scholarly journals Developmental Toxicity of Mycotoxin Fumonisin B1 in Animal Embryogenesis: An Overview

Toxins ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 114 ◽  
Author(s):  
Chompunut Lumsangkul ◽  
Hsin-I Chiang ◽  
Neng-Wen Lo ◽  
Yang-Kwang Fan ◽  
Jyh-Cherng Ju
Keyword(s):  
Chemical Structure ◽  
Biosynthetic Pathway ◽  
De Novo ◽  
Developmental Toxicity ◽  
Fusarium Verticillioides ◽  
Fumonisin B1 ◽  
Primary Component ◽  
Ceramide Synthase ◽  
High Similarity ◽  
Developmental Abnormalities

A teratogenic agent or teratogen can disturb the development of an embryo or a fetus. Fumonisin B1 (FB1), produced by Fusarium verticillioides and F. proliferatum, is among the most commonly seen mycotoxins and contaminants from stale maize and other farm products. It may cause physical or functional defects in embryos or fetuses, if the pregnant animal is exposed to mycotoxin FB1. Due to its high similarity in chemical structure with lipid sphinganine (Sa) and sphingosine (So), the primary component of sphingolipids, FB1 plays a role in competitively inhibiting Sa and So, which are key enzymes in de novo ceramide synthase in the sphingolipid biosynthetic pathway. Therefore, it causes growth retardation and developmental abnormalities to the embryos of hamsters, rats, mice, and chickens. Moreover, maternal FB1 toxicity can be passed onto the embryo or fetus, leading to mortality. FB1 also disrupts folate metabolism via the high-affinity folate transporter that can then result in folate insufficiency. The deficiencies are closely linked to incidences of neural tube defects (NTDs) in mice or humans. The purpose of this review is to understand the toxicity and mechanisms of mycotoxin FB1 on the development of embryos or fetuses.

scholarly journals A Novel Role of IGF1 in Apo2L/TRAIL-Mediated Apoptosis of Ewing Tumor Cells

Sarcoma ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-14 ◽  
Author(s):  
Frans van Valen ◽  
Henning Harrer ◽  
Marc Hotfilder ◽  
Uta Dirksen ◽  
Thomas Pap ◽  
...  
Keyword(s):  
De Novo ◽  
Fumonisin B1 ◽  
Chemotherapeutic Agents ◽  
Ceramide Synthase ◽  
Short Term ◽  
Igf1 Receptor ◽  
Induced Apoptosis ◽  
Survival Effect

Insulin-like growth factor 1 (IGF1) reputedly opposes chemotoxicity in Ewing sarcoma family of tumor (ESFT) cells. However, the effect of IGF1 on apoptosis induced by apoptosis ligand 2 (Apo2L)/tumor necrosis factor (TNF-) related apoptosis-inducing ligand (TRAIL) remains to be established. We find that opposite to the partial survival effect of short-term IGF1 treatment, long-term IGF1 treatment amplified Apo2L/TRAIL-induced apoptosis in Apo2L/TRAIL-sensitive but not resistant ESFT cell lines. Remarkably, the specific IGF1 receptor (IGF1R) antibodyα-IR3 was functionally equivalent to IGF1. Short-term IGF1 incubation of cells stimulated survival kinase AKT and increased X-linked inhibitor of apoptosis (XIAP) protein which was associated with Apo2L/TRAIL resistance. In contrast, long-term IGF1 incubation resulted in repression of XIAP protein through ceramide (Cer) formation derived from de novo synthesis which was associated with Apo2L/TRAIL sensitization. Addition of ceramide synthase (CerS) inhibitor fumonisin B1 during long-term IGF1 treatment reduced XIAP repression and Apo2L/TRAIL-induced apoptosis. Noteworthy, the resistance to conventional chemotherapeutic agents was maintained in cells following chronic IGF1 treatment. Overall, the results suggest that chronic IGF1 treatment renders ESFT cells susceptible to Apo2L/TRAIL-induced apoptosis and may have important implications for the biology as well as the clinical management of refractory ESFT.

scholarly journals Ceramide Synthase-dependent Ceramide Generation and Programmed Cell Death

