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Yamamoto T, Nakayama J, Urabe F, Ito K, Nishida-Aoki N, Kitagawa M, Yokoi A, Kuroda M, Hattori Y, Yamamoto Y, Ochiya T. Aberrant regulation of serine metabolism drives extracellular vesicle release and cancer progression. Cell Rep 2024; 43:114517. [PMID: 39024098 DOI: 10.1016/j.celrep.2024.114517] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Revised: 04/23/2024] [Accepted: 07/01/2024] [Indexed: 07/20/2024] Open
Abstract
Cancer cells secrete extracellular vesicles (EVs) to regulate cells in the tumor microenvironment to benefit their own growth and survive in the patient's body. Although emerging evidence has demonstrated the molecular mechanisms of EV release, regulating cancer-specific EV secretion remains challenging. In this study, we applied a microRNA library to reveal the universal mechanisms of EV secretion from cancer cells. Here, we identified miR-891b and its direct target gene, phosphoserine aminotransferase 1 (PSAT1), which promotes EV secretion through the serine-ceramide synthesis pathway. Inhibition of PSAT1 affected EV secretion in multiple types of cancer, suggesting that the miR-891b/PSAT1 axis shares a common mechanism of EV secretion from cancer cells. Interestingly, aberrant PSAT1 expression also regulated cancer metastasis via EV secretion. Our data link the PSAT1-controlled EV secretion mechanism and cancer metastasis and show the potential of this mechanism as a therapeutic target in multiple types of cancer.
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Affiliation(s)
- Tomofumi Yamamoto
- Department of Molecular and Cellular Medicine, Institute of Medical Science, Tokyo Medical University, Tokyo, Japan; Laboratory of Integrative Oncology, National Cancer Center Research Institute, Tokyo, Japan; Division of Biological Chemistry and Biologicals, National Institute of Health Sciences, Kanagawa, Japan
| | - Jun Nakayama
- Laboratory of Integrative Oncology, National Cancer Center Research Institute, Tokyo, Japan; Department of Oncogenesis and Growth Regulation, Research Institute, Osaka International Cancer Institute, Osaka, Japan
| | - Fumihiko Urabe
- Laboratory of Integrative Oncology, National Cancer Center Research Institute, Tokyo, Japan
| | - Kagenori Ito
- Laboratory of Integrative Oncology, National Cancer Center Research Institute, Tokyo, Japan
| | - Nao Nishida-Aoki
- Waseda Institute for Advanced Study, Waseda University, Tokyo, Japan
| | - Masami Kitagawa
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan; Bell Research Center, Department of Obstetrics and Gynecology Collaborative Research, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Akira Yokoi
- Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan; Nagoya University Institute for Advanced Research, Nagoya, Japan
| | - Masahiko Kuroda
- Department of Molecular Pathology, Tokyo Medical University, Tokyo, Japan
| | - Yutaka Hattori
- Clinical Physiology and Therapeutics, Keio University Faculty of Pharmacy, Tokyo, Japan
| | - Yusuke Yamamoto
- Laboratory of Integrative Oncology, National Cancer Center Research Institute, Tokyo, Japan.
| | - Takahiro Ochiya
- Department of Molecular and Cellular Medicine, Institute of Medical Science, Tokyo Medical University, Tokyo, Japan.
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Riedel S, Abel S, Burger HM, Swanevelder S, Gelderblom WCA. Fumonisin B 1 protects against long-chained polyunsaturated fatty acid-induced cell death in HepG2 cells - implications for cancer promotion. BIOCHIMICA ET BIOPHYSICA ACTA. BIOMEMBRANES 2024; 1866:184310. [PMID: 38479610 DOI: 10.1016/j.bbamem.2024.184310] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Revised: 02/19/2024] [Accepted: 03/08/2024] [Indexed: 04/12/2024]
Abstract
Fumonisin B1 (FB1), a food-borne mycotoxin, is a cancer promoter in rodent liver and augments proliferation of initiated cells while inhibiting the growth of normal hepatocytes by disrupting lipid biosynthesis at various levels. HepG2 cancer cells exhibited resistance to FB1-induced toxic effects presumably due to their low content of polyunsaturated fatty acids (PUFA) even though FB1-typical lipid changes were observed, e.g. significantly increased phosphatidylethanolamine (PE), decreased sphingomyelin and cholesterol content, increased sphinganine (Sa) and sphinganine/sphingosine ratio, increased C18:1ω-9, decreased C20:4ω-6 content in PE and decreased C20:4ω-6_PC/PE ratio. Increasing PUFA content of HepG2 cells with phosphatidylcholine (PC) vesicles containing C20:4ω-6 (SAPC) or C22:6ω-3 (SDPC) disrupted cell survival, cellular redox status and induced oxidative stress and apoptosis. A partially protective effect of FB1 was evident in PUFA-enriched HepG2 cells which may be related to the FB1-induced reduction in oxidative stress and the disruption of key cell membrane constituents indicative of a resistant lipid phenotype. Interactions between different ω-6 and ω-3 PUFA, membrane constituents including cholesterol, and the glycerophospho- and sphingolipids and FB1 in this cell model provide further support for the resistant lipid phenotype and its role in the complex cellular effects underlying the cancer promoting potential of the fumonisins.
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Affiliation(s)
- Sylvia Riedel
- Biomedical Research and Innovation Platform, South African Medical Research Council, PO Box 19070, Tygerberg 7505, South Africa; Centre for Cardiometabolic Research in Africa (CARMA), Division of Medical Physiology, Faculty of Medicine and Health Sciences, Stellenbosch University, PO Box 241, Cape Town 8000, South Africa.
| | - Stefan Abel
- Applied Microbial and Health Biotechnology Institute, Cape Peninsula University of Technology, PO Box 1906, Bellville 7535, South Africa.
| | - Hester-Mari Burger
- Unit of Research Integrity, Research Directorate, Cape Peninsula University of Technology, Bellville 7535, South Africa.
| | - Sonja Swanevelder
- Biostatistics Research Unit, South African Medical Research Council, PO Box 19070, Tygerberg 7505, South Africa.
| | - Wentzel C A Gelderblom
- Department of Biochemistry, Stellenbosch University, Private Bag X1, Matieland 7602, South Africa
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Research Progress on Fumonisin B1 Contamination and Toxicity: A Review. Molecules 2021; 26:molecules26175238. [PMID: 34500671 PMCID: PMC8434385 DOI: 10.3390/molecules26175238] [Citation(s) in RCA: 77] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 08/24/2021] [Accepted: 08/24/2021] [Indexed: 12/19/2022] Open
Abstract
Fumonisin B1 (FB1), belonging to the member of fumonisins, is one of the most toxic mycotoxins produced mainly by Fusarium proliferatum and Fusarium verticillioide. FB1 has caused extensive contamination worldwide, mainly in corn, rice, wheat, and their products, while it also poses a health risk and is toxic to animals and human. It has been shown to cause oxidative stress, endoplasmic reticulum stress, cellular autophagy, and apoptosis. This review focuses on the current stage of FB1 contamination, its toxic effects of acute toxicity, immunotoxicity, organ toxicity, and reproductive toxicity on animals and humans. The potential toxic mechanisms of FB1 are discussed. One of the main aims of the work is to provide a reliable reference strategy for understanding the occurrence and toxicity of FB1.
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Hou L, Yuan X, Le G, Lin Z, Gan F, Li H, Huang K. Fumonisin B1 induces nephrotoxicity via autophagy mediated by mTORC1 instead of mTORC2 in human renal tubule epithelial cells. Food Chem Toxicol 2021; 149:112037. [PMID: 33548371 DOI: 10.1016/j.fct.2021.112037] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 01/12/2021] [Accepted: 01/29/2021] [Indexed: 02/07/2023]
Abstract
Fumonisin B1 (FB1), a worldwide contaminating mycotoxin, can cause global food issue. It has been reported that FB1 is related to chronic kidney disease of unknown etiology. However, the study of FB1-induced nephrotoxicity in vitro is very limited and the mechanism is unknown. Human renal tubule epithelial (HK-2) cells were used in this study. The results showed that FB1 exposure could decrease cell viability, induce cell apoptosis and up-regulate the expression of Kim-1, collagen I, α-SMA and TGF-β1. In addition, autophagy was activated after FB1 exposure, including the conversion of LC3 and up-regulation of ATGs. Furthermore, autophagy inhibitor 3-MA could block FB1-induced abnormalities. And antioxidant enzymes (Gpx1 and Gpx4) were obviously down-regulated and intracellular ROS levels displayed an ascent trend as FB1 exposure concentrations increased. Employing of antioxidant NAC could suppress FB1-induced nephrotoxicity and autophagy. FB1 inhibited the phosphorylation of p70 S6k, a downstream protein of mTORC1. Also, oxidative stress, autophagy and phosphorylation of p70 S6k induced by FB1 was inhibited by MHY1485, an activator of mTOR. But the phosphorylation of AKT, a downstream protein of mTORC2 showed no change with or without MHY1485. Taken together, FB1 induced nephrotoxicity via autophagy mediated by mTORC1 instead of mTORC2 in HK-2 cells.
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Affiliation(s)
- Lili Hou
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu Province, 210095, China; Institute of Nutritional and Metabolic Disorders in Domestic Animals and Fowls, Nanjing Agricultural University, Nanjing, Jiangsu Province, 210095, China; MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu Province, 210095, China
| | - Xin Yuan
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu Province, 210095, China; Institute of Nutritional and Metabolic Disorders in Domestic Animals and Fowls, Nanjing Agricultural University, Nanjing, Jiangsu Province, 210095, China; MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu Province, 210095, China
| | - Guannan Le
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu Province, 210095, China; Institute of Nutritional and Metabolic Disorders in Domestic Animals and Fowls, Nanjing Agricultural University, Nanjing, Jiangsu Province, 210095, China; MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu Province, 210095, China
| | - Ziman Lin
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu Province, 210095, China; Institute of Nutritional and Metabolic Disorders in Domestic Animals and Fowls, Nanjing Agricultural University, Nanjing, Jiangsu Province, 210095, China; MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu Province, 210095, China
| | - Fang Gan
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu Province, 210095, China; Institute of Nutritional and Metabolic Disorders in Domestic Animals and Fowls, Nanjing Agricultural University, Nanjing, Jiangsu Province, 210095, China; MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu Province, 210095, China
| | - Haolei Li
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu Province, 210095, China; Institute of Nutritional and Metabolic Disorders in Domestic Animals and Fowls, Nanjing Agricultural University, Nanjing, Jiangsu Province, 210095, China; MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu Province, 210095, China
| | - Kehe Huang
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu Province, 210095, China; Institute of Nutritional and Metabolic Disorders in Domestic Animals and Fowls, Nanjing Agricultural University, Nanjing, Jiangsu Province, 210095, China; MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu Province, 210095, China.
