J . TOXIC0L.-TOXIN REVIEWS, I8(3&4). 245-262 (1999)

MYCOTOXINS AND MYCOTOXICOSIS IN TUNISIA: WHAT DO WE KNOW AND WHAT DO WE NEED TO KNOW?

H. Bacha'*, K. Maaroufi'. L. Ghedira-Chekir', S. Abid', A. Chenf', A Achou?, E E.

CrePPY'

I Laboratoire de Biochimie et de Toxicologie Moleculaire, Faculte de Medecine Dentaire, Monastir, Tunisia, ' Service de Nephrologie, CHU et Facultt de Mtdecine. Monastir, Tunisia, ' Laboratoire de Toxicologie, UFR des Sciences Pharmaceutiques,

Universite de Bordeaux 11, 146 rue Leo-Saignat, 33076 Bordeaux Cedex, France

Abstract

Mycotoxins and the pathologies they induce are becoming a world-wide preoccupation and a cause of serious economic and sanitary problems. Tunisia is also concerned, due to its climate, geographic situation, and the social and economic conditions of the population. Many data, including our own, have previously implicated several mycotoxins in specific and severe pathologies. In Tunisia a clear cut correlation has been found between the consumption of food contaminated by toxigenic fungi and specific pathologies. Clinical and laboratory-based studies performed in our laboratory provide a mechanistic explanation for the toxic effects of some mycotoxins. Our interest was focused on two mycotoxins: Ochratoxin A and Zearalenone, which are widely found in Tunisia, contaminating various supports of human and animal food chain. Ochratoxin A (OTA), is the main causal agent of Balkan Endemic Nephropathy. We hereby bring evidence that this pathology no longer concerns only Balkans. Tunisia appears to be a second hot spot of this disease in the world. We have shown that zearalenone (Zen), adversely affected normal reproductive function of intoxicated animals. It produced modifications of haematological and hiochemical parameters of hepatic function. Zen is also a cytotoxic and genotoxic toxin. Vitamin E was found to be a good preventive compound for the cytotoxic and genotoxic effects of Zen.

* Author for correspondence

Copyright C 1999 by Marcel Dckker, Inc

245

www.dekker.com

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246 BACHA ET AL.

Mycotoxins and mycotoxicosis are a world-wide concern: what do we know?

The first published observations concerning human pathologies induced by the consumption of mould-contaminated food were reported in the late forties and fifties. Systematic studies were published on alimentary toxic aleukaemia (ATA), primitive liver cancer and Rey's syndrome (1-5). Currently, mycotoxicoses are becoming increasingly implicated in human and animal pathologies, both in industrial and developing countries (6-9). The proliferation of toxigenic fungal species depends on several factors including temperature (10,ll). humidity (12) and oxygen versus carbon dioxide ratio (13). In addition to these climatic factors, particular social conditions and behaviour, such as methods of preservation of food products, traditional feeding and environmental pollution may play a significant role.

Mycotoxins are ubiquitous. All countries are affected (14-34). and they cause substantial economic losses (Table 1). Their diverse chemical structure means they injure more than one organ or metabolic system, and different species may be affected. It is, however, difficult to prove a causal relationship. The aetiology of acute mycotoxicosis can be only established by detection of concentrations in feed, blood or tissue sufficient to cause toxic symptoms (35). This is more difficult for chronic disease, because the degenerative change only occurs months or years after an acute exposure, when it would be impossible to demonstrate mycotoxin levels. In addition, mycotoxin-induced syndromes are clinically the same as a whole range of diseases caused by pathogens, malnutrition and other toxic chemical and therapeutic agents (35).

Toxicological manifestations observed in human or in domestic animals generally result from combined and synergestic effects of multiple associated mycotoxins (36-38). Risk assessment of multiple mycotoxin exposure is difficult due to the number of possible combinations of mycotoxins, and their qualitative and quantitative seasonal variation. Table 2 , summaries clinical and toxicological manifestations caused by combinations of mycotoxins.

The situation in Tunisia

Previous reports have been made addressing mycotoxin contamination in foods and feeds in Tunisia. Samples were taken from the main points of production, storage and distribution of cereals over all of Tunisia and also from principal food products of the Tunisian alimentary chain, showed the presence of several mycotoxins. Various mycotoxins including aflatoxin B and G groups, ahratoxin A, citrinin, patulin, sterigmatocystin and some fusaro-toxins were detected, often at high levels in about 70 to 90% of analysed samples. Table 3 shows the contamination by

(33, 34, 57).

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MYCOTOXINS AND MYCOTOXICOSIS IN TUNISIA 241

Table 1. countries around the world

Occurrence levels of mycotoxins in food and feed commodities in some

Country

Egypt

Kenya

Nigeria

Uganda

Sudan

Tunisia

Congo

~

Mycotoxins

aflatoxins

aflatoxins

aflatoxins

aflatoxins

aflatoxins

aflatoxins

ochratoxin

zearalenone tnc hothecenes

aflatoxins

commodi ty

wheat, corn, lentils, peanuts

wheat, corn, rice

cereals, peanuts

Cereals

peanuts

corn, peanuts, pistachios, chickpea,

fir cone

cereals, various aliments

corn, hay cereals

Cereals

Level ot contamination

(ppb)

3-12

294-1050

200

1000

250

1-62

100-7550

5 -46,000

17,000

(continued)

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248

Hong Kong

India

Japan

Philippines

Thailand

BACHA ET AL.

aflatoxins corn, millet, barley

aflatoxins corn 105 ochratoxin corn, rice, wheat 180

sterigmatoc ystin 150

aflatoxins rice 10 ochratoxin cereals 5-7

citrinin cereals 70 trichothecenes cereals 27-190

aflatoxins rice 16 corns 400

aflatoxins corn 2730

Table 1 (continued)

