells with FBl to test the hy-

on a lower one (total FB ranging from 392 to 814 pg/vervet/

pothesis that FB could inhibit protein kinase C (Huang et al., 1995). The toxin was found to repress expression of protein kinase C, whereas it stimulated the promoter of a cyclic AMP receptor. These workers concluded that altered signal transduction pathway played a role in the carcinogenesis

day). The unexpected result was the appearance of cholesteroaemia, all treated animals having statistically significant increased serum cholesterol over that of controls and with raised plasma fibrinogen and activity of Factor VII, which would enhance atherogenesis. In addition, chronic hepatotoxicity was observed, which is in keeping with the findings

of the FBs. Similar results were found for baby hamster kidney cells treated with FBl (Abeywickrama and Bean, 1992). The mechanism of action of several mycotoxins, including FB, have been reviewed by Coulombe 3. HUMAN 3.1.

aimed at investigating their absorption

(1993).

INVOLVEMENT

Disease

3.1.1. Oesophageal derived directly from group of human OC occurs in geographical (Yang, 1980; Mingxin

cancer. The discovery of the FBs the investigation by the PROMEC in the Transkei in South Africa. OC pockets around the world, e.g., China et al., 1980), and was first reported

in the Transkei in 1957 (Burrell,

1957), an observation

that

was amply confirmed (Jaskiewicz et al., 1987a,b,d; Rose, 1973, 1982; Rose and McLashan, 1975; Van Rensburg, 1985). As in most rural communities in Southern Africa, the main staple of diet is maize. It was well established that maize grown in this region was susceptible to infection by several fungi, in particular Fusarium spp. (Marasas, 1982; Marasas et al., 1979, 1980, 1988a) and, of these, E moniliforme and E sub&.&nuns were the most prevalent, with Diplodiu muydis being third. Because of the high incidence of these fungi together with their mycotoxins, they were investigated in outbreaks of oc. A significant

difference

in the levels of FB in maize and

maize used for making home-brewed beer (Rheeder et al., 1992; Marasas et al., 1993) between high and low OC areas was found. A similar distribution

was found in China (Chu

and Li, 1994; Yoshizawa et al., 1994), where the incidence of FB in high-risk areas was twice that in low-risk areas. 3.1.2. Primate studies. In Section 2, the effects of the FBs on various animal species were considered. From the human point of view, it is disappointing

in other animal species. Further work on primates (Shephard

that no species seemed to

respond to FB in quite the same way and none developed OC. It seemed reasonable, therefore, that the best animal to model human response would be a primate, and several trials involving monkeys were done. Prior to isolation of the FBs, as part of a study on the effect of toxic extracts of E moniliforme on animals, baboons were found to develop hepatic cirrhosis and intraventricular thrombosis (Kriek et al., 1981). In another investigation, 10 young vervet monkeys were fed E moniliforme culture material (Jaskiewicz et al., 1987a). This was found to cause a toxic hepatitis of varying degrees related to the amount fed, with the release of liver enzymes into the serum paralleling the liver damage. In another trial, four male and seven female vervet monkeys were fed cultured material containing FBI, FB2, and FB3 (Fincham et al., 1992). Days of feeding ranged from 40 to 573 on a “high” dose regime (total

et al., 199413) was and excretion of FB,

as previously studied in rats (Shephard et al., 1992~). In this case, however, extraction from faeces was effected using EDTA, which presumably allowed the release of the FBs from their insoluble metal salts, which supports the idea of FBs as metal chelators. In one experiment, 2 vervet monkeys were given radiolabelled FBl at a rate of 8 mg/kg body weight. The bulk of the radiolabel was found in the faeces and consisted mainly of unchanged FBI and partially hydrolysed monoesterase

derivatives.

In a later, more detailed, investigation using four vervet monkeys (Shephard et al., 1994c), radiolabelled toxin was administered by gavage or i.p. injection. From 2 animals treated by i.p. injection, 47% of the dose was recovered in urine and faeces over 5 days as FBl or its partially hydrolysed derivatives, whereas 61% was recovered from dosed by gavage. A further 15% was accounted for latter animals, mainly as intestinal contents, with amounts in skeletal muscle, liver, brain, kidney,

those in the small heart,

erythrocytes, and bile. This result is intriguing, as a quarter of the fed material could not be accounted for, which is in contrast to the experiment with rats.

3.2.

Exposure

As already discussed in Section

1.5, FBs have been found

wherever maize is grown. Systematic examination for these mycotoxins in commodities destined for human consumption does not seem to be in place yet, and such investigations are dependent upon the interest of independent investigators and agencies. Marasas et al. (1993) reviewed the situation in Africa, and this makes spartan reading, considering the importance of maize as a staple for many populations who live in this continent. The figures given are mainly for the Transkei,

where work on OC was done.