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Wu Q, Patocka J, Kuca K. Beauvericin, A Fusarium Mycotoxin: Anticancer Activity, Mechanisms, and Human Exposure Risk Assessment. Mini Rev Med Chem 2019; 19:206-214. [DOI: 10.2174/1389557518666180928161808] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2017] [Revised: 04/19/2018] [Accepted: 04/22/2018] [Indexed: 12/28/2022]
Abstract
Beauvericin (BEA) is a cyclic hexadepsipeptide, which derives from Cordyceps cicadae. It is also produced by Fusarium species, which are parasitic to maize, wheat, rice and other important commodities. BEA increases ion permeability in biological membranes by forming a complex with essential cations, which may affect ionic homeostasis. Its ion-complexing capability allows BEA to transport alkaline earth metal and alkali metal ions across cell membranes. Importantly, increasing lines of evidence show that BEA has an anticancer effect and can be potentially used in cancer therapeutics. Normally, BEA performs the anticancer effect due to the induced cancer cell apoptosis via a reactive oxygen species-dependent pathway. Moreover, BEA increases the intracellular Ca2+ levels and subsequently regulates the activity of a series of signalling pathways including MAPK, JAK/STAT, and NF-κB, and finally causes cancer cell apoptosis. In vivo studies further show that BEA reduces tumour volumes and weights. BEA especially targets differentiated and invasive cancer types. Currently, the anticancer activity of BEA is a hot topic; however, there is no review article to discuss the anticancer activity of BEA. Therefore, in this review, we have mainly summarized the anticancer activity of BEA and thoroughly discussed its underlying mechanisms. In addition, the human exposure risk assessment of BEA is also discussed. We hope that this review will provide further information for understanding the anticancer mechanisms of BEA.
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Affiliation(s)
- Qinghua Wu
- College of Life Science, Institute of Biomedicine, Yangtze University, Jingzhou 434025, China
| | - Jiri Patocka
- Institute of Radiology, Toxicology and Civil Protection, Faculty of Health and Social Studies, University of South Bohemia in Ceske Budejovice, Ceske Budejovice, Czech Republic
| | - Kamil Kuca
- Department of Chemistry, Faculty of Science, University of Hradec Kralove, Hradec Kralove, Czech Republic
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Khan RB, Phulukdaree A, Chuturgoon AA. Concentration-dependent effect of fumonisin B1 on apoptosis in oesophageal cancer cells. Hum Exp Toxicol 2017; 37:762-771. [DOI: 10.1177/0960327117735570] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
The geographical distribution of oesophageal cancer is linked to the exposure of fumonisin B1 (FB1), a mycotoxin produced by fungi that contaminates staple food worldwide. Non-genotoxic carcinogens like FB1 disturb homeostasis through increased cell proliferation or suppression of apoptosis. This study investigated the involvement of FB1 (0–20 μM) in spindle-shaped N-cadherin (+) CD45 (−) osteoblastic (SNO) cell death. Cell viability and death were assessed using the MTS and Annexin V-Fluos assays, respectively. Caspase activities were determined luminometrically and the comet assay assessed DNA damage. Induction of oxoguanine glycosylase 1 (OGG1) was measured using quantitative Polymerase Chain Reaction (qPCR), while cleaved poly (ADP-ribose) polymerase 1 (PARP-1) and Bax were determined by western blotting. Cell viability and PARP-1 cleavage were not affected by 1.25 μM FB1, but phosphatidylserine externalization, Bax protein expression, caspase activity, comet tail length and OGG1 transcripts were increased. The reduced cell viability in 10 μM FB1-treated cells was accompanied by corresponding increases in externalized phosphatidylserine, Bax, caspase-3/7 activity and cleaved PARP-1. The OGG1 transcripts were not significantly increased, but comet tails were increased. Bax, caspase-3/7 activities and cleaved PARP-1 were inhibited at 20 μM FB1. In addition, the OGG1 transcript levels were decreased ( p < 0.0001) along with comet lengths ( p < 0.0001). This study showed that FB1-induced apoptosis in SNO cells may be caspase-dependent or caspase-independent; the pathway used depends on the exposure concentration.
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Affiliation(s)
- RB Khan
- Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa
| | - A Phulukdaree
- Department of Physiology, School of Medicine, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa
| | - AA Chuturgoon
- Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa
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7
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Effect of UV irradiation on aflatoxin reduction: a cytotoxicity evaluation study using human hepatoma cell line. Mycotoxin Res 2017; 33:343-350. [PMID: 28844113 DOI: 10.1007/s12550-017-0291-0] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2017] [Revised: 07/20/2017] [Accepted: 08/01/2017] [Indexed: 12/24/2022]
Abstract
In this proof-of-concept study, the efficacy of a medium-pressure UV (MPUV) lamp source to reduce the concentrations of aflatoxin B1, aflatoxin B2, and aflatoxin G1 (AFB1, AFB2, and AFG1) in pure water is investigated. Irradiation experiments were conducted using a collimated beam system operating between 200 to 360 nm. The optical absorbance of the solution and the irradiance of the lamp are considered in calculating the average fluence rate. Based on these factors, the UV dose was quantified as a product of average fluence rate and treatment time. Known concentrations of aflatoxins were spiked in water and irradiated at UV doses ranging from 0, 1.22, 2.44, 3.66, and 4.88 J cm-2. The concentration of aflatoxins was determined by HPLC with fluorescence detection. LC-MS/MS product ion scans were used to identify and semi-quantify degraded products of AFB1, AFB2, and AFG1. It was observed that UV irradiation significantly reduced aflatoxins in pure water (p < 0.05). Irradiation doses of 4.88 J cm-2 reduced concentrations 67.22% for AFG1, 29.77% for AFB2, and 98.25% for AFB1 (p < 0.05). Using this technique, an overall reduction of total aflatoxin content of ≈95% (p < 0.05) was achieved. We hypothesize that the formation of ˙OH radicals initiated by UV light may have caused photolysis of AFB1, AFB2, and AFG1 molecules. In cell culture studies, our results demonstrated that the increase of UV dosage decreased the aflatoxin-induced cytotoxicity in HepG2 cells. Therefore, our research finding suggests that UV irradiation can be used as an effective technique for the reduction of aflatoxins.
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8
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Degradation and detoxification of aflatoxin B 1 using nitrogen gas plasma generated by a static induction thyristor as a pulsed power supply. Food Control 2017. [DOI: 10.1016/j.foodcont.2016.09.014] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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9
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Pathan J, Mondal S, Sarkar A, Chakrabarty D. Daboialectin, a C-type lectin from Russell's viper venom induces cytoskeletal damage and apoptosis in human lung cancer cells in vitro. Toxicon 2017; 127:11-21. [PMID: 28062165 DOI: 10.1016/j.toxicon.2016.12.013] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2016] [Revised: 12/26/2016] [Accepted: 12/31/2016] [Indexed: 12/15/2022]
Abstract
'Daboialectin', a low molecular weight C-type lectin (18.5 kDa) isolated from Russell's viper venom showed cytotoxic effects on human broncho-alveolar carcinoma derived (A549) cell lines. Daboialectin induced inhibition of A549 cell growth was time and concentration dependent with severe morphological changes by altering the functions of small GTPases such as Rac, Rho and cdc42. ROS induced DNA damage may result in apoptosis by inducing disruption of membrane integrity, blebbing and nuclear disintegration by activating caspases. Our results indicate that Daboialectin, a snake c type lectin (Snaclec) isolated from RVV alters morphology of A549 cells via regulation of cytoskeleton through RHO-GTPases. On other hand, the HSP70 and some other anti-apoptotic proteins required for the survival of cancer cells was found to be down-regulated in presence of Daboialectin. Daboialectin was also found to be inhibitory to anti-adhesive and anti-invasive to A549 cells in vitro. Daboialectin is the first Snaclec reported to induce cytoskeletal changes through regulation of RHO-GTPases and blocking anti-apoptotic pathway for a cancer cell line.
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Affiliation(s)
- Jigni Pathan
- Department of Biological Sciences, Birla Institute of Technology and Science, Pilani, K K Birla Goa Campus, Zuarinagar, Goa, India
| | - Sukanta Mondal
- Department of Biological Sciences, Birla Institute of Technology and Science, Pilani, K K Birla Goa Campus, Zuarinagar, Goa, India
| | - Angshuman Sarkar
- Department of Biological Sciences, Birla Institute of Technology and Science, Pilani, K K Birla Goa Campus, Zuarinagar, Goa, India
| | - Dibakar Chakrabarty
- Department of Biological Sciences, Birla Institute of Technology and Science, Pilani, K K Birla Goa Campus, Zuarinagar, Goa, India.
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Ahmed Adam MA, Tabana YM, Musa KB, Sandai DA. Effects of different mycotoxins on humans, cell genome and their involvement in cancer (Review). Oncol Rep 2017; 37:1321-1336. [PMID: 28184933 DOI: 10.3892/or.2017.5424] [Citation(s) in RCA: 62] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2016] [Accepted: 01/16/2017] [Indexed: 11/06/2022] Open
Abstract
The chemical nature of most of the mycotoxins makes them highly liposoluble compounds that can be absorbed from the site of exposure such as from the gastrointestinal and respiratory tract to the blood stream where it can be dissimilated throughout the body and reach different organs such as the liver and kidneys. Mycotoxins have a strong tendency and ability to penetrate the human and animal cells and reach the cellular genome where it causes a major mutagenic change in the nucleotide sequence which leads to strong and permanent defects in the genome. This defect will eventually be transcribed, translated and lead to the development of cancer. In this review, the chemical and physical nature of mycotoxins, the action of mycotoxins on the cellular genome and its effect on humans, mycotoxins and their carcinogenicity and mycotoxins research gaps are discussed, and new research areas are suggested. The research review posed various questions. What are the different mycotoxins that can cause cancer, what is the role of mycotoxins in causing cancer and what types of cancers can be caused by mycotoxins? These questions have been selected due to the significant increase in the mycotoxin contamination and the cancer incidence rate in the contemporary world. By revealing and understanding the role of mycotoxins in developing cancer, measures to reduce the risks and incidents of cancer could be taken.
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Affiliation(s)
- Mowaffaq Adam Ahmed Adam
- Infectomics Cluster, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Penang, Malaysia
| | - Yasser M Tabana
- Infectomics Cluster, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Penang, Malaysia
| | - Khirun Binti Musa
- Infectomics Cluster, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Penang, Malaysia
| | - Doblin Anak Sandai
- Infectomics Cluster, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Penang, Malaysia
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11
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Riedel S, Abel S, Burger HM, van der Westhuizen L, Swanevelder S, Gelderblom WCA. Differential modulation of the lipid metabolism as a model for cellular resistance to fumonisin B1-induced cytotoxic effects in vitro. Prostaglandins Leukot Essent Fatty Acids 2016; 109:39-51. [PMID: 27269712 DOI: 10.1016/j.plefa.2016.04.006] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2016] [Revised: 04/21/2016] [Accepted: 04/21/2016] [Indexed: 12/30/2022]
Abstract
Differential sensitivity of primary hepatocytes and Chang cells to the cancer promoter fumonisin B1 (FB1)-induced cytotoxic effects were investigated in relation to changes in membrane lipid distribution. In contrast to primary hepatocytes, Chang cells were resistant to FB1-induced cytotoxic effects. This was associated with a high cholesterol (Chol) and sphingomyelin (SM) and low phosphatidylcholine (PC) content, resulting in a significant (P<0.05) decrease in phosphatidylethanolamine (PE)/PC ratio, increased Chol/total phosphoglyceride (TPG) ratios and low total polyunsaturated fatty acids (PUFA) content in PC and PE, suggesting a more rigid membrane structure. High levels of C18:1 and reduced polyunsaturated fatty acid (PUFA) levels are likely to provide selective resistance to FB1-induced oxidative stress. FB1-associated lipid changes included decreases in SM and Chol, increases in sphinganine (Sa) and PE with the increases in key saturated, monounsaturated, and PUFAs in PE as key role players in the differential responses to FB1-induced cell growth responses in cells.