ASIA

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MYCOTOXINS AND MYCOTOXICOSIS IN TUNISIA

EUROPE

Gemany

England

Denmark

France

Italy

Poland

Table I (continued)

aflatoxins

ochratoxin t nc hothecenes

ochatoxin

citrinin

aflatoxins

zearaleone

oc hratoxin

patuline

atlatoxins

trichothecenes

zearaleone

aflatoxins

wheat flour rye flour

corn, corn flour wheat, barley,

corn

barley, rye, wheat

barley

corn wheat

corn

corn wheat flour

peanuts dried sausage

apples apple juice grape juice

industrial cider

foods

cereals

foods

cereals

249

50 100

50-500

370-27.000

2000

11.5 180

2350

15- 200 35 19 25

4400 150 25 58

50- 1000 Tox

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250 BACHA ET AL.

Associated Effects mycotoxins

Ochratoxin A / Aflatoxin B1 Ochratoxin A /

Increase mortality, decrease body weight, increase liver weight, enhance kidney injury in poultry Enhance renal tumourigenesis in mice and pigs

Table 2. Clinical and toxicological manifestations induced by combinations of mycotoxins

Synergy

+ +

Citrinin Ochratoxin A / Deoxynivalenol Ochratoxin A /

decrease body weight, increase relative major organ weights decrease bodv weight, increase rodent mortality and

+ +

Penicillic acid renal roximal tub& necrosis Ochratoxin A / decrease body weight, increase organ weights, T2-Toxin temto enicit Aflatoxin B1 / increased relative organ weights, increased Cyclopiazonic Glutamic-Oxalacetic Transaminase and blood urea

nitogen, decrease serum albumin and phosphorus in chickens

Aflatoxin B1/ Increase mean comuscular haemoelobin and Kojic acid AflatoxinBl / Desoxynivalenol AflatoxinBl / T2-Toxin

Aflatoxin B1/ Rubratoxin B

haemoglobin concentrkions in chickens" Decrease body weight, increase major organ + weights Decrease body weight, increase major organ + weights, affect haematological parameters, impaired the immune system, increase mortality in mice and guinea pigs Increase lethality, change body weight +

References

39-44

45-48

49

50

51

52

53

19

21, 54, 55

18, 56

various mycotoxins of cereals and other typical foods of the Tunisian population. Our first epidemiological investigations in Tunisia showed clearly the link between the consumption of contaminated food by mycotoxins and the appearance of specific diseases (32). Table 4, gives some examples of cases in which mycotoxin contamination of foods were correlated to a specific disease.

Mycotoxins in Tunisia

We focused our attention on two mycotoxins, ochratoxin A and zearalenone, which were regularly detected. Ochratoxin A was regularly found in human and animal foods and in human blood. Zearalenone was found often in humad and animal foods.

Ochratoxin A.

Ochratoxin A (OTA) is a secondary metabolite produced by species of Aspergillus and Penicillium genera Its structure consists of a chlorinated dihydroisocoumarinic core

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MYCOTOXINS AND MYCOTOXICOSIS IN TUNISIA 25 1

Food samples (number)

Wheat (38)

Wheat (3)

Barley (23)

Flour (26)

Semolina (12)

Table 3. Contamination of common foods of the Tunisian population with vanous mycotoxins

Ongin Mycotoxins detected % of contaminated samples

-Tunisian storage and Aflatoxin B1 16 distnbution centers Ochratoxin A 52 - Particular harvests Citnnin 5

Stengmatocystin 5 Imported from Ochratoxin A 100

Canada Stengmatocystin 33 -Tunisian storage and Aflatoxin B1 8 distnbution centers Ochratoxln A 17 - Particular harvests

Aflatoxin B1 61 -Commercial trading Aflatoxin B2 46

-Particular stocks Ochratoxin A 42 Citnnin 7

-Commercial trading Aflatoxin B1 25 -Particular stock? Aflatoxin GI 16

Ochratoxin A 16 Aflatoxin B1 15

Couscous (64) -Commercial trading Aflatoxin G1 6

-Home-made Aflatoxin G2 Ochratoxin A

Noodles, “Tchich”, “Mhames”, “Chorba”

(53)

Bsissa: mixed cereal food

(43) Dried vegetables (12)

Pickled olives (1 1)

Dried meat of a fish (12)

Milk (8)

(OTa) linked by an amide bound to L-phenylalanine through the 7-carboxy group (Figure 1). We showed previously that Aspergillus spp., especially Aspergillus ochruceus is able to synthesize natural analogues of OTA in which the phenylalanine moiety is replaced by other amino acids (58). We think that the presence of a mixture of ochratoxin analogues could have additive or synergestic effects.

Patulin 3 -Commercial trading Aflatoxin GI 6

-Home-made Ochratoxin A 9 Deoxynivalenol 8

41 Aflatoxin B1 Home-made Diacetylnivalenol 35

Ochratoxin A 81 Fusarenone X 67

Commercial trading Ochratoxin A 66 Citrinin 8

-Commercial trading Aflatoxin B I 27 -Home-made Aflatoxin B2 18

Ochratoxin A 18 Home-made Ochratoxin A 58

37 Commercial trading Citrinin

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252

Table 4

Symptoms Patients

1

Disease suspected

2

3

4

5 (child, '

years old)

6

7

BACHA ET AL.