FBl and FB2 were found in “good” homegrown maize in both low and high OC areas, and were significantly different in the survey done in 1985, e.g., FBI ranged from 0 to 550 pg/kg for low and 50 to 7900 pg/kg for high (Sydenham al., 1990b). In a 1989 survey, there was a higher trend for high OC areas, but this was not statistically significant. Nevertheless, FBl ranged up to 5380 pg/kg for “good” maize in the high areas (Sydenham et al., 1991; Rheeder et al., 1992). If these figures are not bad enough, the levels in mouldy maize for this regions were greatly elevated in 1989 showing, in some cases, a lo-fold increase of FBI in the high OC areas (up to 117,520 pg/kg) over low (11,340 fig/kg). The use of

et

mouldy

materials

regions

is common,

co-intoxicants, initiation. South

(Segal

FBI

district,

which

cating

the

The

in locally

size of the

OC

had levels situation

in other

of FBI

Other

studies*+

showed

in the

part of South in the

grown

rural

from

Africa,

as summarized

although

meal

from

2 and

opment

for safe levels vidual

other

intoxicants

to humans

that

approach,

but this,

as to how much for example, and

food

in the United

near

future

the

lated

3.3.2. strategies

Limiting

chain,

i.e., prevention strains

tigated

been

ment

intake.

and

goid bases, Riley

1989),

levels

of the toxin

their

absorbed

in viva measureis not

practical.

that

(Rheeder

indicates

that certain

living

people body

in the Transkei

weight

and this

from

increased

figures are alarming,

and efforts

adopted

and guidelines

and Canada

by indifor human

are expected

Of more farming ing,

in the

sealed that

and

storage

Cure been

are (e.g.,

rural populations of 0.014 “healthy”

for mouldy

maize.

must be made to mini-

facilities

$Sydenham. E. W., Shephard, G. S., Gelderhlom, W. C. A.. Thlel, P. G. and Marasas, W. E 0. (1993) F umonisins: their implications for human and animal health. In: Proceedings of the Unitrd Kingdom Workshop on the Occurrence and Significance of Mycotoxins, London, 21-23 April 1991, pp. 42-48. Skudamore, K. A. (ed.) MAFF, London.

such

Ammoniation

means feasible

has been

this has been attempted 1991b;

ment

to breakdown

1992),

and Scott

mg/L

Rats

were fed maize

FBI

from

E proliferatum

et al.,

1993).

nomas,

or treated Animals

indicating

was supported been hydrolysed. nutrients

et

with calcium

by the

Curiously, adenoma

that

cd.,

1995). made

by treat-

it was sug-

this process

degraded

contaminated then

with

supplemented

hydroxide

(Hendrich fewer ade-

was effective, almost

supplementation formation.

is

loss in wort spiked

diet had much

the treatment finding

in moist

fermentation

flour

had been

on the latter that

promoted

Alcohol

and

that prop-

(1994) obtained

(nixtamalization),

cultures

How-

showed

no mutagenic

in tortilla

that

and

success.

or temperatures

et al. (1991) that

FBs.

with nutrients

by cooking. maize (Norred

and Lawrence

(Scott

(VisDupuy

aflatoxins,

little

with a 3-28%

hydroxide

by Sydenham

with

present. FBl,

up to 0.95

but with

pressures

no FB was found calcium

in solution

to degrade

80%,

has not

mycotoxins

et ul., 1990;

Park et ~2. (1992)

by about

in removing

with

which

for other

with FB-contaminated

no ammonia

levels

rotation,

of the spoilage

are not eliminated

result with higher

Because

with grow-

but effective,

detoxification,

temperatures,

erties being elicited,

with

as crop

much

operation

shown

Voss et al.,

was reduced

ineffective

rhizo-

during

of simple,

minimise

FBs are resistant

with

where

is assistance

formation

Methods

could

agents,

1992).

mycotoxin

rt al., 1993) and, therefore,

maize

1989).

to the rural farmer

in this context

a similar

inves-

and Pandey.

with antagonistic

et al., 1994) and by heat” (Alberts

gested *Dutton, M. E, Robertson, J., Mathews, C. and Beck, B. D. A. (1991) Occurrence of mycotoxms in maze m rural areas of South Africa. In: Proceeding\ <,f the United Kingdom Workshop on the Occurrcncc and Slgn~ficancc of Mycntoxms, London, 21-23 April lY93, pp. 5641, Skudamore, K. A. (4.) MAFF, London. C. and Beck, B. D. A. (1993) + Dutton, M. E, Ruhcrtaon, J., Mathew, Occurrrnce of mycotoxins in maize in a rural area in South Africa and mcthoda of prcvcntion of contamlnatton and ellmmatwn. In: Proceedings of the ICC Inrernattonal Symposium: Cereal Science and Technology; Impact on n Changing Africa, Pretoria, 9-13 May 1993, pp. 821-815, Taylor, J. R. N., Randall, P. G. an d Villoen, J. H. (cd.) CSIR, Pretorta.