2011 ◽  
Vol 286 (18) ◽  
pp. 15929-15942 ◽  
Author(s):  
Thomas D. Mullen ◽  
Russell W. Jenkins ◽  
Christopher J. Clarke ◽  
Jacek Bielawski ◽  
Yusuf A. Hannun ◽  
...  
Keyword(s):  
Cell Death ◽  
Plasma Membrane ◽  
Programmed Cell Death ◽  
De Novo ◽  
Fumonisin B1 ◽  
Membrane Permeabilization ◽  
Ceramide Synthase ◽  
Plasma Membrane Permeabilization ◽  
Ceramide Generation ◽  
Uv C

The sphingolipid ceramide has been widely implicated in the regulation of programmed cell death or apoptosis. The accumulation of ceramide has been demonstrated in a wide variety of experimental models of apoptosis and in response to a myriad of stimuli and cellular stresses. However, the detailed mechanisms of its generation and regulatory role during apoptosis are poorly understood. We sought to determine the regulation and roles of ceramide production in a model of ultraviolet light-C (UV-C)-induced programmed cell death. We found that UV-C irradiation induces the accumulation of multiple sphingolipid species including ceramide, dihydroceramide, sphingomyelin, and hexosylceramide. Late ceramide generation was also found to be regulated by Bcl-xL, Bak, and caspases. Surprisingly, inhibition of de novo synthesis using myriocin or fumonisin B1 resulted in decreased overall cellular ceramide levels basally and in response to UV-C, but only fumonisin B1 inhibited cell death, suggesting the presence of a ceramide synthase (CerS)-dependent, sphingosine-derived pool of ceramide in regulating programmed cell death. We found that this pool did not regulate the mitochondrial pathway, but it did partially regulate activation of caspase-7 and, more importantly, was necessary for late plasma membrane permeabilization. Attempting to identify the CerS responsible for this effect, we found that combined knockdown of CerS5 and CerS6 was able to decrease long-chain ceramide accumulation and plasma membrane permeabilization. These data identify a novel role for CerS and the sphingosine salvage pathway in regulating membrane permeability in the execution phase of programmed cell death.

scholarly journals Ceramide synthase 4 and de novo production of ceramides with specific N-acyl chain lengths are involved in glucolipotoxicity-induced apoptosis of INS-1 β-cells

2011 ◽  
Vol 438 (1) ◽  
pp. 177-189 ◽  
Author(s):  
Julien Véret ◽  
Nicolas Coant ◽  
Evgeny V. Berdyshev ◽  
Anastasia Skobeleva ◽  
Nicole Therville ◽  
...  
Keyword(s):  
Cell Apoptosis ◽  
De Novo ◽  
Acyl Chain ◽  
Fumonisin B1 ◽  
Ceramide Synthase ◽  
Β Cells ◽  
Β Cell ◽  
Induced Apoptosis ◽  
Synthase Inhibitor ◽  
Chain Lengths

Pancreatic β-cell apoptosis induced by palmitate requires high glucose concentrations. Ceramides have been suggested to be important mediators of glucolipotoxicity-induced β-cell apoptosis. In INS-1 β-cells, 0.4 mM palmitate with 5 mM glucose increased the levels of dihydrosphingosine and dihydroceramides, two lipid intermediates in the de novo biosynthesis of ceramides, without inducing apoptosis. Increasing glucose concentrations to 30 mM amplified palmitate-induced accumulation of dihydrosphingosine and the formation of (dihydro)ceramides. Of note, glucolipotoxicity specifically induced the formation of C18:0, C22:0 and C24:1 (dihydro)ceramide molecular species, which was associated with the up-regulation of CerS4 (ceramide synthase 4) levels. Fumonisin-B1, a ceramide synthase inhibitor, partially blocked apoptosis induced by glucolipotoxicity. In contrast, apoptosis was potentiated in the presence of D,L-threo-1-phenyl-2-palmitoylamino-3-morpholinopropan-1-ol, an inhibitor of glucosylceramide synthase. Moreover, overexpression of CerS4 amplified ceramide production and apoptosis induced by palmitate with 30 mM glucose, whereas down-regulation of CerS4 by siRNA (short interfering RNA) reduced apoptosis. CerS4 also potentiates ceramide accumulation and apoptosis induced by another saturated fatty acid: stearate. Collectively, our results suggest that glucolipotoxicity induces β-cell apoptosis through a dual mechanism involving de novo ceramide biosynthesis and the formation of ceramides with specific N-acyl chain lengths rather than an overall increase in ceramide content.

