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Boussabbeh M.,Laboratory for Research on Biologically Compatible Compounds | Salem I.B.,Laboratory for Research on Biologically Compatible Compounds | Prola A.,French Institute of Health and Medical Research | Guilbert A.,French Institute of Health and Medical Research | And 5 more authors.
Toxicological Sciences | Year: 2015

Patulin (PAT) is a toxic metabolite produced by several filamentous fungi of the genera of Penicillium, Aspergillus, and Byssochlamys. PAT is the most common mycotoxin found in apples and apple-based products including juice, compotes, cider, and baby food. Exposure to this mycotoxin has been reported to induce intestinal and kidney injuries. This study investigated the mechanism of PAT-induced toxicity in human colon carcinoma (HCT116) and embryonic kidney cells (HEK293). We demonstrated that PAT activated endoplasmic reticulum (ER) and unfolded protein response as evidenced by up-regulation of GRP78 and GADD34, splicing of XBP1 mRNA, and expression of the proapoptotic factor CHOP. This ER stress response was accompanied by the induction of the mitochondrial apoptotic pathway. Apoptosis occurred with ROS production, drop in mitochondrial membrane potential and caspase activation. Further, we showed that deficiency of the proapoptotic protein Bax or Bak protected cells against PAT-induced apoptosis. The treatment of cells with the ROS scavenger N-acetyl cysteine inhibits the ER stress response and prevents mitochondrial apoptosis. Collectively, our data provide new mechanistic insights in the signaling pathways of the cell death induced by PAT and demonstrate that PAT induces cytotoxicity through a ROS-dependent mechanism involving ER stress and activation of mitochondrial apoptotic pathway in human intestinal and kidney cells. © The Author 2015.


Bensassi F.,Laboratory for Research on Biologically Compatible Compounds | Bensassi F.,National Institute for Agricultural Research | Gallerne C.,French Institute of Health and Medical Research | Sharaf El Dein O.,French Institute of Health and Medical Research | And 4 more authors.
Toxicon | Year: 2014

It is expected that humans are exposed to combined mycotoxins, which occur simultaneously in the food items, than to individual compounds and that can increase their potential toxicity. Considering this coincident production, deoxynivalenol (DON) and zearalenone (ZEN) as they are produced by several Fusarium species, can interfere at a cellular level. Therefore, these two toxins were chosen to study their interactive effects on human colon carcinoma cells (HCT116), using the endpoints including cell viability, cell cycle analysis, mitochondrial transmembrane potential (ΔΨm) determination and permeability transition pore (PTP) opening. Our results showed that DON and ZEN caused a marked decrease of cell viability in a dose-dependent manner, mediated by an activation of the mitochondrial apoptotic process; characterized by PTP opening and the loss of ΔΨm. Nevertheless, combined DON and ZEN reduced all the toxicities observed with the mycotoxins separately. Therefore, the combination of the two mycotoxins appears as a sub-additive response. © 2014 Elsevier Ltd. All rights reserved.


Zaied C.,Laboratory for Research on Biologically Compatible Compounds | Bouaziz C.,Laboratory for Research on Biologically Compatible Compounds | Azizi I.,Laboratory for Research on Biologically Compatible Compounds | Bensassi F.,Laboratory for Research on Biologically Compatible Compounds | And 3 more authors.
Experimental and Toxicologic Pathology | Year: 2011

Ochratoxin A (OTA) produced by Aspergillus and Penicillium genera contaminates cereals and different food compounds. OTA presents a wide range of toxic effects, especially nephrotoxicity. It is also considered to be the main causal agent of Balkan Endemic Nephropathy (BEN) which is similar to the Chronic Interstitial Nephropathy with unknown aetiology seen in Tunisia.In this study, we attempted to confirm the relationship between OTA blood levels and the development of renal pathology. Hence, serum OTA levels were measured in several groups of patients having different renal diseases: a group presenting Chronic Interstitial Nephropathy (CIN) with unknown aetiology, a group presenting Chronic Interstitial Nephropathy (CIN) with known aetiology, a group presenting Chronic Glomerular Nephropathy (CGN), and a group presenting Chronic Vascular Nephropathy (CVN). Each group was compared to a healthy control group.In the healthy group, 49% of individuals showed OTA concentrations ranging from 1.7 to 8.5. ng/ml, with a mean value of 3.3 ± 1.5. ng/ml. However, among nephropathic patients, the group with CIN of unknown aetiology showed the highest incidence (76%), ranging from 1.8 to 65 ng/ml with a mean value of 18 ± 7 ng/ml. Even in the healthy group, the calculated Daily Intake (DI) ranged from 5.0 to 24.9. ng/kg. b.w./day when compared to the recommended DI by the scientific committee on foods of 5 ng/kg. b.w./day, indicating a high degree of exposure to OTA in the Tunisian population.Our study confirms the involvement of this nephrotoxic mycotoxin, present at high blood levels in the Tunisian population, in the outcome of this particular human nephropathy (CIN with unknown aetiology) which is similar to BEN. © 2010 Elsevier GmbH.


