fumonisinas B1

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Short communication

Antinutritional effects of fumonisin B1and pathophysiological

consequences

M.R. Carratu a,*, T. Cassano a, A. Coluccia a, P. Borracci a, V. Cuomo b

a Department of Pharmacology and Human Physiology, Medical School, University of Bari, Policlinico, Piazza G. Cesare, Bari 70124,

Italyb Department of Pharmacology of Natural Substances and General Physiology, University of Rome, La Sapienza, P.le Aldo Moro 5,

Rome 00185, Italy

Received 15 September 2002; accepted 12 December 2002

Abstract

Due to its structural similarity with sphingosine, fumonisin B1 (FB1) inhibits ceramide synthase (a key enzyme of

sphingolipid biosynthesis) leading to an intracellular accumulation of sphingoid bases with a consequent increase of

sphinganine/sphingosine (SA/SO) ratio. In adult male rats, dietary exposure to fumonisin induces a significant increase

in both SA concentrations and SA/SO ratio in kidney, but not in liver and brain, as well as a significant reduction ofbody weight gain. Regarding the brain, the developing rat is more sensitive to FB1 than the adult rat. FB1 treatment

produces in the forebrain and brainstem: (i) an increase in SA levels and SA/SO ratio, (ii) a reduction in myelin

deposition, and (iii) an impairment of 2?,3?-cyclic nucleotide 3?-phosphohydrolase (CNP) activity. FB1effects on myelin

are similar to those produced by starvation (temporary removal of pups from dam during postnatal period), thus

suggesting that hypomyelination could be due, at least partly, to a nutritional deficiency. Finally, FB1 reduces the

uptake of folate in different cell lines. The resulting folate deficiency could explain the association of FB1exposure with

neural tube defects.

# 2003 Elsevier Science Ireland Ltd. All rights reserved.

Keywords: Fumonisin; Ceramide synthase; 2?,3?-Cyclic nucleotide 3?-phosphohydrolase; Folate uptake; Pathophysiology

1. Introduction

Fumonisins are mycotoxins produced by Fusar-

ium verticillioides (/F. moniliforme ) and F. pro-

liferatum which are found in corn crops worldwide

(Bezuidenhout et al., 1988; Hopmans and Mur-

phy, 1993). Ingestion of fumonisin B1, which

contaminates food and feed (Shephard et al.,

1990; Ueno et al., 1993), has been associated

with leucoencephalomalacia in both horses (Mar-

asas et al., 1988) and rabbits (Bucci et al., 1996),

pulmonary oedema in pigs (Harrison et al., 1990),

and nephrotoxicity and liver cancer in rats (Gel-

derblom et al., 1996). Although the effects of this

mycotoxin on human are difficult to evaluate,

* Corresponding author. Tel.: /39-080-5478455; fax: /39-

080-5478444.

E-mail address: [email protected](M.R. Carratu).

Toxicology Letters 140/141 (2003) 459/463

www.elsevier.com/locate/toxlet

0378-4274/03/$ - see front matter # 2003 Elsevier Science Ireland Ltd. All rights reserved.

doi:10.1016/S0378-4274(03)00042-0
mailto:[email protected]:[email protected]


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epidemiological studies show a high incidence of

oesophageal cancer in certain areas of Transkei

(South Africa) and also in China (Yang, 1980;

Rheeder et al., 1992; Chu and Li, 1994).Due to its structural similarity with sphingosine

(Bezuidenhout et al., 1988; Laurent et al., 1989),

FB1inhibits the ceramide synthase activity leading

to an intracellular accumulation of sphingoid

bases (mainly sphinganine relative to sphingosine),

which mediate several key biological processes

such as cell proliferation and DNA replication.

Inhibition of ceramide synthase results in an

increase of SA/SO ratio, which is considered a

useful biomarker to assess fumonisin exposure.

This ratio can be evaluated in tissues (such askidney and liver) and biological fluids of both

human and animals (Riley et al., 1993; Qui and

Liu, 2001). Further mechanisms responsible for

FB1 toxicity include inhibition of protein and

DNA synthesis (Abado-Becognee et al., 1998)

and lipid peroxidation (prevented by vitamin E),

as shown in both primary rat hepatocytes (Abel

and Gelderblom, 1998) and C6 glioma cells

(Mobio et al., 2000).