scholarly journals Sphingosine-1-phosphate phosphohydrolase in regulation of sphingolipid metabolism and apoptosis

2002 ◽  
Vol 158 (6) ◽  
pp. 1039-1049 ◽  
Author(s):  
Hervé Le Stunff ◽  
Ismael Galve-Roperh ◽  
Courtney Peterson ◽  
Sheldon Milstien ◽  
Sarah Spiegel
Keyword(s):  
Cell Fate ◽  
De Novo ◽  
Fumonisin B1 ◽  
Sphingolipid Metabolism ◽  
Ceramide Synthase ◽  
Serine Palmitoyltransferase ◽  
Intracellular Membranes ◽  
Sphingosine 1 Phosphate ◽  
Ceramide Accumulation ◽  
Membrane Treatment

Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite that regulates diverse biological processes by binding to a family of G protein–coupled receptors or as an intracellular second messenger. Mammalian S1P phosphatase (SPP-1), which degrades S1P to terminate its actions, was recently cloned based on homology to a lipid phosphohydrolase that regulates the levels of phosphorylated sphingoid bases in yeast. Confocal microscopy surprisingly revealed that epitope-tagged SPP-1 is intracellular and colocalized with the ER marker calnexin. Moreover, SPP-1 activity and protein appeared to be mainly enriched in the intracellular membranes with lower expression in the plasma membrane. Treatment of SPP-1 transfectants with S1P markedly increased ceramide levels, predominantly in the intracellular membranes, diminished survival, and enhanced apoptosis. Remarkably, dihydro-S1P, although a good substrate for SPP-1 in situ, did not cause significant ceramide accumulation or increase apoptosis. Ceramide accumulation induced by S1P was completely blocked by fumonisin B1, an inhibitor of ceramide synthase, but only partially reduced by myriocin, an inhibitor of serine palmitoyltransferase, the first committed step in de novo synthesis of ceramide. Furthermore, S1P, but not dihydro-S1P, stimulated incorporation of [3H]palmitate, a substrate for both serine palmitoyltransferase and ceramide synthase, into C16-ceramide. Collectively, our results suggest that SPP-1 functions in an unprecedented manner to regulate sphingolipid biosynthesis and is poised to influence cell fate.

scholarly journals Sphingolipid Effects on the Plasma Membrane Produced by Addition of Fumonisin B1 to Maize Embryos

Plants ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 150 ◽  
Author(s):  
Nora A. Gutiérrez-Nájera ◽  
Mariana Saucedo-García ◽  
Liliana Noyola-Martínez ◽  
Christian Vázquez-Vázquez ◽  
Silvia Palacios-Bahena ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Atpase Activity ◽  
Fusarium Verticillioides ◽  
Fumonisin B1 ◽  
Fold Increase ◽  
Membrane Properties ◽  
Ceramide Synthase ◽  
Animal Cells ◽  
Plasma Membrane Fluidity ◽  
Maize Embryos

Fumonisin B1 is a mycotoxin produced by Fusarium verticillioides that modifies the membrane properties from animal cells and inhibits complex sphingolipids synthesis through the inhibition of ceramide synthase. The aim of this work was to determine the effect of Fumonisin B1 on the plant plasma membrane when the mycotoxin was added to germinating maize embryos. Fumonisin B1 addition to the embryos diminished plasma membrane fluidity, increased electrolyte leakage, caused a 7-fold increase of sphinganine and a small decrease in glucosylceramide in the plasma membrane, without affecting phytosphingosine levels or fatty acid composition. A 20%–30% inhibition of the plasma membrane H+-ATPase activity was observed when embryos were germinated in the presence of the mycotoxin. Such inhibition was only associated to the decrease in glucosylceramide and the addition of exogenous ceramide to the embryos relieved the inhibition of Fumonisin B1. These results indicate that exposure of the maize embryos for 24 h to Fumonisin B1 allowed the mycotoxin to target ceramide synthase at the endoplasmic reticulum, eliciting an imbalance of endogenous sphingolipids. The latter disrupted membrane properties and inhibited the plasma membrane H+-ATPase activity. Altogether, these results illustrate the mode of action of the pathogen and a plant defense strategy.

scholarly journals Ceramide accumulation during oxidant renal tubular injury: mechanisms and potential consequences.