Sakly A.,University of Monastir | Ayed Y.,Laboratory for Research on Biologically Compatible Compounds | Chaari N.,EPS Fattouma Bourguiba of Monastir | Akrout M.,EPS Fattouma Bourguiba of Monastir | And 2 more authors.
Genetic Testing and Molecular Biomarkers | Year: 2013

Epidemiological studies suggest that cytogenetic biomarkers, such as micronuclei (MN) in peripheral blood lymphocytes may predict cancer risk because they indicate genomic instability. The objective of the present study was to evaluate the frequencies of MN and chromosome aberrations (CA) in peripheral blood lymphocytes of hospital workers exposed to ionizing radiation and healthy subjects. The study was conducted using peripheral blood lymphocytes from 30 workers from the radiology department and 30 from the cardiology department. This study included 27 healthy age- and sex-matched individuals as the control group. The assessment of chromosomal damage was carried out by the use of CA and micronucleus assays in peripheral lymphocytes. Our results show that CA and micronucleus frequencies were significantly higher among the exposed groups when compared to controls. Our finding of significant increase of CA and MN frequencies in peripheral lymphocytes in exposed workers indicates a potential cytogenetic hazard due to this exposure. The enhanced chromosomal damage of subjects exposed to genotoxic agents emphasizes the need to develop safety programs. © Copyright 2013, Mary Ann Liebert, Inc. 2013.


PubMed | University of Monastir, Laboratory for Research on Biologically Compatible Compounds and University of Carthage
Type: Journal Article | Journal: Human & experimental toxicology | Year: 2016

Zearalenone (ZEN) is a mycotoxin from Fusarium species commonly found in food commodities and is known to cause reproductive disorders. Several in vivo studies have shown that ZEN is haematotoxic and hepatotoxic and causes several alterations of immunological parameters. Meantime, the available information on the cardiotoxic effects of ZEN is very much limited. In the present study, we investigated the toxic effects of ZEN in heart tissues of Balb/c mice. We demonstrated that ZEN (40 mg kg(-1) body weight (b.w.)) increased creatine phosphokinase, lactate dehydrogenase, aspartate transaminase, alanine transaminase, total cholesterol and triglyceride levels and induced oxidative stress as monitored by measuring the malondialdehyde level, the generation of protein carbonyls, the catalase and superoxide dismutase activity and the expression of the heat shock proteins (Hsp 70). We also demonstrated that acute administration of ZEN triggers apoptosis in cardiac tissue. Furthermore, we aimed to evaluate the safety and efficacy of crocin (CRO), a natural carotenoid, to prevent ZEN-induced cardiotoxicity in mice. In fact, combined treatment of ZEN with different doses of CRO (50, 100, and 250 mg kg(-1) b.w.) showed a significant reduction of ZEN-induced toxicity for all tested markers in a dose-dependent manner. It could be concluded that CRO was effective in the protection against ZEN-induced toxicity in cardiac tissue.


Bensassi F.,Laboratory for Research on Biologically Compatible Compounds
Toxicology | Year: 2011

Alternariol monomethyl ether (AME) is a major mycotoxin produced by fungi of the genus Alternaria and a common contaminant of food products such as fruits and cereals worldwide. AME can cause serious health problems for animals as well as for humans. In this study, human colon carcinoma cells (HCT116) were used to explore the mechanisms of cell death induced by AME. Exposure of HCT116 cells to AME resulted in significant cytotoxicity manifested by a loss in cell viability mainly mediated by activation of apoptotic process. AME activated the mitochondrial apoptotic pathway evidenced by the opening of the mitochondrial permeability transition pore (PTP), loss of the mitochondrial transmembrane potential (ΔΨm) downstream generation of O(2)(-), cytochrome c release and caspase 9 and 3 activation. Experiments conducted on isolated organelles indicated that AME does not directly target mitochondria to induce PTP-dependent permeabilization of mitochondrial membranes. Moreover, no difference was observed in Bax-KO cells in comparison to parental cells, suggesting that the pro-apoptotic protein Bax is not involved in AME-induced mitochondrial apoptosis. Our findings demonstrate for the first time that AME induces cell death in human colon carcinoma cells by activating the mitochondrial pathway of apoptosis. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.


Bensassi F.,Laboratory for Research on Biologically Compatible Compounds | Bensassi F.,The National Institute for Agricultural Research | Gallerne C.,French Institute of Health and Medical Research | Sharaf El Dein O.,French Institute of Health and Medical Research | And 4 more authors.
Toxicology in Vitro | Year: 2012

Mycotoxins are unavoidable contaminants of most foods and feeds, and some are known to be detrimental to human health. It is thus worthwhile to understand how cells of the intestinal system, one of the primary targets of these toxins, respond to their toxic effects. In this study, human colon carcinoma cells were used to elucidate the cell death mode and the pathways triggered by Alternariol (AOH), the most important mycotoxin produced by Alternaria species, which are the most common mycoflora infecting small grain cereals worldwide. Treatment of cells with AOH resulted in a loss of cell viability by inducing apoptosis. AOH-induced apoptosis was mediated through a mitochondria-dependent pathway, characterized by a p53 activation, an opening of the mitochondrial permeability transition pore (PTP), a loss of mitochondrial transmembrane potential (ΔΨm), a downstream generation of O2- and caspase 9 and 3 activation. Besides, deficiency of the pro-apoptotic protein Bax partially protected cells against AOH-induced mitochondrial alterations. In addition, experiments performed on purified mitochondria indicated that AOH does not directly target this organelle to induce cell death. Our results demonstrate for the first time that AOH-induced cytotoxicity is mediated by activation of the mitochondrial pathway of apoptosis in human colon carcinoma cells. © 2012 Elsevier Ltd.