De Leon

to infection

are being

occurs.*

to date. The

FBl

strains

and construction

a commercially

conti

Such

broad

can be assisted

are resistant

Williamson,

storage.

of crops,

currently

Prevention

at planting

to limit

two

in the food

is the use of biocontrol

importance

harvest,

are

mycotoxins

that

of fungi.

and

practice

sun drying

There

et al., 1990a,b;

(Bacon

ever, at higher

investigated

so-called

bacteria

et ul.,

had a daily intake mg/kg

been

in limiting

are treated

of sphin-

et al. (1992) estimated

consuming to 0.44

Guidelines

have

cultivars

suggestion

these

1993b). evidence

that

These

1993)

Scott,

and this can be corre-

species

to high levels of FB. Thiel

mg/kg

With,

Kensler,

to suppose

are exposed

maize,

answer

could be the measurement animal

risk

is one

and

of exposure

is no reason

as in other

et al.,

Current

approach

the

of food

FBs are not easily

excreted,

or marker

as there

affected,

Because

As with

and

whereby

and animals,

are rapidly

as an index

A more fruitful not

developed

it is cer-

to FBs.

have ingested.

(Groopman

of analysis,

the world.

and cure.

with toxigenic

give a definitive

(Kuiper-Goodman

methods

around

contamination.

to be followed

alarming,

environment,

might

(Zoller

for the devel-

1995).

crop

et al.’

Analysis

cannot

aflatoxins

in humans

to recent

in animals

in itself,

A

have

are measured

in the

to ascertain.

in Switzerland not only

States,

States

(Miller,

being

analytical

in feeds

states in the United

by developing

the above statistics, are exposed

any individual

ochratoxin

methods

From

occur

is difficult

of FBs

et al., 1991).

is equally

by Sydenham

who eat maize

routine

Legislation

level for FBs in food

recommended

of sensitive

maize kernels

Control 3.3.1. Risk assessment.

tolerance

hut also for maize producers

lower,

3.3.

people

has been

levels.

foods is already

et al., 1994). This has ramifications,

Another

tain that

a preliminary

of 1 mg/kg

South

0 to 475 wg/kg, and

rest of the world

in Table

indi-

permitted

maize-based

populations.

maize,

Maize

the

KaNgwane

1780 to 2980 pg/kg (Sydenham

in the

of

et al., 1992) and

maize

ranging

parts

it has been

by FB does not cause

grown

problem

in OC

with the con-

Furthermore,

complacency.

that from Egypt, The

and

is in the northern

encourage

Africa

its action

of maize (Bothast

levels in commercially

not

contemplated;

1988).

breakdown.

of FBl

mise FB in food and to control

to promote

et cd., 1995) contaminated

appreciable

in these

of FBs levels in commercial

beer

et al.,

that fermentation

wort (Scott

making

does seem to be a connection

of home-brewed

presence

beer

well be that FB needs other

and it could

such as ethanol,

Africa

shown

in home-brewed

There

sumption

do

E Dutton

M.

150

all the

which FBl

had

of the diet with Maize

treated

with

bDupuy, J., Lc Bars, I’., Boudra, H. and Le Bars, J. (1993) Effect of thermal treatment of fumonism B, in maize. In: Proceedings of the United Kingdom Workshop on the Occurrence and Significance of Mycotoxins, London, 21-21 April 1993, pp. 191-195. Skudamore, K. A. (cd.) MAFF, London.

Fumonisins, Mycotoxins of Increasing Importance

151

0.1 M calcium hydroxide at room temperature for 24 hr lost the major part of their FBl content (‘75% and above) as hydrolysed product (Sydenham

et al., 1995a) in a two-step sequen-

tial process via a mixture of the monoesters

(Sydenham

et

al., 1995b). A method of reducing FB contamination is based on the observation that maize screenings generally contain the highest levels of FB (Colvin and Harrison, 1992; Wilson et al., 1992; Murphy et u1., 1993). This is a problem in animal feed, but it can be used in flour milling to improve the quality of grain, as increased

4.

refinement

nary, but are still at an early stage. Consequently,

many ques-

tions and puzzles still remain, e.g.: the polarity and presumable

from the GIT and passage through FBs transported The amount

lack of uptake

membranes,

how are

to exert their effect?