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Affiliation(s)
- S Riedel
- Biomedical Research and Innovation Platform, South African Medical Research Council, PO Box 19070, Tygerberg 7505, South Africa.
| | - S Abel
- Mycotoxicology and Chemoprevention Research Group, Institute of Biomedical and Microbial Biotechnology, Cape Peninsula University of Technology, PO Box 1906, Bellville 7535, South Africa.
| | - H-M Burger
- Mycotoxicology and Chemoprevention Research Group, Institute of Biomedical and Microbial Biotechnology, Cape Peninsula University of Technology, PO Box 1906, Bellville 7535, South Africa.
| | - L van der Westhuizen
- Oxidative Stress Research Centre, Institute of Biomedical and Microbial Biotechnology, Cape Peninsula University of Technology, PO Box 1906, Bellville 7535, South Africa.
| | - S Swanevelder
- Biostatistics Unit, South African Medical Research Council, PO Box 19070, Tygerberg, South Africa.
| | - W C A Gelderblom
- Mycotoxicology and Chemoprevention Research Group, Institute of Biomedical and Microbial Biotechnology, Cape Peninsula University of Technology, PO Box 1906, Bellville 7535, South Africa; Department of Biochemistry, University of Stellenbosch, Private Bag X1, Matieland 7602, South Africa.
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12
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Reisinger N, Dohnal I, Nagl V, Schaumberger S, Schatzmayr G, Mayer E. Fumonisin B₁ (FB₁) Induces Lamellar Separation and Alters Sphingolipid Metabolism of In Vitro Cultured Hoof Explants. Toxins (Basel) 2016; 8:89. [PMID: 27023602 PMCID: PMC4848616 DOI: 10.3390/toxins8040089] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2016] [Revised: 03/14/2016] [Accepted: 03/15/2016] [Indexed: 12/22/2022] Open
Abstract
One of the most important hoof diseases is laminitis. Yet, the pathology of laminitis is not fully understood. Different bacterial toxins, e.g. endotoxins or exotoxins, seem to play an important role. Additionally, ingestion of mycotoxins, toxic secondary metabolites of fungi, might contribute to the onset of laminitis. In this respect, fumonsins are of special interest since horses are regarded as species most susceptible to this group of mycotoxins. The aim of our study was to investigate the influence of fumonisin B1 (FB1) on primary isolated epidermal and dermal hoof cells, as well as on the lamellar tissue integrity and sphingolipid metabolism of hoof explants in vitro. There was no effect of FB1 at any concentration on dermal or epidermal cells. However, FB1 significantly reduced the separation force of explants after 24 h of incubation. The Sa/So ratio was significantly increased in supernatants of explants incubated with FB1 (2.5–10 µg/mL) after 24 h. Observed effects on Sa/So ratio were linked to significantly increased sphinganine concentrations. Our study showed that FB1 impairs the sphingolipid metabolism of explants and reduces lamellar integrity at non-cytotoxic concentrations. FB1 might, therefore, affect hoof health. Further in vitro and in vivo studies are necessary to elucidate the effects of FB1 on the equine hoof in more detail.
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Affiliation(s)
| | - Ilse Dohnal
- BIOMIN Research Center, Tulln 3430, Austria.
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De Lorenzi L, De Giovanni A, Malagutti L, Molteni L, Sciaraffia F, Tamburini A, Zannotti M. Genotoxic activity of the Fumonisin B1 mycotoxin in cultures of bovine lymphocytes. ITALIAN JOURNAL OF ANIMAL SCIENCE 2016. [DOI: 10.4081/ijas.2005.395] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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14
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Li J, Li X, Cai W, Liu Y. Comparison of different polar compounds-induced cytotoxicity in human hepatocellular carcinoma HepG2 cells. Lipids Health Dis 2016; 15:30. [PMID: 26879050 PMCID: PMC4754997 DOI: 10.1186/s12944-016-0201-z] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2015] [Accepted: 02/09/2016] [Indexed: 11/23/2022] Open
Abstract
Total polar compounds (TPC) formed during successive frying have the negative healthy effects. However, little researches focused on the cytotoxicity of different parts of TPC. The present study was carried out to elucidate the different polar compounds-induced apoptosis in human hepatocellular carcinoma (HCC) HepG2 cells. The polar compounds of frying oil named oxidized triglycerides oligo (TGO), oxidized triglycerides dimer (TGD), and oxidize triglycerides (ox-TG) were isolated and collected via HPLC. MTT assay was selected to determine the cell viability, and apoptosis rate of the cells was analyzed with the help of flow cytometry. The results indicated that TGO, TGD, or ox-TG could suppress the proliferation of HepG2 cells and improve the cell apoptosis in the concentration- and time- dependent manner. Different polar compounds have the different activity of cytotoxicity and apoptosis (p < 0.05), and ox-TG was the most serious deleterious on HepG2 cell viability and apoptotic, followed by TGO and TGD. At the concentration of 2.00 mg/ml and incubated for 48 h, the cell inhibition rate and apoptotic rate of HepG2 induced by ox-TG could reach 23.0 % and 16.05 %, respectively. Cell cycle analysis showed that the inhibition of TGO, TGD, and ox-TG on HepG2 cells mainly occurred in S phase.
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Affiliation(s)
- Jinwei Li
- State Key Laboratory of Food Science and Technology, Synergetic Innovation Center of Food Safety and Nutrition, School of Food Science and Technology, Jiangnan University, Wuxi, 214122, P.R. China
| | - Xiaodan Li
- State Key Laboratory of Food Science and Technology, Synergetic Innovation Center of Food Safety and Nutrition, School of Food Science and Technology, Jiangnan University, Wuxi, 214122, P.R. China
| | - Wenci Cai
- State Key Laboratory of Food Science and Technology, Synergetic Innovation Center of Food Safety and Nutrition, School of Food Science and Technology, Jiangnan University, Wuxi, 214122, P.R. China
| | - Yuanfa Liu
- State Key Laboratory of Food Science and Technology, Synergetic Innovation Center of Food Safety and Nutrition, School of Food Science and Technology, Jiangnan University, Wuxi, 214122, P.R. China. .,School of Food Science and Technology, Jiangnan University, 214122, Wuxi, Jiangsu Province, China.
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15
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Igarashi D, Bethke G, Xu Y, Tsuda K, Glazebrook J, Katagiri F. Pattern-triggered immunity suppresses programmed cell death triggered by fumonisin b1. PLoS One 2013; 8:e60769. [PMID: 23560104 PMCID: PMC3613394 DOI: 10.1371/journal.pone.0060769] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2012] [Accepted: 03/02/2013] [Indexed: 12/22/2022] Open
Abstract
Programmed cell death (PCD) is a crucial process for plant innate immunity and development. In plant innate immunity, PCD is believed to prevent the spread of pathogens from the infection site. Although proper control of PCD is important for plant fitness, we have limited understanding of the molecular mechanisms regulating plant PCD. Plant innate immunity triggered by recognition of effectors (effector-triggered immunity, ETI) is often associated with PCD. However pattern-triggered immunity (PTI), which is triggered by recognition of elicitors called microbe-associated molecular patterns (MAMPs), is not. Therefore we hypothesized that PTI might suppress PCD. Here we report that PCD triggered by the mycotoxin fumonisin B1 (FB1) can be suppressed by PTI in Arabidopsis. FB1-triggered cell death was suppressed by treatment with the MAMPs flg22 (a part of bacterial flagellin) or elf18 (a part of the bacterial elongation factor EF-Tu) but not chitin (a component of fungal cell walls). Although plant hormone signaling is associated with PCD and PTI, both FB1-triggered cell death and suppression of cell death by flg22 treatment were still observed in mutants deficient in jasmonic acid (JA), ethylene (ET) and salicylic acid (SA) signaling. The MAP kinases MPK3 and MPK6 are transiently activated and inactivated within one hour during PTI. We found that FB1 activated MPK3 and MPK6 about 36–48 hours after treatment. Interestingly, this late activation was attenuated by flg22 treatment. These results suggest that PTI suppression of FB1-triggered cell death may involve suppression of MPK3/MPK6 signaling but does not require JA/ET/SA signaling.
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Affiliation(s)
- Daisuke Igarashi
- Department of Plant Biology, Microbial and Plant Genomics Institute, University of Minnesota, St. Paul, Minnesota, United States of America
- Institute for Innovation, Ajinomoto Co., Inc., Kawasaki-ku, Kawasaki, Japan
| | - Gerit Bethke
- Department of Plant Biology, Microbial and Plant Genomics Institute, University of Minnesota, St. Paul, Minnesota, United States of America
| | - Yuan Xu
- Department of Plant Biology, Microbial and Plant Genomics Institute, University of Minnesota, St. Paul, Minnesota, United States of America
| | - Kenichi Tsuda
- Department of Plant Biology, Microbial and Plant Genomics Institute, University of Minnesota, St. Paul, Minnesota, United States of America
| | - Jane Glazebrook
- Department of Plant Biology, Microbial and Plant Genomics Institute, University of Minnesota, St. Paul, Minnesota, United States of America
| | - Fumiaki Katagiri
- Department of Plant Biology, Microbial and Plant Genomics Institute, University of Minnesota, St. Paul, Minnesota, United States of America
- * E-mail:
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16
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Nones J, Nones J, Trentin AG. Flavonoid hesperidin protects neural crest cells from death caused by aflatoxin B(1). Cell Biol Int 2012; 37:181-6. [PMID: 23319336 DOI: 10.1002/cbin.10015] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2012] [Accepted: 10/29/2012] [Indexed: 12/21/2022]
Abstract
The neural crest (NC) corresponds to a collection of multipotent and oligopotent progenitors endowed with both neural and mesenchymal potentials. The derivatives of the NC at trunk level include neurons and glial cells of the peripheral nervous system. Despite the well-known influence of aflatoxins on the development of cancer, the issue of whether they also influence NC cells has not been yet addressed. In the present work, we have investigated the effects of aflatoxin B(1) on quail NC cells and the concomitant effects of the flavonoid hesperidin associated with this mycotoxin. We show for the first time that aflatoxin B(1) decreases the viability and the total number of glial and neuronal cells/field, although their proportions in relation to the total number of cells were not altered. Therefore, aflatoxin has no effect on NC differentiation. However, this compound was able to reduce NC proliferation and NC survival. Furthermore, the co-administration of hesperidin, a well-known polyphenolic protector of cell death, partially prevented the effect of aflatoxin B(1) . Taken together, our results demonstrate that aflatoxin B(1) is toxic to NC cells, an effect partially prevented by the flavonoid hesperidin. This study may contribute to the understanding of the effects of these compounds during early embryonic development and offer potentially more assertive diets and treatments for pregnant animals.
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Affiliation(s)
- Jader Nones
- Department of Cell Biology, Embryology and Genetics, Center for Biological Sciences, Federal University of Santa Catarina, Trindade, 88040-900 Florianópolis, SC, Brazil
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17
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Human skin penetration of selected model mycotoxins. Toxicology 2012; 301:21-32. [DOI: 10.1016/j.tox.2012.06.012] [Citation(s) in RCA: 91] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2012] [Revised: 05/24/2012] [Accepted: 06/19/2012] [Indexed: 12/13/2022]
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18
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Cytotoxicity of Triptolide and Triptolide loaded polymeric micelles in vitro. Toxicol In Vitro 2011; 25:1557-67. [DOI: 10.1016/j.tiv.2011.05.020] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2009] [Revised: 03/08/2011] [Accepted: 05/18/2011] [Indexed: 01/29/2023]
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19
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Doi K, Uetsuka K. Mechanisms of mycotoxin-induced neurotoxicity through oxidative stress-associated pathways. Int J Mol Sci 2011; 12:5213-37. [PMID: 21954354 PMCID: PMC3179161 DOI: 10.3390/ijms12085213] [Citation(s) in RCA: 110] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2011] [Revised: 07/21/2011] [Accepted: 08/04/2011] [Indexed: 01/08/2023] Open
Abstract
Among many mycotoxins, T-2 toxin, macrocyclic trichothecenes, fumonisin B(1) (FB(1)) and ochratochin A (OTA) are known to have the potential to induce neurotoxicity in rodent models. T-2 toxin induces neuronal cell apoptosis in the fetal and adult brain. Macrocyclic trichothecenes bring about neuronal cell apoptosis and inflammation in the olfactory epithelium and olfactory bulb. FB(1) induces neuronal degeneration in the cerebral cortex, concurrent with disruption of de novo ceramide synthesis. OTA causes acute depletion of striatal dopamine and its metabolites, accompanying evidence of neuronal cell apoptosis in the substantia nigra, striatum and hippocampus. This paper reviews the mechanisms of neurotoxicity induced by these mycotoxins especially from the viewpoint of oxidative stress-associated pathways.