Ayed Y.,Laboratory for Research on Biologically Compatible Compounds | Chayma B.,Laboratory for Research on Biologically Compatible Compounds | Hayla A.,Laboratory for Research on Biologically Compatible Compounds | Abid S.,Laboratory for Research on Biologically Compatible Compounds | Bacha H.,Laboratory for Research on Biologically Compatible Compounds
Environmental Toxicology | Year: 2013

Pelagia noctiluca, a jellyfish widely distributed in the Mediterranean waters, especially in coastal areas of Tunisia, has garnered attention because of its stinging capacity and the resulting public health hazard. Crude extracts of P. noctiluca nematocysts have been tested for their cytotoxicity on Vero cells. Our results clearly showed that nematocysts induced cell mortality in a dose- and time-dependent manner. A cytoprotective effect against cell mortality was obtained when Vero cells were treated with Vitamin E. This process was further confirmed by the generation of reactive oxygen species (ROS) and the induction of Hsp 70 and 27 protein expressions. Thus, our findings suggested that oxidative stress is involved in the toxicity of pelagia nematocysts and may therefore constitute the major mechanism of this medusa nematocysts toxicity. © 2011 Wiley Periodicals, Inc.


Bensassi F.,Laboratory for Research on Biologically Compatible Compounds | Bensassi F.,The National Institute for Agricultural Research | Zaied C.,Laboratory for Research on Biologically Compatible Compounds | Abid S.,Laboratory for Research on Biologically Compatible Compounds | And 2 more authors.
Food Control | Year: 2010

Wheat is frequently contaminated by the deoxynivalenol (DON) which is a member of the trichotecene family, the most important group of mycotoxins produced by the Fusarium moulds. As Tunisian population is a big consumer of cereals mainly durum wheat, human exposure to DON can be, consequently high. This survey was performed to study the occurrence of DON in Tunisian durum wheat area during the crop of 2007. A total of 65 samples of durum wheat from five cultivating locations in the North of Tunisia, the major cropping area, were analysed. To detect and to quantify the mycotoxin DON, an efficient HPLC/UV method was developed, including immunoaffinity step for DON extraction from durum wheat followed by liquid chromatography (LC) for quantification. As DON is a water soluble toxin, the extraction procedure from wheat samples was performed using water. Samples were centrifuged then passed through the immunoaffinity columns. After column's washing, the toxin was slowly eluted by methanol. Wheat sample extracts were injected to the LC system set at a wavelength of 220 nm. From 65 samples, 83% showed DON contamination with averages ranging from 12.8 ± 5% to 30.5 ± 13.3% μg/g exceeding the maximum permitted limit of 1.75 μg/g set by the European Commission in wheat. © 2009 Elsevier Ltd. All rights reserved.


Bensassi F.,Laboratory for Research on Biologically Compatible Compounds | Bensassi F.,The National Institute for Agricultural Research | Gallerne C.,French Institute of Health and Medical Research | Sharaf El Dein O.,French Institute of Health and Medical Research | And 4 more authors.
Food and Chemical Toxicology | Year: 2012

Deoxynivalenol (DON) is a widespread trichothecene mycotoxin which contaminates cereal crops and harmfully affects the gastrointestinal tract. Since it is well known that mitochondria play a central role in apoptosis triggered by many stimuli, an effort was made to examine whether DON-induced cytotoxicity occurs through mitochondria-mediated apoptotic pathway. The intestinal system being one of the primary targets of mycotoxins, the human colon carcinoma cell line HCT116 was used in this study. Using flow cytometric analyses and immunofluorescence, we showed that DON at 100. μM induced a mitochondria-dependent apoptotic pathway associated with opening of the mitochondrial permeability transition pore (PTP), loss of the mitochondrial transmembrane potential (ΔΨm), downstream generation of O2- and cytochrome c release. The DON-induced apoptosis was accompanied by an activation of caspase 9 and 3, as demonstrated by Western blot and caspase activity assay. In addition, by taking advantage of HCT116 cells invalidated for Bax, we showed that this pro-apoptotic protein favored mitochondrial alterations induced by the mycotoxin. Besides, incubation of purified mitochondria with DON indicated that this mycotoxin does not directly target mitochondria to induce PTP-dependent permeabilization of mitochondrial membranes. Altogether, our results indicate that mitochondria-related caspase-dependent apoptotic pathway is involved in this in vitro model of DON induced-cytotoxicity. © 2012 Elsevier Ltd.

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