1998 ◽  
Vol 9 (9) ◽  
pp. 1670-1680
Author(s):  
R A Zager ◽  
D S Conrad ◽  
K Burkhart
Keyword(s):  
Cell Death ◽  
Cell Injury ◽  
De Novo ◽  
Oxidant Stress ◽  
Fumonisin B1 ◽  
Ceramide Synthase ◽  
Proximal Tubular ◽  
Renal Tubular ◽  
Fe Toxicity ◽  
Ceramide Accumulation

Ceramide is an important signaling molecule that is typically generated via sphingomyelinase (SMase)-mediated sphingomyelin (SM) hydrolysis. Although diverse forms of renal injury elicit ceramide accumulation, the molecular determinants of this change and its contribution to tissue damage are poorly defined. The present study uses iron (Fe/hydroxyquinoline)-mediated injury of cultured human proximal tubular (HK-2) cells to gain additional insights into these issues. A 4-h Fe exposure doubled ceramide levels in the absence of cell death. This was independent of de novo synthesis, since ceramide synthase inhibition (with fumonisin B1) had no effect. Oxidant stress directly suppressed, rather than stimulated, SMase activity by: (1) decreasing SMase levels; (2) depleting SMase-stimulating glutathione; and (3) increasing SM resistance to SMase attack. Fe suppressed cell sphingosine levels (3 to 4 times ceramide/sphingosine ratio increments), suggesting a possible ceramidase block. Fe did not directly affect HK-2 ceramidase levels. However, arachidonic acid (C20:4) accumulation, a consequence of oxidant-induced phospholipase A2 (PLA2) activation, markedly suppressed ceramidase and stimulated SMase activity. Exogenous C20:4, as well as PLA2 (in doses simulating Fe-induced deacylation) recapitulated Fe's ceramide-generating effect. Because C20:4 is directly cytotoxic, it was hypothesized that ceramide might offset some of C20:4's adverse effects. Supporting this possibility were the following: (1) C20:4 exacerbated Fe toxicity; (2) this was abrogated by ceramide treatment; and (3) ceramide blunted Fe-mediated cell death. Conclusions: (1) ceramide accumulation during acute cell injury can be an adaptive response to PLA2 activation/C20:4 generation; (2) C20:4-induced ceramidase inhibition, coupled with SMase stimulation, may trigger this result; and (3) these ceramide increments may exert a "biostat" function, helping to offset C20:4/PLA2- and "catalytic" iron-mediated tubular cell death.

A review of the toxic effects and mechanisms of action of fumonisin B1

2008 ◽  
Vol 27 (11) ◽  
pp. 799-809 ◽  
Author(s):  
H Stockmann-Juvala ◽  
K Savolainen
Keyword(s):  
Fusarium Species ◽  
Fusarium Verticillioides ◽  
Fumonisin B1 ◽  
Structural Similarity ◽  
Mechanisms Of Action ◽  
Agricultural Products ◽  
Ceramide Synthase ◽  
Fusarium Mycotoxins ◽  
Cellular Mechanisms ◽  
Toxic Potential

Fumonisin B1 (FB1) 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 FB1 may take place. FB1 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. FB1 is neurotoxic, hepatotoxic, and nephrotoxic in animals, and it has been classified as a possible carcinogen to humans. The cellular mechanisms behind FB1-induced toxicity include the induction of oxidative stress, apoptosis, and cytotoxicity, as well as alterations in cytokine expression. The effects of FB1 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 FB1.

scholarly journals Self-Protection against the Sphingolipid Biosynthesis Inhibitor Fumonisin B1 Is Conferred by a FUM Cluster-Encoded Ceramide Synthase

mBio ◽  
2020 ◽  
Vol 11 (3) ◽  
Author(s):  
Slavica Janevska ◽  
Iuliia Ferling ◽  
Katarina Jojić ◽  
Julia Rautschek ◽  
Sandra Hoefgen ◽  
...  
Keyword(s):  
Cellular Localization ◽  
Fusarium Verticillioides ◽  
Animal Health ◽  
Fumonisin B1 ◽  
Ceramide Synthase ◽  
Content Type ◽  
Protection Mechanisms ◽  
Fungal Natural Products ◽  
Ceramide Synthases ◽  
Self Protection