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Affiliation(s)
- Kunio Doi
- Nippon Institute for Biological Science, 9-2221-1, Shin-Machi, Ome, Tokyo 198-0024, Japan
- Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1, Yayoi, Bunkyo, Tokyo 113-8657, Japan
- Author to whom correspondence should be addressed; E-Mail: ; Tel.: +81-428-33-1086; Fax: +81-428-31-6166
| | - Koji Uetsuka
- Nippon Institute for Biological Science, 9-2221-1, Shin-Machi, Ome, Tokyo 198-0024, Japan
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20
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Liu R, Jin Q, Huang J, Liu Y, Wang X, Zhou X, Mao W, Wang S. In vitro toxicity of aflatoxin B1 and its photodegradation products in HepG2 cells. J Appl Toxicol 2011; 32:276-81. [DOI: 10.1002/jat.1669] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2010] [Revised: 01/13/2011] [Accepted: 01/13/2011] [Indexed: 12/20/2022]
Affiliation(s)
- Ruijie Liu
- State Key Laboratory of Food Science and Safety; School of Food Science and Technology; Jiangnan University; China
| | - Qingzhe Jin
- State Key Laboratory of Food Science and Safety; School of Food Science and Technology; Jiangnan University; China
| | - Jianhua Huang
- State Key Laboratory of Food Science and Safety; School of Food Science and Technology; Jiangnan University; China
| | - Yuanfa Liu
- State Key Laboratory of Food Science and Safety; School of Food Science and Technology; Jiangnan University; China
| | - Xingguo Wang
- State Key Laboratory of Food Science and Safety; School of Food Science and Technology; Jiangnan University; China
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21
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Abstract
Humans are exposed to mycotoxins via ingestion, contact and inhalation. This must have occurred throughout human history and led to severe outbreaks. Potential diseases range from akakabio-byo to stachybotryotoxicosis and cancer. The known molecular bases of toxicology run the gamut of 23 compounds, from aflatoxins (AFs) to zearalenone, ochratoxin A and deoxynivalenol. Ergotism is one of the oldest recognized mycotoxicosis, although mycotoxin science only commenced in the 1960s with the discovery of AFs in turkey feed. AFs are carcinogenic. Some others are suspected carcinogens. The effects of mycotoxins are acute or chronic in nature. Mycotoxins are well known in the scientific community, although they have a low profile in the general population. An incongruous situation occurs in United States where mycotoxins from "moldy homes" are considered to be a significant problem, although there is a general debate about seriousness. This contrasts with the thousands of deaths from mycotoxins that occur, even now, in the technologically less developed countries (e.g., Indonesia, China, and Africa). Mycotoxins are more toxic than pesticides. Studies are moving from whole animal work to investigating the biochemical mechanisms in isolated cells, and the mechanisms of toxicity at the molecular level are being elucidated. The stereochemical nature of AFs has been shown to be important. In addition, the effect of multiple mycotoxins is being increasingly investigated, which will more accurately represent the situation in nature. It is anticipated that more fungal metabolites will be recognized as dangerous toxins and permitted statutory levels will decrease in the future.
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Affiliation(s)
- Robert R M Paterson
- IBB-Institute for Biotechnology and Bioengineering, Universidade do Minho, Portugal.
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22
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Schwerdt G, Königs M, Holzinger H, Humpf HU, Gekle M. Effects of the mycotoxin fumonisin B(1) on cell death in human kidney cells and human lung fibroblasts in primary culture. J Appl Toxicol 2009; 29:174-82. [PMID: 18989866 DOI: 10.1002/jat.1398] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Fumonisins are mycotoxins produced by Fusarium verticillioides. The toxic effects of fumonisin B(1) (FB(1)) at the cellular level consist of a mixture of both necrosis and apoptosis. We studied the effect of FB(1) in human lung fibroblasts (NHLF) and human kidney epithelial cells (RPTEC) in primary culture. Apoptotic and necrotic cell death, collagen and fibronectin secretion were determined mainly after 14 days' exposure. The protein content of NHLF and RPTEC cells was slightly increased after 14 days' exposure to low FB(1) concentrations (0.1 or 1 microm). Caspase-3 activity tended to increase in NHLF and to decrease in RPTEC cells with higher FB(1) concentrations after 14 days' exposure. LDH release was slightly decreased in both cell types after 14 days. Collagen I and III secretion was enhanced in NHLF cells. Collagen III was decreased in RPTEC. Collagen IV was not changed in both cell types. Fibronectin secretion was uninfluenced in RPTEC and interim increased in NHLF. Furthermore LC-MS/MS studies did not give any hints for a metabolism of FB(1). Therefore, the main risk of prolonged FB(1) exposure seems to be altered collagen secretion pattern.
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Affiliation(s)
- G Schwerdt
- Julius-Bernstein-Institut für Physiologie, Martin-Luther-Universität Halle-Wittenberg, Germany.
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23
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Stockmann-Juvala H, Mikkola J, Naarala J, Loikkanen J, Elovaara E, Savolainen K. Oxidative Stress Induced by Fumonisin B1in Continuous Human and Rodent Neural Cell Cultures. Free Radic Res 2009; 38:933-42. [PMID: 15621711 DOI: 10.1080/10715760412331273205] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
Fumonisin B1 (FB1) is a mycotoxin produced by Fusarium verticillioides, which is a common infectant of corn and other cereal grains. Of concern to human health is also a possible airborne exposure to FB1-producing strains of F. verticillioides, which may grow in moisture-damaged buildings. In this study, we have characterized oxidative stress-related parameters induced by FB1 in three different neural cell lines, human SH-SY5Y neuroblastoma, rat C6 glioblastoma and mouse GT1-7 hypothalamic cells. The cells were exposed to graded doses of FB1 between 0.1 and 100 microM for 0-144 h after which the production of reactive oxygen species (ROS), lipid peroxidation, intracellular glutathione (GSH) levels and cell viability were measured. FB1 caused a dose-dependent increase of ROS production in C6 glioblastoma and GT1-7 hypothalamic cells but was without an effect in SH-SY5Y cells. Decreased GSH levels, increased MDA-formation, indicative of lipid peroxidation and necrotic cell death were observed in all cell lines after incubation with FB1. These findings indicate that FB1 induces oxidative stress in human, rat and mouse neural cell cultures.
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Affiliation(s)
- Helene Stockmann-Juvala
- Department of Industrial Hygiene and Toxicology, Finnish Institute of Occupational Health, Topeliuksenkatu 41 a A, FIN-00250 Helsinki, Finland
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24
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Stockmann-Juvala H, Savolainen K. A review of the toxic effects and mechanisms of action of fumonisin B1. Hum Exp Toxicol 2009; 27:799-809. [PMID: 19244287 DOI: 10.1177/0960327108099525] [Citation(s) in RCA: 202] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Fumonisin B(1) (FB(1)) is a mycotoxin produced by the fungus Fusarium verticillioides, which commonly infects corn and other agricultural products. Fusarium species can also be found in moisture-damaged buildings, and, therefore, exposure of humans to Fusarium mycotoxins including FB(1) may take place. FB(1) bears a clear structural similarity to the cellular sphingolipids, and this similarity has been shown to disturb the metabolism of sphingolipids by inhibiting the enzyme ceramide synthase leading to accumulation of sphinganine in cells and tissues. FB(1) is neurotoxic, hepatotoxic, and nephrotoxic in animals, and it has been classified as a possible carcinogen to humans. The cellular mechanisms behind FB(1)-induced toxicity include the induction of oxidative stress, apoptosis, and cytotoxicity, as well as alterations in cytokine expression. The effects of FB(1) on different parameters vary markedly depending on what types of cells are studied or what species they originate from. These aspects are important to consider when evaluating the toxic potential of FB(1).
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Affiliation(s)
- H Stockmann-Juvala
- Unit of Excellence for Immunotoxicology, Finnish Institute of Occupational Health, Helsinki, Finland.
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25
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Fang R, Houghton PJ, Hylands PJ. Cytotoxic effects of compounds from Iris tectorum on human cancer cell lines. JOURNAL OF ETHNOPHARMACOLOGY 2008; 118:257-263. [PMID: 18508214 DOI: 10.1016/j.jep.2008.04.006] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/16/2007] [Revised: 03/11/2008] [Accepted: 04/06/2008] [Indexed: 05/26/2023]
Abstract
In the course of searching for novel cytotoxic compounds which can be used in chemotherapy, several Traditional Chinese Medicines (TCM) have been screened by bioassay-guided fractionation and isolation. An extract of rhizomes of Iris tectorum Maxim., a TCM used to treat cancer, exhibited highest potency and led to the isolation of two flavonoids, 7-O-methylaromadendrin and tectorigenin, and four iridal-type triterpenes, iritectols A and B, isoiridogermanal and iridobelamal A. The cytotoxicities of the isolated compounds against four human cancer cell lines were evaluated by the SRB assay. Iritectol B, isoiridogermanal and iridobelamal A showed similar cytotoxicity with IG(50) around 11 microM and 23 microM against MCF-7 and C32 cell lines, respectively. Cell cycle-specific inhibition and apoptosis induced by the isolated compounds were determined using flow cytometry with two sets of co-labelling systems: annexin V-FITC/propidium iodide and fluorescein diacetate/propidium iodide. Iritectol B demonstrated dose-dependent apoptotic effect against COR-L23 cells with an apoptotic rate of 33% at 100 microM. Tectorigenin (an analogue of genistein) showed cell cycle specific inhibition and arrested cells at G(2)/M phase up to 400 microM, but did not demonstrate apoptotic effect against COR-L23 cells up to 1 mM. The overall activities of isolated compounds observed in the present study support the traditional use of Iris tectorum Maxim. in the treatment of cancer.
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Affiliation(s)
- Rui Fang
- Centre for Natural Medicines Research, King's College London, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, United Kingdom
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26
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del Río García JC, Moreno Ramos C, Pinton P, Mendoza Elvira S, Oswald IP. [Evaluation of the cytotoxicity of aflatoxin and fumonisin in swine intestinal cells]. Rev Iberoam Micol 2007; 24:136-41. [PMID: 17604433 DOI: 10.1016/s1130-1406(07)70029-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
The coexistence of the aflatoxin (AFB) and fumonisin (FB) has been widely documented in many parts of the world. However, few studies describing the synergy effect of both mycotoxins in vivo and/or in vitro are available. The objective of this study consisted on evaluating the effect of AFB and FB on the morphology, the capacity of cellular proliferation, cytotoxicity and interleukin-8 (IL-8) synthesis in a porcine intestinal epithelial cell line (IPEC-1). Concerning to the cellular morphology it was only affected in the concentrations higher of AFB (50 microM) and FB (500 microM). However, the cellular proliferation, the cellular damage and synthesis of IL-8 they were affected when present in combination the AFB/FB (1.3/3.7; 2/3.7 and 5/10 microM respectively) with that showed by the individual effect of similar concentrations of these mycotoxins (p < 0.05). Our data indicate that the combination of AFB/FB in low concentrations showed a synergy effect, altering the cellular morphophysiology, which can imply in vivo the entrance of other toxins or biological agents for alteration of the intestinal barrier impacting negatively in the human or animal health.