Presence of alimentary mycotoxin contamination correlated with a disease induced by specific mycotoxins

-Inflammation of the mucous membrane and gastrointestina tracts -Haemorrhagic diarrhoea - Leucopenia and decrease of blood platelets - Fever

Alimentary toxic

aleukaemia

Cirrhosis

Cirrhosis

-Intestinal inflammation -Haemorrhagic diarrhoea -Gastric ulcer -Fever

-Fever, convulsions, vomiting -Liver and kidney fatty degeneration -Chronic marrhoea -Intestinal inflammation -Haemorrhagic darrhoea -Decrease of blood platelets -Fever

Cirrhosis

Primary liver

carcinoma

Mycotoxins expected

Tricothecenes

Aflatoxins

Mycotoxins detected in foods

(frequently consumed)

-Fusarenone X -Diacet ylnivalenol -Aflatoxin B 1 -0chratoxin A -Citrinin

-Aflatoxin Bl -Aflatoxin B2 -Aflatoxin G1 -0chratoxin A -Aflatoxin B1 I P 7 z e y 1 Aflatoxins 1 -0chratoxin A -Citrinin

carcinoma

Alimentary t aleukaemia toxic Tricothecens

Rey's syndrome

Aflatoxins

Alimentary toxic

aleukaemia Tricothecenes

Primary liver

carcinoma Aflatoxins

-Deoxynivalenol -Diacetylnivalenol -Aflatoxin B 1 -Aflatoxin G1 -Citrinin

-Aflatoxin B 1 -Aflatoxin B2

-Deoxynivalenol -Diacetylnivalenol -Atlatoxin B 1 -Aflatoxin G1 -0chratoxin A -Citrinin

1 -Aflatoxin B 1 -Atlatoxin B2 -Aflatoxin G1 -0chratoxin A -Citrinin -Deoxynivalenol

Several studies performed in the Balkan Peninsula, principally in the former Yugoslavia, Bulgaria and Rumania, pointed to ochratoxin as the causal agent in Balkan Endemic Nephropathy (BEN) (14,15,59,60). This disease i s often associated with a high incidence of carcinoma of the renal pelvis, ureter and urinary bladder (61). In Tunisia our studies showed a connection between the presence of OTA in human blood and nephropathy (62-64). Our results concerning the determination of Ochratoxin in human

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MYCOTOXINS AND MYCOTOXICOSIS I N TUNISIA 253

Figure 1. Structure o f ochratoxin A (OTA)

blood in Tunisia indicated a probable high rate of human contamination. The range of contamination was found to be between 0.7 to 7.8 ng/ml for the general population and 12 to 5 5 ng/ml for people suffering from chronic renal failure. It appears that 21 to 6470 of people suffering from nephropathy are OTA-positive with a detection limit of 1 ng/ml. This situation prompted us to search for ii possible association of OTA contamination and nephropathy resembling Balkan Endemic Nephropathy. The classification of the patient population into Chronic Interstitial Nephropathy (CIN), Chronic Glomerular Nephropathy (CGN), Chronic Vascular Nephropathy (CVN) and others indicated that the largest is the CIN group, the number of which is significantly different from the other groups and from the control (P<O.OOS). Furthermore, i t presented the highest OTA mean values (25 to 59 nglml) compared with the control or with CGN. CVN and other groups (6 to 18 ng/ml) according to the designated region in Tunisia. The rural population seems to be more exposed to ochratoxins in Tunisia, as has been previously reported in the Balkans and Western Europe (65). These results suggest that in Tunisia, a new endemic hotbed of OTA-related nephropathy is likely occurnng (63).

Supplementary arguments were obtained from our results concerning OTA- contamination of the Tunisian food chain showing the link with blood contamination and CIN (66). Alimentary inquiry including the principal foodstuffs of the Tunisian alimentary chain in control and healthy population and in the CIN-OTA positive population was performed. To clarify the situation, food and blood samples were collected from nephropathic patients and controls (i.e., with no familial case of nephropathy). The OTA assay showed very different scales of OTA food and blood contamination from 0.1 to 16.6 nglkg and 0.1 to 2.3 ng/ml. respectively, in healthy individuals and 0.3 to 46830 nglkg for food and 0.7 to 1134 ng/ml for blood in nephropathic patients. The disease seems related to OTA-blood levels and food contamination since the control group was significantly different from the nephropathic group (P<O.OOS) for both food and blood ochratoxin contamination. On the basis of the average blood and food OTA concentrations found, the continuous daily intake (ng/kg body weight per day) could be 4.5 to 1522 ng/kg (66). This is very much higher than the

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254 BACHA ET AL.

level recommended by the Nordic Working Group (5 nglkg) (6768), and it could easily explain the existence of a possible endemic nephropathy in Tunisia.

In other studies we proved an OTA genotoxic effect i n a patient presenting with OTA in blood and suffering from chronic interstitial nephropathy of unknown aetiology. OTA-DNA adduct (the covalent complex between OTA and DNA bases) formation has been detected in DNA of kidney tissue (biopsy). DNA-adducts constitute the first steps of the carcinogenesis process (69). Cases of karyomegaly were described (70) in patients affected with tubular interstitial nephropathy. The karyomegalic cells showed enlarged nuclei with accumulation of genetic material. No aetiology was suggested. Our study in rats experimentally intoxicated with OTA, indicated the presence of karyomegaly with alteration of the tubular tissue. These results suggest that karyomegaly with megacytosis may be caused by OTA (71).

Zearalenone

Zearalenone (Zen) (Figure 2) is a non-steroidal estrogenic mycotoxin produced as a secondary metabolite by several species of Fusariurn which are contaminants of cereals all over the world (72-74). The concentration of this toxin can reach 289 wg/g in human food (75,76). In Tunisia, Zen was detected in cereals, and in corn and hay intended for feeding to domestic animals (33).