ABSTRACT Fumonisin (FB) mycotoxins produced by species of the genus Fusarium detrimentally affect human and animal health upon consumption, due to the inhibition of ceramide synthase. In the present work, we set out to identify mechanisms of self-protection employed by the FB1 producer Fusarium verticillioides. FB1 biosynthesis was shown to be compartmentalized, and two cluster-encoded self-protection mechanisms were identified. First, the ATP-binding cassette transporter Fum19 acts as a repressor of the FUM gene cluster. Appropriately, FUM19 deletion and overexpression increased and decreased, respectively, the levels of intracellular and secreted FB1. Second, the cluster genes FUM17 and FUM18 were shown to be two of five ceramide synthase homologs in Fusarium verticillioides, grouping into the two clades CS-I and CS-II in a phylogenetic analysis. The ability of FUM18 to fully complement the yeast ceramide synthase null mutant LAG1/LAC1 demonstrated its functionality, while coexpression of FUM17 and CER3 partially complemented, likely via heterodimer formation. Cell viability assays revealed that Fum18 contributes to the fungal self-protection against FB1 and increases resistance by providing FUM cluster-encoded ceramide synthase activity. IMPORTANCE The biosynthesis of fungal natural products is highly regulated not only in terms of transcription and translation but also regarding the cellular localization of the biosynthetic pathway. In all eukaryotes, the endoplasmic reticulum (ER) is involved in the production of organelles, which are subject to cellular traffic or secretion. Here, we show that in Fusarium verticillioides, early steps in fumonisin production take place in the ER, together with ceramide biosynthesis, which is targeted by the mycotoxin. A first level of self-protection is given by the presence of a FUM cluster-encoded ceramide synthase, Fum18, hitherto uncharacterized. In addition, the final fumonisin biosynthetic step occurs in the cytosol and is thereby spatially separate from the fungal ceramide synthases. We suggest that these strategies help the fungus to avoid self-poisoning during mycotoxin production.

Short-term magnesium deficiency upregulates ceramide synthase in cardiovascular tissues and cells: cross-talk among cytokines, Mg2+, NF-κB, and de novo ceramide

2012 ◽  
Vol 302 (1) ◽  
pp. H319-H332 ◽  
Author(s):  
Burton M. Altura ◽  
Nilank C. Shah ◽  
Gatha Shah ◽  
Aimin Zhang ◽  
Wenyan Li ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
De Novo ◽  
Magnesium Deficiency ◽  
Smooth Muscles ◽  
Fumonisin B1 ◽  
Left Ventricular ◽  
Ceramide Synthase ◽  
Short Term ◽  
Aortic Smooth Muscle ◽  
Cytokines And Chemokines

The present study tested the hypotheses that 1) short-term dietary deficiency (MgD) of magnesium (21 days) would result in the upregulation of ceramide synthase (CS) in left ventricular (LV), right ventricular, atrial, and aortic smooth muscle, as well as induce a synthesis/release of select cytokines and chemokines into the LV and aortic smooth muscle and serum; 2) exposure of primary cultured vascular smooth muscle cells (VSMCs) to low extracellular Mg concentration would lead to the synthesis/release of select cytokines/chemokines, activation of N-SMase, and the de novo synthesis of ceramide; and 3) inhibition of CS by fumonisin B1 (FB1) or inhibition of neutral sphingomyelinase (N-SMase) by scyphostatin (SCY) in VSMCs exposed to low Mg would result in reductions in the levels of the cytokines/chemokines and lowered levels of ceramide concomitant with inhibition of NF-κB activation. The data indicated that short-term MgD (10% normal dietary intake) resulted in the upregulation of CS in ventricular, atrial, and aortic smooth muscles coupled to the synthesis/release of 12 different cytokines/chemokines, as well as activation of NF-κB in the LV and aortic smooth muscle and sera; even very low levels of water-borne Mg (e.g., 15 mg·l−1·day−1) either prevented or ameliorated the upregulation and synthesis of the cytokines/chemokines. Our experiments also showed that VSMCs exposed to low extracellular Mg resulted in the synthesis of 5 different cytokines and chemokines concomitant with synthesis/release of ceramide. However, inhibition of the synthesis and release of ceramide by either FB1 or SCY attenuated, markedly , the generation of ceramide, release of the cytokines/chemokines, and activation of NF-κB (as measured by activated p65 and cRel).

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