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Affiliation(s)
- Juan Carlos del Río García
- Unidad de Investigación en Granos y Semillas UNIGRAS, Facultad de Estudios Superiores Cuautitlán, Universidad Nacional Autónoma de México, 54729 México.
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27
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El-Nekeety AA, El-Kholy W, Abbas NF, Ebaid A, Amra HA, Abdel-Wahhab MA. Efficacy of royal jelly against the oxidative stress of fumonisin in rats. Toxicon 2007; 50:256-269. [PMID: 17490698 DOI: 10.1016/j.toxicon.2007.03.017] [Citation(s) in RCA: 72] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2007] [Revised: 03/22/2007] [Accepted: 03/23/2007] [Indexed: 12/14/2022]
Abstract
Fumonisins (FB) are mycotoxins produced by Fusarium verticillioides, frequently associated with corn. It produces toxicity, including teratogenicity, equine leukoencephalomalacia, porcine pulmonary edema, hepatic or renal damage in most animal species and perturb sphingolipid metabolism. The aim of the present study was to evaluate the protective effects of royal jelly (RJ) against FB toxicity. Sixty male Sprague-Dawley rats were divided into six treatment groups including the control group; group fed FB-contaminated diet (200mg/kg diet) and the groups treated orally with RJ (100 or 150mg/kg body weight) with or without FB for 3 weeks. FB alone decreased body weight gain, feed intake, GPX and SOD. Whereas it increased in ALT, AST, triglycerides, cholesterol, HDL, LDL, createnine and uric acid levels. Animals received FB showed severe histological and histochemical changes in liver and kidney tissues. Cotreatment with FB plus RJ resulted in a significant improvement in all the tested parameters and the histological and histochemical pictures of the liver and kidney. These improvements were pronounced in animals fed FB-contaminated diet plus the high dose of RJ. It could be concluded that RJ have a protective effects against FB toxicity and this protection was dose dependent.
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Affiliation(s)
- Aziza A El-Nekeety
- Food Toxicology and Contaminants Department, National Research Center, Dokki, Cairo, Egypt
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28
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Hoat TX, Nakayashiki H, Tosa Y, Mayama S. Specific cleavage of ribosomal RNA and mRNA during victorin-induced apoptotic cell death in oat. THE PLANT JOURNAL : FOR CELL AND MOLECULAR BIOLOGY 2006; 46:922-33. [PMID: 16805727 DOI: 10.1111/j.1365-313x.2006.02752.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/10/2023]
Abstract
Here we report that rRNA and mRNA are specifically degraded in oat (Avena sativa L.) cells during apoptotic cell death induced by victorin, a host-selective toxin produced by Cochliobolus victoriae. Northern analysis indicated that rRNA species from the cytosol, mitochondria and chloroplasts were all degraded via specific degradation intermediates during victorin-induced apoptotic cell death but, in contrast, they were randomly digested in necrotic cell death induced by 30 mM CuSO(4) and heat shock. This indicates that specific rRNA cleavage could be controlled by an intrinsic program. We also observed specific cleavage of mRNA of housekeeping genes such as actin and ubiquitin during victorin-induced cell death. Interestingly, no victorin-induced mRNA degradation was detected with stress-responding genes such as PR-1, PR-10 and GPx throughout the experimental period. The RNA degradation mostly, but not always, occurred in parallel with DNA laddering, but pharmacological studies indicated that these processes are regulated by different signaling pathways with some overlapping upstream signals.
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Affiliation(s)
- Trinh X Hoat
- Laboratory of Plant Pathology, Graduate School of Science and Technology, Kobe University, Rokkodai, Nada-ku, Kobe 657-8501, Japan
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29
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McKean C, Tang L, Billam M, Tang M, Theodorakis CW, Kendall RJ, Wang JS. Comparative acute and combinative toxicity of aflatoxin B1 and T-2 toxin in animals and immortalized human cell lines. J Appl Toxicol 2006; 26:139-47. [PMID: 16229058 DOI: 10.1002/jat.1117] [Citation(s) in RCA: 56] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Aflatoxin B1 (AFB1) and T-2 toxin (T-2) are important food-borne mycotoxins that have been implicated in human health and as potential biochemical weapons threats. In this study the acute and combinative toxicity of AFB1 and T-2 were tested in F-344 rats, mosquitofish (Gambusia affinis), immortalized human hepatoma cells (HepG2) and human bronchial epithelial cells (BEAS-2B). Preliminary experiments were conducted in order to assess the acute toxicity and to obtain LD50, LC50 and IC50 values for individual toxins in each model, respectively. This was followed by testing combinations of AFB1 and T-2 to obtain LD50, LC50 and IC50 values for the combination in each model. All models demonstrated a significant dose response in the observed parameters to treatment. The potency of the mixture was gauged through the determination of the interaction index metric. The results of this study demonstrate that these two toxins interacted to produce alterations in the toxic responses generally classifiable as additive; however, a synergistic interaction was noted in the case of BEAS-2B. It can be gathered that this combination may pose a significant threat to public health and further research needs to be completed addressing alterations in metabolism and detoxification that may influence the toxic manifestations in combination.
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Affiliation(s)
- Christopher McKean
- The Institute of Environmental and Human Health, Department of Environmental Toxicology, Texas Tech University, Box 41163, Lubbock TX 79409-1163, USA
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30
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McKean C, Tang L, Tang M, Billam M, Wang Z, Theodorakis CW, Kendall RJ, Wang JS. Comparative acute and combinative toxicity of aflatoxin B1 and fumonisin B1 in animals and human cells. Food Chem Toxicol 2006; 44:868-76. [PMID: 16427177 DOI: 10.1016/j.fct.2005.11.011] [Citation(s) in RCA: 126] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2005] [Accepted: 11/22/2005] [Indexed: 10/25/2022]
Abstract
Aflatoxin B(1) (AFB(1)) and fumonisin B(1) (FB(1)) are important food-borne mycotoxins. The co-contamination of food stuffs with these two mycotoxins is well known and has been possibly implicated in the development of human hepatocellular carcinoma in high risk regions around the world. In this study the acute and combinative toxicity of AFB(1) and FB(1) were tested in F-344 rats, mosquitofish (Gambusia affinis), immortalized human hepatoma cells (HepG2) and human bronchial epithelial cells (BEAS-2B). Preliminary experiments were conducted in order to assess the acute toxicity and obtain LD(50), LC(50) and IC(50) values for individual toxins in each model, respectively. This was followed by testing combinations of AFB(1) and FB(1) to obtain LD(50), LC(50) and IC(50) values for the combination in each model. All models demonstrated a significant dose response in relation to toxin treatment. The potency of the mixture was gauged through the determination of the interaction index metric. Results of this study demonstrate that these two toxins interacted to produce alterations in the toxic responses with a strong additive interaction noted in the cases of F344 rats and mosquitofish. It can be gathered that this combination may pose a significant threat to public health and further research needs to be completed addressing alterations in metabolism and detoxification that may influence the toxic manifestations in combination. These results will provide foundational knowledge for future studies on long-term combinative toxic and health effects of these mycotoxins.
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Affiliation(s)
- C McKean
- Department of Environmental Toxicology, The Institute of Environmental and Human Health, Texas Tech University, Lubbock, TX 79409-1163, USA
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31
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Osuchowski MF, Sharma RP. Fumonisin B1 Induces Necrotic Cell Death in BV-2 Cells and Murine Cultured Astrocytes and is Antiproliferative in BV-2 Cells While N2A Cells and Primary Cortical Neurons are Resistant. Neurotoxicology 2005; 26:981-92. [PMID: 16005069 DOI: 10.1016/j.neuro.2005.05.001] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2004] [Accepted: 04/05/2005] [Indexed: 11/29/2022]
Abstract
Fumonisin B1 (FB1), a mycotoxin produced by Fusarium verticillioides, causes equine leukoencephalomalacia, impairs myelination, and inhibits neuronal growth in vitro. Intact mice do not show brain damage after systemic administration of FB1. We recently reported that intracerebroventricular administration of FB1 in mice caused neurodegeneration in the cortex and activation of astrocytes in the hippocampal area; results suggested that the neuronal damage may be secondary to activation of immunocompetent non-neuronal cells. Current study investigated effects of FB1 upon murine microglial (BV-2) and neuroblastoma (N2A) cell lines, and primary astrocytes and cortical neurons. BV-2 and N2A cultures and cells prepared from neonatal and postnatal brains of BALB/c mice were exposed to various concentrations of FB1 for 4 (BV-2 and N2A) or 4 and 8 (astrocytes and cortical neurons) days. FB1 at 25 microM decreased viability in BV-2 cells, whereas at 50 microM caused necrotic but not apoptotic cell death in both BV-2 and primary astrocytes (at day 8 only), assessed by lactic dehydrogenase release, and pripidium iodide and annexin V staining. Thymidine incorporation indicated that 2.5 microM FB1 decreased proliferation in BV-2 cells. DNA analysis by flow cytometry showed that the inhibition was not caused by cell cycle arrest. The mitochondrial activity decreased dose-dependently in BV-2 cells and was significantly elevated at 25 microM FB1, but not at 50 microM at days 4 or 8 in astrocytes. In BV-2 cells and primary astrocytes, the expression of TNFalpha and IL-1beta analyzed by real-time polymerase chain reaction was downregulated at 6 or 24 h. In all cell types tested the FB1 treatment caused accumulation of free sphinganine and decrease in free sphingosine levels at selected time points. Results indicated that primary and established murine brain immunocompetent cells are vulnerable to the FB1-dependent cytotoxicity in vitro whereas neuronal cells are not. The toxic effects on the neuronal tissue may therefore be secondary to modulation of astrocyte or glial cell function.
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Affiliation(s)
- Marcin F Osuchowski
- Department of Physiology and Pharmacology, College of Veterinary Medicine, The University of Georgia, Athens, GA 30602-7389, USA
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32
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Zhu LX, Liu J, Xie YH, Kong YY, Ye Y, Wang CL, Li GD, Wang Y. Expression of hepatitis C virus envelope protein 2 induces apoptosis in cultured mammalian cells. World J Gastroenterol 2004; 10:2972-8. [PMID: 15378776 PMCID: PMC4576255 DOI: 10.3748/wjg.v10.i20.2972] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM: To explore the role of hepatitis C virus (HCV) envelope protein 2 (E2) in the induction of apoptosis.
METHODS: A carboxyterminal truncated E2 (E2-661) was transiently expressed in several cultured mammalian cell lines or stably expressed in Chinese hamster ovary (CHO) cell line. Cell proliferation was assessed by 3H thymidine uptake. Apoptosis was examined by Hoechst 33258 staining, flow cytometry and DNA fragmentation analysis.
RESULTS: Reduced proliferation was readily observed in the E2-661 expressing cells. These cells manifested the typical features of apoptosis, including cell shrinkage, chromatin condensation and hypodiploid genomic DNA content. Similar apoptotic cell death was observed in an E2-661 stably expressing cell line.
CONCLUSION: HCV E2 can induce apoptosis in cultured mammalian cells.