Zen has been implicated in numerous mycotoxicosis in animals in which an estrogenic response was produced, impairing the normal reproductive function (77). Our experiments on female rats confirmed that Zen induces important perturbations in the gestation cycle. Repeated intraperitoneal (i.p.) administration of Zen to female rats resulted in a decrease of progesterone level associated with a decrease of fertility along the cycle of fertilisation and gestation (78). The doses of Zen used were kept 60% below L.D. 50% value which is about 10 mg/kg (78). Animals administrated Zen before fertilisation were highly sensitive (low progesterone levels, fertility almost zero, absence of abortions and absence of resorption sites). Animals administrated Zen after fertilisation showed abortions and reduction of litter size. Our results indicate that Zen is not fetotoxic compound. It seems rather to induce a sterilization or at least exhibits a contraceptive effect in animals treated before fertilisation.

In addition to the impairment of the normal reproductive function, we observed that Zen administration to rats (i.p. administration of 1.5 to 5 mgkg) produced forty- eight hours later a change of same blood parameters (hematocrit, mean corpuscular volume, the number of platelets and white blood corpuscles) as well as some biochemical markers such as aminotransferase (ALT, AST), alkaline phosphatase (ALP), serum

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MYCOTOXINS AND MYCOTOXICOSIS I N TUNISIA 255

Figure 2 . Structure of zearalenone (Zen)

creatinine, bilirubin, indicating liver toxicity and likely impairment of blood coagulation process (79).

We have also conducted studies of genotoxicity with Zen. Zen and its metabolites showed a positive DNA-damaging effect in recombination tests with Bacillus subfilis (80). We also detected and quantitated DNA-adducts in female mice and rats treated i.p. or orally with Zen (81). Several DNA-adducts (12 to 15) were found in the kidney and liver of female mice treated with a single dose of Zen (2 mg/kg i.p. or orally). The total DNA-adduct levels reached 114 and 1393 adducts/109 nucleotides, respectively, in kidney and liver. In mouse ovaries DNA-adducts appeared only after repeated doses ( I m a g body weight every two days during 10 days). These results confirm the genotoxicity of Zen and its ability to induce hepatocellular adenomas, rather than turnours of genital organs (81). The effects of some vitamins such as retinol (vitamin A), ascorbic acid (vitamin C) and a-tocopherol (vitamin E), which are known to act as a superoxide anion scavengers, were tested on ochrdtoxin A genotoxicity (82). Our experiments showed that pretreatment of mice by vitamin E decreased DNA-adducts by 80% in liver and inhibited totally DNA-adduct formation in kidney and genital organs (83).

Interactions between the DNA and xenobiotics are considered to be the critical step in the initiation of mutagenesis and carcinogenesis (84, 85). Furthermore, a good correlation was found between the number of DNA-adducts formed and the frequency of mutations and tumour incidence during chronic carcinogen exposure (86). To fully assess the genotoxic potential of Zen and its implication in mutagenesis and carcinogenesis, we tested the SOS repair gene response in lysogenic bacteria (E. coli which have an integrated lambda-bacteriophage in their genome) after incubation with Zen. This response was measured by the bacterial lysis induced in the release of lambda- bacteriophage as a consequence of DNA damage caused by Zen. Since vitamin E was found to prevent the cytotoxicity and lipid-peroxidation induced by Zen (87) and to prevent DNA-adduct formation, we also investigated its preventive effect on the SOS

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256 BACHA ET AL.

repair system in the presence of Zen (88). Our results showed that Zen was found to be genotoxic in the bacterial system from a concentration of 1.50 mM and it was also bactericidal (IC5,=1.45mM). In addition, vitamin E (6.0-12.0 mM) added one hour prior to the toxin prevented both the genotoxic and bactericidal effects of Zen. This vitamin could be acting both as an antioxidant and as a radical scavenger.

Altogether our data confirm that Zen is genotoxic, and a likely mutagenic compound, since it induced the SOS-DNA repair system. The results also showed specific prevention of genetoxicity by vitamin E, especially when present in the medium before addition of the toxin. The specificity of this prevention is probably due to the similarity of structure between vitamin E and Zen (88). The protective effect of vitamin E against the cytotoxicity and the genotoxicity of Zen, suggests that this vitamin could be added to animal and human feed as a protective agent.

MYCOTOXINS AND MYCOTOXICOSIS IN TUNISIA: WHAT WE NEED TO KNOW ?

In Tunisia ochratoxin A has been regularly found in food samples, as well as in human blood for many years. Since there is a correlation between ochratoxin A in human food, blood contamination and chronic interstitial nephropathy, and since biological, biochemical, clinical and radiological parameters seem very similar to those of Balkan Endemic Nephropathy, it might be assumed that human nephropathy related to ochratoxin A is occurring in Tunisia. A case-control inquiry is now necessary to evaluate the role of ochratoxin A as risk factor for inducing end stage renal disease.

In order to better define the role of mycotoxins in human and animal diseases future studies that are needed are:

monitoring of mycotoxins in food, animal feeds and blood, using standard and comparable methods; improving food storage conditions in exposed population to minimise intake criteria for diagnosis of mycotoxin-related disease need to have standard clinical

criteria and diagnostic features 9 more sensitive morphological and biochemical markers are needed to detect early

degenerative changes epidemiological and clinical studies should use standardised questionnaires and of

new molecular markers of target organ injury preventive techniques should be developed including:

exhaustive information of exposed population against mycotoxin hazards

search and tests of antidotal compounds (phenylalanine, aspartam, peroxicam for ochratoxins (89). vitamin E for zearalenone (83,88)).

