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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.,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.


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.


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.


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.

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