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Affiliation(s)
- Li-Xin Zhu
- State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
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33
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Minervini F, Fornelli F, Flynn KM. Toxicity and apoptosis induced by the mycotoxins nivalenol, deoxynivalenol and fumonisin B1 in a human erythroleukemia cell line. Toxicol In Vitro 2004; 18:21-8. [PMID: 14630058 DOI: 10.1016/s0887-2333(03)00130-9] [Citation(s) in RCA: 122] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
The toxicity of the mycotoxins nivalenol (NIV), deoxynivalenol (DON) and fumonisin B1 (FB1) were studied in the K562 human erythroleukemia cell line using the Trypan Blue, MTT and BrdU uptake analyses of cytotoxicity, cell metabolism and cell proliferation, respectively. Nuclear staining with propidium iodide and DNA analysis by flow cytometry were used to identify apoptosis and cell cycle distribution. By the MTT and BrdU tests, both NIV and DON were significantly more toxic than FB1 by at least one order of magnitude, with ID50s ranging from 0.5 microM for NIV to 70 microM for FB1. The MTT test indicated that NIV was significantly (approximately four times) more toxic than DON. In contrast, the Trypan Blue test did not reveal any effects of mycotoxin exposure suggesting that, at the concentrations tested, NIV, DON and FB1 did not induce cytotoxicity through plasma membrane damage. Cell cycle analysis suggested apoptotic cytotoxicity, revealing 100% cellular debris at the highest concentrations of NIV and DON and approximately 2.9 times more debris than control at the highest FB1 concentration. Morphological evidence of apoptosis was related to the toxicity of the substances, such that the more toxic NIV and DON resulted in more late stage apoptotic events than FB1. This study suggests that human blood cells are sensitive to mycotoxin exposure, that NIV is more toxic than DON which is more toxic than FB1, and that DNA damage and apoptosis rather than plasma membrane damage and necrosis may be responsible for the observed cytotoxicity.
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Affiliation(s)
- F Minervini
- Istituto di Scienze delle Produzioni Alimentari, Consiglio Nazionale delle Ricerche, Viale Einaudi, 51, 70125 Bari,
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34
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Fornelli F, Minervini F, Mulè G. CYTOTOXICITY INDUCED BY NIVALENOL, DEOXYNIVALENOL, AND FUMONISIN B1 IN THE SF-9 INSECT CELL LINE. ACTA ACUST UNITED AC 2004; 40:166-71. [PMID: 15479121 DOI: 10.1290/1543-706x(2004)40<166:cibnda>2.0.co;2] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
The toxicity of the mycotoxins nivalenol (NIV), deoxynivalenol (DON), and fumonisin B1 (FB1) was studied in the lepidopteran Spodoptera frugiperda (SF-9) cells, by the trypan blue dye-exclusion and 3-(4,5-dimethylthiozole-2-yl)-2,5-biphenyl tetrazolium bromide (MTT) tests, uptake analyses of cytotoxicity, and cell metabolism, respectively. Deoxyribonucleic acid analysis by flow cytometry was used to identify apoptosis and cell cycle distribution. After 48 h of exposure, the MTT and trypan blue dye-exclusion tests indicated that NIV was significantly more toxic than DON, and both were significantly more toxic than FB1. The IC50 (mycotoxin concentration resulting in 50% inhibition of proliferation) values for NIV and DON were 4.5 and 41 microM, and the CC50 (mycotoxin concentration that caused 50% cytotoxicity) values were 9.5 and 45 microM, respectively. At the highest concentration of FB1 (100 microM), there was 80% viability. With the same incubation time, cell cycle distribution showed an arrest of cells in the G0/G1 phase in the presence of NIV (up to 0.3 microM), DON (up to 3 microM), and FB1 (up to 10 microM). Morphological evidence of apoptosis was related to the toxicity of the substances in that the more toxic NIV induced late apoptosis, whereas DON and FB1 produced less-severe morphological changes characteristic of early apoptosis. This study suggests that NIV is more toxic than DON, which in turn is more toxic than FB1. These mycotoxins can modify the normal progression of the cell cycle and induce an apoptotic process.
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Affiliation(s)
- Francesca Fornelli
- Institute of Sciences of Food Production (ISPA), National Research Council (CNR), Via Amendola 122, 70126 Bari, Italy
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35
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Kodell RL, Turturro A. Risk-assessment implications of mechanistic model's prediction of low-dose nonlinearity of liver tumor risk for mice fed fumonisin b(1). NONLINEARITY IN BIOLOGY, TOXICOLOGY, MEDICINE 2004; 2:35-43. [PMID: 19330107 PMCID: PMC2647820 DOI: 10.1080/15401420490426981] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/27/2023]
Abstract
A two-stage, clonal-expansion model of liver tumor risk in mice was developed by Kodell et al. (Food Addit Contam 18:237-253, 2001) based on the hypothesis that fumonisin B(1), a naturally occurring mycotoxin in corn, is not genotoxic, but rather causes cancer through the disruption of sphingolipid metabolism. This disruption is assumed to cause an increase in apoptosis, in response to which cells proliferate to compensate for reduced tissue mass. The resulting differential increase in the number of pre-neoplastic cells at risk of mutation during cell division is assumed to lead to an increase in the incidence of tumors. Two-year liver tumor incidences predicted by the model using data on organ weight, cell proliferation, and sphingolipid metabolism provided a reasonable match to the actual 2-year observed incidences in a study conducted at the National Center for Toxicological Research. The predictions indicated no risk at low doses (even a possible hormetic effect) and high risk at high doses in females, as well as a complete absence of a dose response (or perhaps, a hormetic effect) in males. This paper provides a commentary on the risk-assessment implications of the modeling results, pointing out that the model's low-dose predictions provide scientific support and justification for the U.S. Food and Drug Administration's low-ppm guidance levels in corn products. These guidance levels are significantly higher than would be obtained using linear extrapolation, the method most often used for genotoxic carcinogens and other carcinogens for which low-dose linearity cannot be ruled out.
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Affiliation(s)
- Ralph L Kodell
- Division of Biometry and Risk Assessment, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, Arkansas
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36
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Gopee NV, He Q, Sharma RP. Fumonisin B1-induced apoptosis is associated with delayed inhibition of protein kinase C, nuclear factor-kappaB and tumor necrosis factor alpha in LLC-PK1 cells. Chem Biol Interact 2003; 146:131-45. [PMID: 14597127 DOI: 10.1016/s0009-2797(03)00102-9] [Citation(s) in RCA: 20] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Fumonisin B1 (FB1), the most potent of the fumonisin mycotoxins, is a carcinogen and causes a wide range of species-specific toxicoses. FB1 modulates the activity of protein kinase C (PKC), a family of phospholipid-dependent serine/threonine kinases that play important role in modulating a variety of biologic responses ranging from regulation of cell growth to cell death. Although it has been demonstrated that FB1 induces apoptosis in many cell lines, the precise mechanism of apoptosis is not fully understood. In this study, we investigated the membrane localization of various PKC isoforms, PKC enzyme activity, and its downstream targets, namely nuclear factor-kappa B (NF-kappaB), tumor necrosis factor alpha (TNFalpha), and caspase 3, in porcine renal epithelial (LLC-PK1) cells. FB1 repressed cytosol to membrane translocation of PKC-alpha, -delta, -epsilon, and -zeta isoforms over 24-72 h. The FB1-induced membrane PKC repression was corroborated by a concentration-dependent decrease in total PKC activity. Exposure of cells to phorbol 12-myristate 13-acetate (PMA) for this duration also resulted in repressed PKC membrane localization and activity comparable to FB1. Exposure of cells to FB1 (10 microM) was associated with inhibition of cytosol to nuclear translocation of NF-kappaB and NF-kappaB-DNA binding at 72 h. The expression of TNFalpha was significantly inhibited at 24 and 48 h in response to 1 and 10 microM FB1. Increased caspase 3 activity was observed in LLC-PK1 cells exposed to > or =1 microM FB1 at 48 h. PMA also increased the caspase 3 activity at 24 and 48 h. Results suggest that FB1-induced apoptosis involves the activation of caspase 3, which is associated with the repression of PKC and possibly its down-stream effectors, NF-kappaB and TNFalpha.
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Affiliation(s)
- Neera V Gopee
- Department of Physiology and Pharmacology, College of Veterinary Medicine, The University of Georgia, Athens, GA 30602-7389, USA
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37
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Mobio TA, Tavan E, Baudrimont I, Anane R, Carratú MR, Sanni A, Gbeassor MF, Shier TW, Narbonne JF, Creppy EE. Comparative study of the toxic effects of fumonisin B1 in rat C6 glioma cells and p53-null mouse embryo fibroblasts. Toxicology 2003; 183:65-75. [PMID: 12504343 DOI: 10.1016/s0300-483x(02)00441-9] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
The present experiments have been carried out in order to study (comparatively) oxidative stress and its consequences (i.e. modifications of DNA bases and/or DNA fragmentation), cell cycle progression (through two generations) and apoptosis in C6 glioma cells (with normal p53 status) and p53-null mouse embryonic fibroblasts (MEF) after incubation with fumonisin B(1) (FB(1)). Further endpoints, including protein and DNA syntheses as well as cytotoxicity, have been also studied. The results show that FB(1) (incubation) produced a significant increase of malondialdehyde (MDA) production (suggestive of lipid peroxidation) which was prevented by antioxidant agents in both cell types. Moreover, FB(1) induced a significant and dose-related increase of 8-OH-dG and DNA fragmentation in both C6 glioma and MEF cells. Unlike MEF cells, apoptotic C6 glioma cells were observed after FB(1) incubation. Moreover, suppression of cell cycle progression was observed in C6 glioma but not in MEF cell incubated with FB(1). The results suggest a possible loss of protective mechanisms (such as p53-dependent apoptosis and cell cycle arrest) in FB(1)-damaged MEF cells and confirm that cells lacking of mechanisms governed by p53 gene would be more susceptible to neoplastic cascade or mutation following DNA lesions induced by this mycotoxin.
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Affiliation(s)
- Théophile A Mobio
- Laboratory of Toxicology, University Victor Segalen Bordeaux 2, 146 rue Léo-Saignat, 33076 Bordeaux, France
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38
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He Q, Bhandari N, Sharma RP. Fumonisin B(1) alters sphingolipid metabolism and tumor necrosis factor alpha expression in heart and lung of mice. Life Sci 2002; 71:2015-23. [PMID: 12175895 DOI: 10.1016/s0024-3205(02)01988-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Fumonisin B(1) (FB(1)), produced by Fusarium verticillioides, is a common contaminant in foods and feeds. Increase in tissue free sphingoid bases resulting from the inhibition of ceramide synthase is a biomarker of fumonisin exposure. Tumor necrosis factor alpha (TNFalpha) is induced in liver in response to FB(1) treatment. This study determined whether fumonisin B(1) caused increases in free sphingoid bases and altered the expression of TNFalpha in heart and lung, organs that are not targets of FB(1) toxicity, of male and female mice treated with 5-daily subcutaneous injection of 2.25 mg/kg FB(1). A significant increase in free sphingoid bases was observed in both heart and lung of FB(1)-exposed mice. The magnitude of increases in free sphingoid bases in both organs of female mice was much higher than that in males. The expression of TNFalpha was increased by FB(1) treatment in the lung of male mice and in the heart of female mice, whereas the expression of interferon gamma was unaltered. Results suggest that both sphingolipid accumulation and TNFalpha induction are observed in the tissues of mice that are not associated with FB(1) toxicity.