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MYCOTOXINS A N D MYCOTOXICOSIS IN TUNISIA 257

REFERENCES

1 Sarkisov, A , in Doklad na Komissi Posepticheskoi Angine Ychenogo Meditsins Kikh Soveta Narkonsdrawa, S S R , 1946

2. Mironov, S.G., Joffe, A.Z., Bakbardina, M.K., Fok, R.A. and Davidowa, V.L., Phytopathological analysis of toxic samples of overwintered millet in alimentary toxic aleukaemia, Orenburg Inst. Epidemiol. Microbiol., 2: 11, 1947.

3. Bilai, V.I., in Izdatel’stuo Akad Nauk. p. 93, Ukrain S.S.R., 1953

4. Uraguchi, K., Tatsumo. M., Tsukioka, M., Sakai, F., Kobayashi, Y . , Saito. M., Enomoto, M. and Miyake, M., Toxicological approach to the metabolites of Penicilliurn islandicuni Spp growing on the yellowed rice, Jpn J . Exp. Med., 31: I , 1961.

5 . Reye, R.D.K., Morgan, G . and Baral, J. , Encephalopathy and fatty degeneration of the viscera, a disease entity in childhood, Lancet, i i : 749, 1963.

6. Senti, F.R.. in mycotoxins in Human and Animal Health, edited by J.V. Rodricks, C.W. Hesseltine and M.A. Mehlman, p. 779, Pathotox Publishers, Park Forest South, Illinois, 1977.

7. First International Symposium of Monastir “Pollution, Bioconversion, Toxicology” (April 19-21, 1993). Biologia de Tunisie, H. Bacha (volume I , February 1993).

8. Colloque INSERM “Human ochratoxicosis and its pathologies” (Bordeaux, July 4-6, 1993), INSERWJohn Libbey EUROTEXT, E.E. Creppy, M. Castegnaro and G. Dirheimer, (volume 231, 1993).

9. Mycotox 98 “Mycotoxins in food chain, processing and toxicological aspects” (Toulouse, July 2-4, 1998), Revue de Medecine VCtCrinaire, J . Le Bars and P. Galtier (volume: June 1998).

10. Moreau, C., in Moisissures Toxiques dans I’alimentation, edited by MASSON ET Cie, p. 471, Paris, 1974.

11. Le Bars, J., Ecologie des Moisissures Toxinogbnes, Cah. Nutr. Diet. (Mycotoxines), 2: 23. 1976.

12. Golumbic, C. and Kulik, M.M.. i n Aflatoxin, edited by L.A. Goldblatt, p. 307,

13. Landers, K.E., Davis, N.D. and Diener, U.L., Influence of atmosphenc gas on aflatoxin production by Aspergillus flavus in peanuts, Phytopathology, 57: 1086, 1967.

Academic Press, New York, 1969.

14. WHO, Word Heath Organisation, IPCS Environmental Health Criteria Document 11, Mycotoxins, WHOIIPCS, Geneve, 1979.

15. WHO, Word Heath Organisation, IPCS Environmental Health Criteria Document 105, Selected Mycotoxins, Ochratoxin, Trichothenes, Ergot, WHO/IPCS, Geneve, 1990.

16. Chelkowslu, J., Golinski, P. and Wiewiorowska, M., Mycotoxins in cereal grain. Part 12. Contamination with ochratoxin A and penicillic acid as indicator of improper storage of cereal grain, Nhrung, 31: 81, 1987.

Tox

in R

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from

info

rmah

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care

.com

by

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n Fr

anci

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on 0

5/11

/14

For

pers

onal

use

onl

y.

258 BACHA ET AL.

17. Ciegler, A,, Bioproduction of ochratoxin and penicillic acid by members of the Aspergillus ochruceus group, Canad. J . Microbiol.. 18: 631, 1972.

18. Hayes, A.W.. Cain, J.A. and Moore, B.G., Effect of aflatoxin BI. ochratoxin A and rubratoxin B on infant rats. Foot Cosmet. Toxicol., 15: 23, 1977.

19. Huff, W.E., Kubena, L.F., Harvey, R.B., Hagler, W.M., Swanson, S.P., Phillips, T.D. and Creger, C.R., Individual and combined effects of aflatoxin and deoxynivalenol (DON, Vomitoxin) in broiler chickens, Poult. Sci., 65: 1291, 1986.

20. Huff, W.E., Kubena, L.F., Harvey, R.B. and Doerr, J.A., Mycotoxin interactions in poultry and swine, J. Animal. Sci., 66: 2351, 1988a.

21. Huff, W.E., Harvey, R.B., Kubena, L.F. and Rottinghaus, G.E., Toxic synergism between aflatoxin and T-2 toxin in broiler chickens, Poult. Sci., 67: 1418, 1988b.

22. Jelinek, C.F., Pohland, A.E. and Wood, G.E., Worldwide occurence of mycotoxins in food and feeds, an update. J. Assoc. Off. Anal. Chem., 72: 223, 1989.

23. Jonsyn, F.E.. Seedbome fungi of sesame (Sesumum indicum L) in Sierra Leone and their potential aflatoxidmycotoxin production, Mycopathologia, 104: 123, 1988.

24. Krogh, P., Hald, B. and Pederson, E.J., Occurrence of ochratoxin A and citrinin in cereals associated with mycotoxic porcine nephropathy , Acta Pathol. Microbiol Scand. B, 81: 689, 1973.

25. Lillehoj, E.B. and Ciegler, A,, in Microbiology, edited by D. Schlessinger, p. 344,

26. Pathre, S.V. and Mirocha, C.J., in Mycotoxins in Human and Animal Health, edited by J.V. Rodricks, C.W. Hesseltine and M.A. Mehlman, p. 229, Pathotox Publishers, Park Forest South, Illinois, 1977.