This paper briefly reviews the results of our

recent studies as well as literature data dealingwith FB1-induced disruption of sphingolipid me-

tabolism and its consequences on folate deficiency

and brain development.

2. Effects of dietary fumonisin exposure on tissue

levels of sphingoid bases

In agreement with the literature data (Merrill et

al., 1996; Riley et al., 1993), our recent studies

(Solfrizzo et al., 2001) have shown that dietary

exposure to fumonisin induces, in the adult rat, anincrease in SA concentration and SA/SO ratio in

kidney. In particular, mean kidney SA/SO ratios

are found to be 5.8-fold higher in rats fed FB1-

contaminated diet than in rats fed control diet.

Dietary exposure to fumonisin does not alter SA/

SO ratio and SA concentrations in liver and brain,

thus suggesting that kidney could be considered

the main target of this mycotoxin. Data relative to

body weight gain, feed consumption, and organ

weights are reported inTable 1. Exposure to FB1-

contaminated diets produces a significant reduc-

tion of body weight gain and a significant increase

of liver weight.

3. FB1 and nutritional deficiency outcomes on

developing brain

As far as the brain is concerned, the developing

rat is a more sensitiv

e model to study FB1 effectsthan the adult rat since this mycotoxin is a

hydrophilic, lipid-insoluble compound with a re-

latively large molecular weight. In this regard, it

has been shown that FB1 administration from

postnatal day (PND) 2/12 produces the following

effects in the forebrain and brainstem: (i) increase

in SA levels and SA/SO ratio, (ii) reduction in

myelin deposition, and (iii) impairment of 2?,3?-

cyclic nucleotide 3?-phosphohydrolase (CNP) ac-

tivity (Kwon et al., 1997). Moreover, a significant

decrease in body weight gain is observed in FB1-

treated animals. The effects produced by FB1 aresimilar to those induced by nutritional deficiencies.

Temporary removal of pups from dam during

postnatal period (6/7 h per day from PND 3 to

12) significantly decreases body weight gain as well

as myelin deposition and CNP activity in forebrain

and brainstem. However, unlike FB1, nutritional

deficiencies during postnatal period do not affect

sphingoid base levels and SA/SO ratios in the

brain. These data, summarized in Table 2, show

that FB1exposure affects sphingolipid metabolism

Table 1

Body weight, feed consumption, and organ weight data of male

Wistar rats fed control diet and fumonisin-contaminated diets

for 1 week

Parameters Control FB1 (4 ppm)

Initial body weight (g) 268.79/5.5 277.59/5.9

Final body weight (g) 308.09/6.8 282.09/4.3

Body weight gain (g) 39.29/9.4 4.59/5.7*

Feed consumption (g) 15.09/1.3 15.69/1.6

Absolute liver weight (g) 7.279/0.30 9.459/0.45*

Relative liver weight (mg/g)a 23.629/1.04 33.549/1.77*

Absolute kidney weight (g) 1.929/0.05 2.089/0.12

Relative kidney weight (mg/g)a 6.259/0.28 7.49/0.53

a Organ weight (mg) to body weight (g) ratio.

* PB/0.05 (one-way ANOVA; n/4).

M.R. Carratu et al. / Toxicology Letters 140/141 (2003) 459/463460


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in the central nervous system of developing rats by

specifically impairing ceramide synthase activity as

indicated by the increased SA levels. Furthermore,

these findings point out that, unlike FB1, nutri-

tional deficiency resulting in hypomyelination and

impairment of CNP activity, does not alter sphin-

golipid biosynthesis since no change in brain SA

levels are observed after starvation. Therefore,

nutritional deficiency has no effect on ceramide

synthase activity.

4. Is there any link between FB1-induced

sphingolipid depletion and folate deficiency?