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Affiliation(s)
- Quanren He
- Department of Physiology and Pharmacology, College of Veterinary Medicine, The University of Georgia, Athens, GA 30602-7389, USA
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39
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Gelderblom WCA, Moritz W, Swanevelder S, Smuts CM, Abel S. Lipids and delta6-desaturase activity alterations in rat liver microsomal membranes induced by fumonisin B1. Lipids 2002; 37:869-77. [PMID: 12458622 DOI: 10.1007/s11745-002-0973-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Alterations in the membrane structure and function of hepatocyte membranes by fumonisin B1 (FB1) have been proposed to play an important role in the disruption of growth regulatory effects and hence in the cancer-promoting ability of the mycotoxin. Detailed analyses of lipids in liver microsomal fractions of rats exposed to different dietary levels of FB1 over a period of 21 d indicated an increase in PC, PE, PI, and cholesterol (Chol). These changes decreased the PC/PE and increased the total phospholipid/Chol ratios. When considering FA content, the quantities of total FA increased (P < 0.05) in the major phospholipid fractions as a result of the increased phospholipid levels. However, when considering the relative levels (mg/100 mg of the total FA) of specific FA, the monounsaturated FA (16:1 n-7 and 18:1n-9) and 18:2n-6 increased (P < 0.05), whereas the long-chain PUFA decreased (P < 0.05) in the main phospholipid fractions. Enzyme analyses indicated that the activity of the delta6-desaturase was significantly reduced in liver microsomal preparations in a dose-dependent manner. An increase in the 20:3n-6/20:4n-6 ratio also suggested a decrease in the activity of the delta5-desaturase. Disruption of microsomal lipid metabolism at different levels by FB1 could play an important role in the alteration of growth regulatory effects in the liver.
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Affiliation(s)
- W C A Gelderblom
- PROMEC Unit, Medical Research Council, Tygerberg 7505, South Africa.
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40
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Caloni F, Spotti M, Pompa G, Zucco F, Stammati A, De Angelis I. Evaluation of Fumonisin B(1) and its metabolites absorption and toxicity on intestinal cells line Caco-2. Toxicon 2002; 40:1181-188. [PMID: 12165322 DOI: 10.1016/s0041-0101(02)00125-3] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
The aim of the present paper is to investigate intestinal absorption and toxicity of Fumonisin B(1) (FB(1)) and its partially (PHFB(1) and PHFB(2)) and totally hydrolyzed (HFB(1)) metabolites, using the human intestinal cell line Caco-2, a very well known in vitro model of intestinal epithelium for absorption and metabolism studies. Caco-2 cells were treated for 48 h with several toxin concentrations (in the range of 1-138 microM). At the end of exposure period, no significant variation on cell viability has been observed with all chemicals tested, either in undifferentiated cells or in differentiated ones, suggesting a poor toxicity of these mycotoxins for intestinal cells. In any case, FB(1) appears the most active in this respect. For which concerns the cellular absorption, FB(1), PHFB(1) and PHFB(2) are never detected into Caco-2 cells. On the contrary, a dose-dependent absorption of HFB(1) has been observed in differentiated cells, which express enzymatic and metabolic characteristics of mature enterocytes. Thus HFB(1), losing the tricarballylic acid chain, is more bioavailable than FB(1) on intestinal cell, supporting the hypothesis that in risk evaluation of fumonisins exposure its metabolites are also relevant.
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Affiliation(s)
- F Caloni
- Department of Veterinary Sciences and Technologies for Food Safety, University of Milan, Via Celoria 10, 20133, Milan, Italy.
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Dresden-Osborne C, Noblet GP. Fumonisin B1 affects viability and alters nitric oxide production of a murine macrophage cell line. Int Immunopharmacol 2002; 2:1087-93. [PMID: 12349946 DOI: 10.1016/s1567-5769(02)00054-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Fumonisin B1 (FB1), the major toxin produced by Fusarium verticillioides contaminating corn, is known to elicit many organ- and species-specific toxicities in animals. In the present study, exposure to FB1 decreased viability of a murine macrophage cell line (RAW264.7) in a dose-dependent manner (1-100 microM). Further, when cells exposed to FB1 were stimulated with lipopolysaccharide (LPS), a dose-dependent increase in production of nitric oxide (NO) was observed, but only at FB1 concentrations (10-50 microM) that induced significant cytotoxicity. Stimulation of cells with phorbol myristate acetate (PMA) resulted in increased NO production at 50 microM FB1, but induced a variable NO response at 1-10 microM FB1. Results suggest that FB1 affected cell viability and altered inducible NO production by RAW macrophages in a manner that was dependent on the pathway of stimulation.
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42
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Liu BH, Yu FY, Chan MH, Yang YL. The effects of mycotoxins, fumonisin B1 and aflatoxin B1, on primary swine alveolar macrophages. Toxicol Appl Pharmacol 2002; 180:197-204. [PMID: 12009859 DOI: 10.1006/taap.2002.9406] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Mycotoxins were fungal metabolites that were widely present in feed and food; some of them were known to associate with human and animal disease. In the present study, the effects of fumonisin B1 (FmB1) and aflatoxin B1 (AFB1) on swine alveolar macrophages (AM) were examined by exposing primary cultures of swine AM to various concentrations of mycotoxins. Incubation of AM with 5 microg/ml of FmB1 for 72 h led to a reduction in the number of viable cells to 65% of the control levels. In the presence of 1.5 microg/ml of AFB1, the viability of AM falls to less than 41% of controls after 24 h exposure. FmB1, but not AFB1, induced the apoptosis of swine AM with evidence of DNA laddering and nuclear fragmentation. However, both FmB1 and AFB1 exposure induced the expression of apoptosis-related heat shock protein 72 (HSP 72) in AM. Swine AM treated with 50 ng/ml of FmB1 and 100 ng/ml of AFB1 for 24 h led to a reduction in phagocytic ability to approximately 55 and 36% of the control levels, respectively. Incubation of AM with FmB1 (2 and 10 microg/ml) for 24 h dramatically decreased the mRNA levels of interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha). However, AFB1 treatment did not affect the expression of IL-1beta and TNF-alpha mRNA. The results suggest that both FmB1 and AFB1 are immunotoxic to swine AM but that they exert their toxic effects via different biochemical mechanisms.
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Affiliation(s)
- Biing-Hui Liu
- Department of Life Science, Chung Shan Medical University, Taichung, Taiwan.
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43
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He Q, Riley RT, Sharma RP. Pharmacological antagonism of fumonisin B1 cytotoxicity in porcine renal epithelial cells (LLC-PK1): a model for reducing fumonisin-induced nephrotoxicity in vivo. PHARMACOLOGY & TOXICOLOGY 2002; 90:268-77. [PMID: 12076308 DOI: 10.1034/j.1600-0773.2002.900507.x] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Fumonisin B1 is a mycotoxin commonly found on corn. It is hepatotoxic and nephrotoxic in domestic and experimental animals, and causes equine leukoencephalomalacia and porcine pulmonary oedema. It is a potent inhibitor of ceramide synthase. Inhibition leads to accumulation of free sphingoid bases in cells and tissues. In pig kidney epithelial cells (LLC-PK1), fumonisin B1 induces increased tumour necrosis factor alpha (TNFalpha) expression independent of the accumulation of sphingoid bases. The objective of this study was to investigate pharmacological approaches for intervening in fumonisin B1 toxicity using the LLC-PK1 cell model. The toxicity of fumonisin B1 was assayed using cell viability and lactate dehydrogenase (lactate dehydrogenase) release. Pretreatment of cells with myriocin, preventing sphinganine accumulates, prevented the fumonisin B1-induced decrease in cell viability and increased lactate dehydrogenase release. Modulation of adenosine receptor activity did not reduce the fumonisin B1 cytotoxicity. As with myriocin, silymarin pretreatment prevented the fumonisin B1-induced effects on cell viability and lactate dehydrogenase release. When added 6 or 24 hr after treatment of cells with fumonisin B1, both myriocin and silymarin reversed the decreased cell viability and suppressed the increased lactate dehydrogenase release. Myriocin, but not silymarin, blocked the accumulation of sphinganine in fumonisin B1-treated cells. Silymarin, unlike myriocin, induced expression of TNFalpha to an extent similar to fumonisin B1, but pretreatment with silymarin decreased the fumonisin B1-induced TNFalpha expression in LLC-PK1 cells. Results suggest that the mechanisms by which myriocin and silymarin protect renal cells are different, and silymarin potentially prevents fumonisin B1-induced toxicity by modulating TNFalpha expression or signals downstream of the inhibition of ceramide synthase.
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Affiliation(s)
- Quanren He
- Department of Physiology and Pharmacology, College of Veterinary Medicine, The University of Georgia, Athens 30602-7389, USA
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44
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Galvano F, Campisi A, Russo A, Galvano G, Palumbo M, Renis M, Barcellona ML, Perez-Polo JR, Vanella A. DNA damage in astrocytes exposed to fumonisin B1. Neurochem Res 2002; 27:345-51. [PMID: 11958538 DOI: 10.1023/a:1014971515377] [Citation(s) in RCA: 42] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
Fumonisins are a group of toxic metabolites mainly produced by Fusarium moniliforme and Fusarium proliferatum, fungi that commonly occur on corn throughout the world. Fumonisin B1 (FB1), structurally resembling sphingoid bases, is an inhibitor of ceramide synthase, a key enzyme involved in de novo sphingolipid biosynthesis and in the reacylation of free sphingoid bases derived from sphingolipid turnover. This inhibitory effect leads to accumulation of free sphinganine (SA) and sphingosine (SO), inducing cell death. However, little is known on the down stream effectors activated by these sphingolipids in the cell death signaling pathway. We exposed rat astrocytes to FB1 with the aim of evaluating the involvement of oxygen free radicals and of some other biochemical pathways such as caspase-3 activity and DNA damage. Our results indicate that FB1 treatment (48, 72 h and 6 days in vitro, DIV, and 10, 50, 100 microM) does not affect cell viability. Conversely, after 72 h of treatment, FB1 (50 and 100 microM) induced DNA damage and an enhancement of caspase-3 activity compared to controls. In addition, FB1 increased the expression of HSP70 at 10 and 50 microM at 48, 72 h, and 6 DIV of treatment. We conclude that DNA damage of apoptotic type in rat astrocytes is caused by FB1 and that the genotoxic potential of FB1 has probably been underestimated and should be reconsidered.
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Affiliation(s)
- F Galvano
- Department of Agro-forestry, Environmental Science and Technology, University of Reggio Calabria, Italy
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Abstract
Fumonisin B1 (FB1) is a naturally occurring mycotoxin produced primarily by Fusarium verticillioides and related fungi, common contaminants of corn throughout the world. FB1 is a carcinogen and causative agent of several lethal animal diseases, including equine leukoencephalomalacia and porcine pulmonary edema. Liver is the primary target organ in mice. In vivo and vitro, cells exposed to FB1 undergo a mixture of necrotic and apoptotic cell death. Our previous studies showed gender differences in hepatotoxicity caused after 5 day FB1 treatment. Gene alterations in cytokine network and apoptosis signaling molecules were also observed after an acute single dose of FB1. To further investigate the gene alterations after a subchronic FB1 exposure and its correlation to observed gender differences, male and female BALB/c mice (five per group) were injected subcutaneously with either saline or 2.25 mg/kg per day of FB1 for 5 days. FB1 caused increased expression of tumor necrosis factor alpha (TNFalpha), interleukin (IL)-1alpha, IL-1beta, IL-1 receptor antagonist (IL-1Ra), IL-6, IL-10, IL-12 p40, IL-18 and interferon gamma (IFNgamma) in male liver, with a similar increase in females except for IL-1beta and IL-18. Control females showed higher basal levels of IL-1alpha, IL-1Ra, IL-10, IL-12 p40 and IFNgamma compared with males. Expression of TNF receptor 55 and TNF receptor associated death domain (TRADD) was increased, with no changes in Fas signaling molecules, Fas, Fas ligand (FasL), Fas associated death domain (FADD) and Fas-associated protein factor (FAF). Expression of oncogenic transcription factors, c-Myc, B-Myc, Max and Mad, and apoptotic genes, namely Bcl-2, Bax and Bad, was increased after FB1 treatment. FB1 caused an activation of cytokine network in liver, particularly the TNFalpha signaling pathway, suggesting its involvement in hepatotoxic mechanisms. Induction of IL-1Ra and oncogenes is a likely mechanism for the cancer promoting properties of FB1, through a mechanism involving apoptotic necrosis, oncotic necrosis and consequent regeneration.