27. Scott, P.M., van Walbeek, W., Kennedy, B. and Anyeti, D., Mycotoxins (ochratoxin A, citrinin and sterigmatocystin) and toxigenic fungi in grains and other agricultural products, J. Agric. Food Chem., 20: 1103, 1972.

American Society for Microbiology, Washington DC, 1975.

28. Scott, P.M., Mycotoxins in feeds and ingredients and their origin, J . Food Protect., 41: 385, 1978.

29. Soares, L.M. and Rodriguez-Amaya, D.B., Survey of aflatoxins, ochratoxin A, zearalenone and sterigmatocystin in some Brazilian foods by using multi-toxin thin- layer chromathographic method, J.A.O.A.C.. 72: 22, 1989.

30.Ueno. Y., in Mycotoxins in Food, edited by P. Krogh, p. 123, Academic Press, Cambridge, 1987.

31. Watson, D.H., Toxic fungal metabolites in foods, CRC Critical Reviews in Food

32. Hadidane, R., Roger-Regnault, C., Bouattour, H., Ellouz, F., Bacha, H., Creppy, E.E. and Dirheimer, G., Correlation between alimentary mycotoxin contamination and specific diseases, Hum. Toxicol., 4: 491, 1985.

33. Bacha, H., Hadidane, R., Regnault, C.R., Ellouz, F., Creppy, E.E. and Dirheimer, G., Mycotoxines et Mycotoxicoses en Tunisie, Cahiers MCdicaux de Tunisie-Nutrition et sant6,49: 34, 1986.

Science and Nutrition, 22: 177, 1985. Tox

in R

evie

ws

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

ity o

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anci

sco

on 0

5/11

/14

For

pers

onal

use

onl

y.

MYCOTOXINS AND MYCOTOXICOSIS IN TUNISIA 259

34. Bacha, H., Hadidane, R., Creppy, E.E., Regnault, C.R., Ellouz, F. and Dirheimer, G., Monitoring and identification of fungal toxins in food products, animal feed and cereals in Tunisia, J. Stored Prod. Res., 24: 199, 1988.

35. Pier, A.C., Richard, J.L. and Cysewski, S.J., Implications of mycotoxins in animal diseases, J. Am. Vet. Med. Assoc.. 176: 719, 1980.

36. Huff, W.E. and Doerr, J.A. , Synergism between aflatoxin and ochratoxin A in broiler chikens. Poutl. Sci., 60: 550, 1981.

37. Blaude, M.N., Goethals, F.M., Ansay, M.A. and Roberfroid, M.B., Interaction between aflatoxin B 1 and oxytetracycline in isolated rat hepatocytes, Cell Biol. Toxicol., 6: 339, 1990.

38. Blaude, M.N., Goethals, F.M., Ansay, M.A. and Roberfroid, M.B., Synergism between aflatoxin B1 and oxytetracycline on fatty acid esterification in isolated rat hepatocytes, Toxicol. Lett., 61: 159, 1992.

39. Brownie, C.F. and Brownie, C., Preliminary study on serum enzyme changes in Long Evans rats given parenteral ochratoxin A, aflatoxin B1 and their combination, Vet. Human Toxicol., 30: 21 I , 1988.

40. Campbell, M.L., May, J.D., Huff, W.E. and Doerr, J.A., Evaluation of immunity of young broiler chickens during simultaneous aflatoxicosis and ochratoxicosis, Poult. Sci., 62: 2138, 1983.

41. Harvey, R.B., Huff, W.E., Kubena, L.F. and Phillips, T.D., Evaluation of diets cocontaminated with aflatoxin and ochratoxin fed to growing pigs, Am. J. Vet. Res., SO: 1400,1989.

42. Huff, W.E., Doerr, J.A., Wabeck, C.J., Chaloupka, G.W., May, J.D. and Merkley, J.W., Individual and combined effects on aflatoxin and ochratoxin A on bruising in broiler chickens, Poult. Sci., 62: 1764, 1983.

43. Micco, C., Miraglia, M., Benelli, L., Onori, R., Ioppolo, A. and Mantovani, A.L., Long term administration of low doses of mycotoxins in poultry. 2. Residues of ochratoxin A and aflatoxin in broilers and laying hens after combined administration of ochratoxin A and aflatoxin B I , Food Add. Contam., 5: 309, 1988.

44. Tapia, M.O. and Seawright, A.A., Experimental combined aflatoxin B1 and ochratoxin A intoxication in pigs, Australian Veterinary Journal, 62: 33, 1985.

45. Creppy, E.E., Lorkowski, G., Beck, G., Roschenthaler, R. and Dirheimer, G., Combined action of citrinin and ochratoxin A on hepatoma tissue culture cells, Toxicol. Lett., 5: 375, 1980.

46. Kanisawa, M., Synergistic effect of citrinin on hepatorenal carcinogenesis of

47. Manning, R.O., Brown, T.P., Wyatt, R.D. and Fletcher, O.J., The individual and combined effects of citrinin and ochratoxin A in broiler chicks, Avian. Dis., 29: 986, 1985.

ochratoxin A in mice, Devel. Food Sci.. 7: 245, 1984.

48. Sandor, G., Busch, A., Watzke, H., Reek, J. and Vanyi, A., Subacute toxicity testing of ochratoxin A and citrinin in swine, Acta Vet. Hung., 39: 149, 1991.

49. Kubena, L.F., Huff, W.E., Harvey, R.B., Comer, D.E., Phillips, T.D. and Creger, C.R., Influence of ochratoxin A and deoxynivalenol on growing broiler chicks, Poult. Sci., 67: 253, 1988.