taken up from a single p.o. dose is
is

the toxin that potent? Where

does the unaccounted

primates? Why have not incidences

25% of the dose go in

of OC been reported

in test

animals? Why are there considerable

differences in the way various

species respond to the toxin? What effect does FB have on humans, and at what level? The question of absorption

of FBl from the GIT has not

been resolved by p.o. administration

of pure toxin, because

the uptake is very small in all animal models, and there is no reason to suspect that humans are any different. Several possibilities

and excre-

FBs, the problem of liver cancer in high-incidence areas, such as Southern Africa, should be reopened because they could well play a role alongside aflatoxins and hepatitis virus in the aetiology of this disease, in addition to other observed conditions such as idiopathic congestive cardi-

mans (1994), for example, suggest that toxicokinetics, as well as toxicodynamics, of these metabolites need to be thoroughly

studies on the FBs cannot be described as prelimi-

Considering

and lung oedema may hinge on detoxification

tion factors peculiar to the animals that exhibit them. Because of the distinct possibility of human intoxication with

opathy (Campbell, 1990). Clearly, further work is needed to elucidate the specific action of the FBs. Diaz and Boer-

reduces FB levels.

CONCLUSION

Current

as it appears, because all animal models tested had evidence of liver and kidney damage. Effects such as brain damage

present themselves:

potent or its absorption

either the toxin is highly

is aided by other dietary factors,

such as alcohol or fat. It seems unlikely that, in the digestive

investigated. Several reviews, e.g., Nelson et al. (1993) and Riley et al. (1993b), draw attention

as are safe levels

for animal

to the fact that

humans

consumption,

are ingesting

(Coulombe,

the toxin

on a world-wide

basis* by

the finding that “healthy” looking maize can be infected with Fusurium (Thomas

and Buddenhagen,

1980) and have high

levels of FBs (Thiel et al., 1992). Infection with Fusurium does not affect the outward quality of the grain, whereas other moulds do, e.g., Diplodia, constituting

‘ear rot” (Rheeder

et al., 1990b). Riley et al. (1993b) reported mittee of the American ratory Diagnosticians

that the Mycotoxin

Association

recommends

of Veterinary

ComLabo-

limits in feed (mg/kg)

as: equidue, 5; pigs, 10; cattle, 50; and poultry,

50. These

figures seem high and possibly are permitted because of the variation in levels of contamination

on a day-to-day basis.

A problem is the lack of residual FB in treated animals, which does not allow for assessment suring

in viva toxin

conjugates,

of exposure by mea-

as found

toxins (Gan et al., 1988). An alternative

tract, the toxin is modified into a more accessible form, e.g.,

sure sphinganine using established

systems that

and pointing

1993). The problem is further compounded

by esterification,

or that there are transport

to the concern that the effect of low

levels of FBs in human food is unknown,

and sphingosine methods

with the afla-

approach to mea-

levels, which are elevated

(Merrill

et al., 1988), however,

assist its passage, either present in an active or latent form.

holds out some hope for exposure studies, but detailed work

In their experiments

will be needed to correlate

with a horse given FBl by gavage or

i.p., Laurent et al. (1989a) concluded that other factors assisted absorption

from the stomach

As with

during digestion.

The presence of other toxic fungal metabolites rally contaminated dies with

unpurified

investigations or unrelated

commodities materials,

in natu-

does not help to clarify stuand

reports

from

may be flawed because of synergistic

such action

toxic effects. E moniliforme and E subglutinans

can produce several potent toxins in addition

to FBs, and

Dipiodia may&s, which was found to infect 9.4% of maize seeds in the Transkei (Marasas, 1982), is known to have strains that produce metabolites that are highly toxic towards chickens. These possibilities, factors, such as alcohol,

and the action of other dietary may explain the noninducement

of OC in model animals. The question of species response may not be as specific

exposure

levels with dose and

time periods. dangerous

most

mycotoxins,

and a problem,

the

FBs

are regarded

as

but there is a positive side. It

has been suggested that they may serve as templates for the development

of anti-atherosclerotic

and anticancer

drugs

(Norred, 1993). They will be used to elucidate the role of sphingolipids in cell regulatory mechanisms (see Hanada et al., 1993; Bose et al., 1995; and an excellent review by Merrill et ui., 1993b).

*Marasas, W. F. O., Shephard, G. S., Sydenham, E. W. and Thiel, l? G. (1993) World-wide contamination of maize wxh fumonisins: foodborne carcinogens produced by Fusnrium moniliforme. In: Proceedings of the ICC International Symposium: Cereal Science and Technology; Impact on a Changing Africa, Pretoria, 9-13 May 1993, pp. 791-805, Taylor, J. R. N., Randall, P. G. and Viljoen, J. H. (eds.) CSIR, Pretoria.

152

M. F. Dutton

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