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Affiliation(s)
- Neetesh Bhandari
- Department of Physiology and Pharmacology, College of Veterinary Medicine, The University of Georgia, Athens, GA 30602-7389, USA
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Bhandari N, Enongene EN, Riley RT, Meredith FI, Sharma RP. Temporal expression of fumonisin B(1)-induced tumor necrosis factor-alpha and interferon gamma in mice. Comp Biochem Physiol C Toxicol Pharmacol 2002; 131:113-22. [PMID: 11879779 DOI: 10.1016/s1532-0456(01)00280-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Fumonisin B(1) (FB(1)), a toxic metabolite of Fusarium verticillioides, is a carcinogen and causative agent of various animal diseases. Our previous studies indicated the involvement of tumor necrosis factor-alpha (TNF alpha) in FB(1)-induced toxic responses. To further investigate the time-course of TNF alpha production and signaling, mice (four/group) were treated subcutaneously (s.c.) or per os (p.o.) with either vehicle or 25 mg/kg of FB(1) as a single dose and sacrificed at 0, 2, 4, 8, 12 and 24 h after treatment. The TNF alpha expression was increased in liver and kidney after both routes of FB(1) exposure without any alterations in spleen. The p.o.-route FB(1) treatment caused greater hepatotoxicity compared to the s.c. route, as depicted by increased alanine aminotransferase and aspartate aminotransferase level in plasma, observed only after p.o. FB(1) treatment. The increase in enzymes at 8 h after p.o. treatment correlated with the highest TNF alpha expression, also noted at 8 h after p.o. treatment, thus further confirming the involvement of TNF alpha in FB(1) toxicity. The interferon (IFN)-gamma expression was increased in liver at 4 h after p.o. FB(1) treatment, suggesting a possible combined role of TNF alpha and IFN gamma in their induction and hepatotoxicity.
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Affiliation(s)
- Neetesh Bhandari
- Department of Physiology and Pharmacology, College of Veterinary Medicine, The University of Georgia, Athens, GA 30602-7389, USA
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Galvano F, Russo A, Cardile V, Galvano G, Vanella A, Renis M. DNA damage in human fibroblasts exposed to fumonisin B(1). Food Chem Toxicol 2002; 40:25-31. [PMID: 11731033 DOI: 10.1016/s0278-6915(01)00083-7] [Citation(s) in RCA: 60] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Fumonisins are mycotoxins produced by several Fusarium species (Fusarium verticilloides and F. proliferatum) that infest corn and other cereals. Fumonisin B(1) (FB(1)), structurally resembling sphingoid bases, is an inhibitor of ceramide synthetase, a key enzyme involved in de novo sphingolipid biosynthesis and in the reacylation of free sphingoid bases derived from sphingolipid turnover. This inhibitory effect leads to accumulation of free sphinganine and sphingosine and subsequent induction of cell death. However, the downstream effectors activated by these sphingolipids in the cell death-signalling pathway are little known. The aim of this study was to evaluate, in FB(1)-exposed human fibroblasts, the involvement of oxygen free radicals and of some other biochemical pathways, caspase-3 activity, poly(ADP-ribose)polymerase (PARP) cleavage and DNA damage evaluated by comet assay. Our results indicate that FB(1) treatment (48, 72 h and 10, 50, 100 microM) does not affect cellular viability. Conversely, after 72 h of treatment, FB(1) (50 and 100 microM) induced DNA damage, an enhancement of caspase-3-activity and cleavage of PARP compared to controls. In addition, FB(1) increased the expression of HSP70 in a concentration and time-dependent manner. Our results indicate that DNA damage of apoptotic type in human fibroblasts is caused by exposure to FB(1) at high concentrations and for a prolonged time and that the genotoxic potential of FB(1) has probably been underestimated and should be reconsidered.
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Affiliation(s)
- F Galvano
- Department of Agro-forestry, Environmental Science and Technology, University of Reggio Calabria, P.zza S. Francesco 7, Reggio Calabria, Italy.
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Kim MS, Lee DY, Wang T, Schroeder JJ. Fumonisin B(1) induces apoptosis in LLC-PK(1) renal epithelial cells via a sphinganine- and calmodulin-dependent pathway. Toxicol Appl Pharmacol 2001; 176:118-26. [PMID: 11601888 DOI: 10.1006/taap.2001.9188] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Fumonisins are a family of mycotoxins produced by Fusarium moniliforme, which is the most common mold found on corn throughout the world. These compounds are both toxic and carcinogenic for animals, and perhaps humans, with the kidney being the most sensitive organ to fumonisin toxicity. The molecular mechanism of fumonisin toxicity appears to involve disruption of de novo biosynthesis of sphingolipids and accumulation of sphinganine. The goals of this study were to determine whether fumonisin B(1) kills LLC-PK(1) renal kidney epithelial cells by inducing apoptosis and to identify genes affected by sphinganine that mediate fumonisin B(1)-induced cell death. Fumonisin B(1) produced morphological changes (i.e., cell shrinkage, membrane blebbing) and time-dependent increases in DNA fragmentation demonstrating that the toxin induces apoptosis. Simultaneously, fumonisin B(1) blocked sphingolipid biosynthesis and caused accumulation of sphinganine. To further investigate the role of sphinganine in fumonisin B(1)-induced apoptosis, beta-fluoroalanine (betaFA) was used to inhibit serine palmitoyltransferase, which catalyzes an earlier step in the sphingolipid biosynthetic pathway. betaFA blocked sphinganine accumulation and prevented fumonisin B(1)-induced DNA fragmentation, confirming that apoptosis induced by fumonisin B(1) is dependent upon accumulation of sphinganine. To examine gene expression, differential display reverse transcriptase polymerase chain reaction (DDRT-PCR) was applied to RNA isolated after 16 h of exposure to fumonisin B(1). Differential expression in response to fumonisin B(1) of a gene identified as calmodulin has been verified by Northern analysis. Sphinganine appears to mediate the effect because betaFA reduces induction of calmodulin mRNA by fumonisin B(1). Fumonisin B(1) also increases calmodulin protein in a concentration-dependent manner and the calmodulin antagonist W7 blocks fumonisin B(1)-induced DNA fragmentation, supporting a role for calmodulin in fumonisin B(1)-induced apoptosis. In contrast, fumonisin B(1) had no effect on expression of bcl-2 family genes (bax, bcl-2, and bcl-x). These findings demonstrate that fumonisin B(1) kills LLC-PK(1) kidney cells by inducing apoptosis. Further, the results establish a sequence of events for fumonisin B(1)-induced apoptosis involving initial disruption of sphingolipid metabolism and accumulation of sphinganine (or a metabolite), which, in turn, induces expression of calmodulin.
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Affiliation(s)
- M S Kim
- Department of Food Science and Human Nutrition, Michigan State University, East Lansing, Michigan, 48824-1224, USA
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He Q, Riley RT, Sharma RP. Fumonisin-induced tumor necrosis factor-alpha expression in a porcine kidney cell line is independent of sphingoid base accumulation induced by ceramide synthase inhibition. Toxicol Appl Pharmacol 2001; 174:69-77. [PMID: 11437650 DOI: 10.1006/taap.2001.9189] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Previous studies have shown that fumonisin B1 (FB1) inhibits ceramide synthase, resulting in accumulation of free sphinganine and sphingosine. Tumor necrosis factor-alpha (TNFalpha) plays an important role in FB1 toxicity and the expression of TNFalpha mRNA in liver and kidney is increased following FB1 exposure in mice. The objective of the current study was to investigate whether these two events (sphingoid bases accumulation and TNFalpha induction) are dependent on each other. An increase in expression of TNFalpha mRNA was detected in LLC-PK1 cells as early as 4 h after FB1 treatment but decreased to the control levels after 8 h. A positive linear correlation was observed between the expression of TNFalpha mRNA and FB1 concentration. Increases of intracellular sphingoid bases were also detected after 4 h of FB1 treatment and progressively increased until 24 h. Exposure of the cells to sphinganine or sphingosine did not significantly alter the expression of TNFalpha. Inhibition of sphingoid base biosynthesis by ISP-1, a specific inhibitor of serine palmitoyltransferase, the first enzyme in de novo sphingolipid biosynthesis, efficiently blocked the accumulation of free sphingoid bases in response to FB1, but it did not prevent the induction of TNFalpha expression. Results indicate that FB1-induced increase in TNFalpha expression is independent of sphingoid base accumulation-induced by ceramide synthase inhibition in LLC-PK1 cells.
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Affiliation(s)
- Q He
- Department of Physiology and Pharmacology, College of Veterinary Medicine, The University of Georgia, Athens, Georgia 30602, USA
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Hard GC, Howard PC, Kovatch RM, Bucci TJ. Rat kidney pathology induced by chronic exposure to fumonisin B1 includes rare variants of renal tubule tumor. Toxicol Pathol 2001; 29:379-86. [PMID: 11442024 DOI: 10.1080/019262301316905345] [Citation(s) in RCA: 43] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
The carcinogenicity of fumonisin B1 (FB1), a worldwide contaminant of corn produced by Fusaria species of fungi, has been tested recently in 2-year feeding studies in Fischer F344 rats and B6C3F1 mice. Inclusion of FB1 at 50 and 80 ppm in the diet induced liver tumors in female mice, and at 50 and 150 ppm induced renal tumors in male rats (22). In the present study, the kidneys from the rat bioassay were examined to characterize the various histopathological changes associated with renal tumor induction. In all high-dose (150 ppm) and mid-dose (50 ppm) male rats, and to a lesser extent in high-dose (100 ppm) female rats, there was evidence of sustained nephrotoxicity manifested as basophilia, apoptosis, cell regeneration, and simple tubule hyperplasia, affecting proximal convoluted tubules in the deep cortex, extending into the outer region of the outer stripe of outer medulla. A further alteration consisted of sporadic areas of interstitial hyalinization in deep cortex, suggestive of expanded basement membrane, coupled with tubule atrophy. The continued presence of nephrotoxicity throughout chronic exposure to FB1 suggested that renal tumor development may have been an outcome of sustained cell loss and compensatory regeneration. In some cases, preneoplastic tubules or incipient renal tumors presented an immature or fetal form in association with interstitial hyalinization. The renal tubule tumors induced by FB1 were typified by a rare, highly malignant, anaplastic variant capable of growth by infiltration. Of the 10 renal tubule tumors diagnosed in the mid-dose males, and the 16 in the high-dose males, 8 and 10, respectively, were graded as carcinomas. Anaplastic variants represented 50% of the mid-dose carcinomas and 80% of the high-dose carcinomas. One of the anaplastic carcinomas in a mid-dose male was a true sarcomatoid phenotype not previously recorded in the rodent. Metastatic invasion of the lung occurred with 25% of the mid-dose carcinomas and 50% of the high-dose carcinomas. It was speculated that FB1 may have been influencing the growth characteristics of the induced renal tumors via its inhibitory action on the synthesis of sphingolipids, which in turn, participate in regulating cell contact, growth, and differentiation, or alternatively by affecting cell adhesion molecules.
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Affiliation(s)
- G C Hard
- American Health Foundation, Valhalla, New York 10595, USA.
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