Tox

in R

evie

ws

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

ity o

f C

alif

orni

a Sa

n Fr

anci

sco

on 0

5/11

/14

For

pers

onal

use

onl

y.

260 BACHA ET AL.

50. Kubena, L.F., Phillips, T.D., Witzel, D.A. and Heidelbaugh, N.D., Toxicity of ochratoxin A and penicillic acid to chicks, Bull. Environ. Contain. Toxicol., 32: 717, 1984.

51. Kubena, L.F., Harvey, R.B., Huff, W.E., Corrier, D.E., Phillips, T.D. and Rottinghaus, G.E., Influence of ochratoxin A and T-2 Toxln singly and in combination on broiler chickens, Poult. Sci., 68: 867, 1989.

52. Smith, E.E., Kubena, L.F., Braithwaite, C.E.. Harvey, R.B., Phillips, T.D. and Reine, A.H., Toxicological evaluation of aflatoxin and cyclopiazonic acid in broiler chickens, Poult. Sci., 71: 1136, 1992.

53. Giroir, L.E., Huff, W.E., Kubena, L.F., Harvey, R.B., Elissalde, M.H., Witzel, D.A., Yersin, A.G. and Ivie, G.W., The individual and combined toxicity of kojic acid and aflatoxin in broiler chickens, Poult. Sci., 70: 1351, 1991.

54. Pier, A.C., Varman, M.J., Dahlgren, R.R., Belden, E.L. and Maki, L.R., in Mycotoxins and Phycotoxins, edited by P.S. Steyn and R . Vleggaar, p. 423, Elsevier Science Publishers, Amsterdam, 1986.

55. Harvey, R.B., Kubena, L.F., Huff, W.E., Corrier, D.E., Rottinghaus. G.E. and Phillips, T.D., Effects of treatment of growing swine with aflatoxin and T-2 toxin, Am. J. Vet. Res., 51: 1688, 1990.

56. Wogan, G.N., Edwards, G.S. and Newberne, P.M., Acute and chronic toxicology of

57. Boutrif, E., Jemmali, M., Campbell, A.D. and Pohland, A.E., Aflatoxin in Tunisian

58. Hadidane, R., Bacha, H., Creppy, E.E., Hammami, M., Ellouz, F. and Dirheimer, G.. Isolation and structure determination of natural analogues of the mycotoxin ochratoxin A produced by Aspergillus Ochraceus, Toxicology, 76: 233, 1992.

59. Krogh, P., Hald, B., Plestina, R. and Ceovic, S., Balkan Endemic Nephropathy and foodborn ochratoxin A: preliminary results of survey of foodstuffs, Acta Pathol. Microbiol. Scand., Sect. B, 85: 238, 1977.

rubratoxin B, Toxicol. Appl. Pharmacol., 19: 712, 1971.

food and foodstuffs, Ann. Nutr. Alim., 31: 431, 1977.

60. Krogh, P., Elling, F., Friss, C.H.R., Hald, B., Larsen, A.E., Lillehoj. E.B., Madsen, A,, Mortensen, H.P., Rasmussen, F. and Ravoskov, V., Porcine nephropathy induced by long term ingestion of ochratoxin A, Vet. Pathol., 16: 466, 1979.

61. Castegnaro, M. and Chemozemsky, I.N., Endemic nephropathy and urinary tract tumors in the Balkans, Cancer Res., 47: 3608, 1987.

62- Bacha, H., Maaroufi, K., Achour, A., Hammami, M., Ellouz, F. and Creppy, E.E. in Human ochratoxicosis and its pathologies, edited by E.E. Creppy, M. Castegnaro and G. Dirheimer, p. I l l , INSERWJohn Libbey EUROTEXT, 1993.

63. Maaroufi, K., Achour, A,, Hammami, M., El May, M., Betbeder. A.M., Ellouz, F., Creppy, E.E. and Bacha, H., Ochratoxins in human blood and nephropathy in Tunisia, Human Exp. Toxicol., 14: 609, 1995.

64. Maaroufi, K., Achour, A,, Zakhama, A,, Ellouz, F., EL May, M.. Creppy, E.E. and Bacha, H., Human nephropathy related to ochratoxin A in Tunisia, J. Toxico1.-Toxin Reviews, 15 (3): 223, 1996.

65. Chernozemsky, I.N., Stoyanov, I.S.. Petkova-Bocharova, T.K., Nocolov, I.G., Draganov, I.G., Stoichev, I., Tanchev, Y., Naidenov, D. and Kalcheva, N.D., Geographic correlation between the occurence of endemic nephropathy and unnary tract tumours in Vratza district, Bulgaria, J. Cancer., 19: I . 1977.

Tox

in R

evie

ws

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

ity o

f C

alif

orni

a Sa

n Fr

anci

sco

on 0

5/11

/14

For

pers

onal

use

onl

y.

MYCOTOXINS AND MYCOTOXICOSIS I N WNISIA 26 I

66. Maaroufi, K.. Achour. A.. Bethcdei. A.M., Hammami. M., Ellouz.. F.. Creppy. E.E. and Bacha. H.. Foodstuffs and human blood contamination by the mycotoxin ochratoxin A: correlation with chronic interstitial nephropathy in Tunisia, Archives of Toxicology. 69: 552. 1995.

67. Hagelberg, S., Hult. K . and Fuchs. R.. Toxicokinetics of Ochratoxin A i n several species and its plasma-binding propcities. J . Appl. Toxicol., 9: 91. 1989.

68. Klaassen C.D., in: The basic science of poisons. Casarett and Doull’s Toxicology, edited by C.D. Klaassen and J. Doull. p. 33. New-York. MacMillan. 1986.