Sphingolipids seem to play an important role in

folate receptor function. This high-affinity recep-

tor, a glycosylphosphatidylinositol (GPI)-an-

chored protein, is responsible for the transport of

folate into cells of several tissues with elevated

requirements for this vitamin. The folate vitamins

play an essential role as cofactors in many

biochemical reactions including the biosynthesis

of purines and thymidine, the regeneration of

methionine from homocysteine, and histidine me-

tabolism. Cellular processes dependent upon folatecan be compromised if dietary levels of this

vitamin are insufficient or its transport into cells

is affected. The GPI-anchored folate receptor is

associated with membrane domains that are en-

riched in cholesterol and phospholipids. Depletion

of cellular cholesterol has been shown to inhibit

vitamin uptake by this receptor (Chang et al.,

1992). Moreover, the importance of sphingolipids

for folate receptor function has been demonstrated

in CaCo-2 cells treated with FB1 that inhibits the

biosynthesis of these lipids (Stevens and Tang,

1997). In FB1-treated cells, the folate receptor-

mediated transport of 5-methyltetrahydrofolate is

inhibited in a concentration- and time-dependentmanner. The sphingolipid levels of these cells also

decrease in a concentration- and time-dependent

manner, thus suggesting that the inhibition of 5-

methyltetrahydrofolate uptake in FB1-treated cells

is mediated by changes in the sphingolipid com-

position. Moreover, a concurrent loss in the total

amount of folate binding capacity in the cells is

observed, as sphingolipids are depleted, thus

suggesting a causal relationship between folate

receptor density and vitamin uptake. Similarly, an

inhibition of folate uptake is also observed incultured primary embryonic cells treated with

fumonisin. Collectively, these findings suggest

that dietary exposure to FB1could adversely affect

folate uptake and potentially compromise cellular

processes dependent on this vitamin. Finally, it

should be pointed out that, since folate deficiency

causes neural tube defects, some birth defects

unexplained by other known risk factors may be

caused by exposure to FB1.

5. Conclusions

Inhibition of sphingolipid biosynthesis, leading

to an intracellular accumulation of sphingoid

bases, still seems to be the main mechanism of

fumonisin toxicity. The consequent increase in SA/

SO ratio provides a useful biomarker to assess

exposure to this mycotoxin in both human and

experimental animals.

Investigations into the consequences of fetal

exposure to this mycotoxin have also shown

relevant developmental toxicity. The mouse fetusessurviving to birth have gross skeletal and tissutal

abnormalities (Floss et al., 1994; Gross et al.,

1994). Similarly to nutritional deficiency, FB1exposure induces hypomyelination and it impairs

CNP-specific activity. Factors affecting myelin

deposition after FB1 exposure may include (i)

antinutritional effects, (ii) consequences of in-

creased brain SA levels, and/or (iii) SA-indepen-

dent FB1-induced toxicity. Since postnatal

nutritional deprivation also reduces myelin synth-

Table 2

Effects of nutritional deficiency (ND) and FB1 exposure in the

developing rat

Parameters FB1 ND

Body weight gain / /

Myelin deposition (forebrain and brainstem) / /

CNP activity (forebrain and brainstem) / /

SA concentration / NE

SA/SO ratio / NE

//reduction; //increase; NE/no effect.

M.R. Carratu et al. / Toxicology Letters 140/141 (2003) 459/463 461


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esis (Wiggins et al., 1976), hypomyelination asso-

ciated with FB1treatment is supposed to be due, at

least partly, to a nutritional deficiency.

Finally, FB1-induced depletion of sphingolipidsinhibits folate uptake leading to an intracellular

deficiency in this vitamin. Folate deficiency during

the first trimester of pregnancy is associated with

an increased risk of neural tube defects (Hibbard,

1993; Butterworth, 1993; Dansky et al., 1992).

Therefore, it is possible that some birth defects

unexplained by the known risk factors might be

linked to dietary FB1exposure. For instance, high

rates of neural tube defects have been observed

among Hispanic (Canfield et al., 1996), for whom

corn and corn products represent a sizeableportion of their diet. In conclusion, the experi-

mental evidence that FB1-induced depletion of

cellular sphingolipids inhibits folate uptake sug-

gests that further investigations are needed to

explore the possibility that this mycotoxin may

contribute to some birth defects not accounted for

by other known risk factors.

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