69. Maaroufi, K.. Pfohl-Leszkowicz, A , , Achour, A,. El May, M., Grosse, Y . . Hammami. M., Ellouz, F., Creppy. E.E. and Bacha. H., Gtnotoxicitt de I’ochratoxine A. relation avec la tumeur renale, Archs. Inst. Pasteur Tunis, 71: 21. 1994.

70. Godin. M., Rancois, A,. Le Roy, F., Morin, J.P., Creppy. E.E., Hemet, J. and Fillastre. J.P., Karyomegalic interstitial nephritis. American Journal of Kidney Diseases. 27: 166, 1996.

71. Maaroufi. K.. Abid. S . , Cherif, A,. Zakhama. A,, Achour, A,, Creppy, E.E. and Bacha, H.. Human ochratoxicosis in Tunisia, Molecular aspects, Journal of Toxicology-Toxin Reviews, 1999 (this volume).

72. Bennet, G.A. and Shotwell. O.L.. Zearalenone in cereal grains. J . Amer. Oil Chem. Soc., 56: 812, 1979.

73. Sutton, J.C., Balik, W. and Funnett, H.S.. Relation of weather variables to incidence of zearalenone in corn in Southern Ontano, Can. J. Plant. Sci., 60: 149, 1980.

74. Trenholm, H.L., Thompson, B.K.. Standish. J.F. and Seamen, W.L., in Mycotoxins: A Canadian Perspective, edited hy P.M. Scott, H.L. Tranholm and M.D. Sutton, p. 43, National Research Council o f Canada, Ottawa, Ontario, 22848, 1985.

75. Kim, J.C., Kang, H.J.. Lee, D.H.. Lee, Y.W. and Yoshizawa, T., Natural occurence of Fusariirrtr mycotoxins (trichothecenes and zearalenone) in barley and corn in Korea, Appl. Environ. Microbiol.. 59: 3798, 1993.

76. Yuwai, K.E., Rao, K.L., Singh, K., Tanaka, T. and Ueno, Y., Occurence of nivalenol, deoxynivalenol and zearalenone i n imported cereals in Papua. New Guinea, Natural Toxins, 2: 19, 1994

77. Etienne, M. and Jemmali, M.. Effects of zearalenone (F2) on estrus activity and reproduction in gilts, J. Anim. Sci., 55: I, 1982.

78. Bacha, H., Chekir, L., Ellouz. F. and Creppy, E.E., in Proceeding of a UK workshop held at Brunel, the University of West London, edited by K.A. Scudamore, p. 258, London, 1994.

79. Maaroufi. K., Chekir, L., Creppy, E.E., Ellouz, F. and Bacha, H., Zearalenone induces modifications of haematological and biochemical parameters in rats, Toxicon, 34: 535. 1996.

80. Ueno. Y , and Kubota. K., DNA-attacking ability of carcinogenic mycotoxins in recombination-deficient mutant cells of Bacillus subtilis, Cancer Res., 36: 445, 1976.

8 I . Pfohl-Leszkowicz, A., Chekir-Ghedira. L. and Bacha, H.. Genotoxicity of zearalenone, an oestrogenic mycotoxin: DNA adduct formation in female mouse tissues, Carcinogenesis, 16: 23 15. lY95.

Tox

in R

evie

ws

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

ity o

f C

alif

orni

a Sa

n Fr

anci

sco

on 0

5/11

/14

For

pers

onal

use

onl

y.

262 BACHA ET AL.

82. Pfohl-Ixszkowicz, A., Grosse, Y., Kane, A,, Gharbi, A,, Baudnmont, I., Obrecht, S., Creppy, E.E. and Dirheimer, G., in Human ochratoxicosis and its pathologies, edited by E.E. Creppy, M. Castegnaro and G. Dirheirner, p. 177, I N S E M J o h n Libbey EUROTEXT, 1993.

83. Grosse, Y., Chekir-Ghedira, L., Huc, A,, Obrecht-Pflumio, S., Dirheirner, G., Bacha, H. and Pfohl-Leszkowicz, A,, Retinol, ascorbic acid and a-tocopherol prevent DNA adduct formation in mice treated with the mycotoxins ochratoxin A and zearalenone, Cancer Letters, 114: 225, 1997.

84. Miller, E.C. and Miller, J.A., Searches for ultimate chemical carcinogens and their

85. Beland, F.A. and Kadhiban, F.F., Formation and persistence of arylamine DNA- adducts in vivo, Environ. Health Perspect., 62: 19, 1985.

86. Poirier, M.C. and Beland, F.A., DNA adducts measurements and tumor incidence during chronic carcinogen exposure in animal models: implications for DNA adduct- based human cancer risk assessment, Chem. Res. Toxicol., 5: 749, 1992.

87. Ghedira-Chekir, L., Maaroufi, K., Creppy, E.E. and Bacha, H., Cytotoxic and genotoxic effects of zearalenone: prevention by vitamin E, Journal of Toxicology- Toxin reviews, 1999 (this volume).

88. Ghedira-Chekir, L., Maaroufi, K., Zakhama, A,, Ellouz, F.. Dhouib, S., Creppy, E.E. and Bacha, H., Induction of a SOS repair system in lysogenic bactena by zearalenone and its prevention by vitamin E, Chemico-Biol. Int., 113: 15, 1998.

89. Baudrirnont, I., Variation de la nkphrotoxicite de I’ochratoxine A sous I’effet de facteurs mktaboliques et non mttaboliques. PhD Thesis (N”2). Bordeaux 2 University, France, 1995.

reactions with cellular macromolecules, Cancer, 47: 2327, 1981.

Tox

in R

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ws

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from

info

rmah

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care

.com

by

Uni

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onl

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