Fumonisin B1
Encyclopedia
Fumonisin B1 is the most prevalent member of a family of toxins, known as fumonisins, produced by several species of Fusarium
mold
s, such as Fusarium verticillioides, which occur mainly in maize (corn), wheat and other cereals. Fumonisin B1 contamination of maize has been reported worldwide at mg/kg levels. Human exposure occurs at levels of micrograms to milligrams per day and is greatest in regions where maize products are the dietary staple.
Fumonisin B1 is hepatotoxic and nephrotoxic in all animal species tested. The earliest histological change to appear in either the liver or kidney of fumonisin-treated animals is increased apoptosis followed by regenerative cell proliferation. While the acute toxicity of fumonisin is low, it is the known cause of two diseases which occur in domestic animals with rapid onset: equine leukoencephalomalacia and porcine pulmonary oedema syndrome. Both of these diseases involve disturbed sphingolipid metabolism and cardiovascular dysfunction.
of human esophageal cancer
in a region in South Africa. The diet of the people living in this area was homegrown corn and F. verticillioides was the most prevalent fungus in the corn consumed by the people with high incidence of esophageal cancer . Further outbreaks of ELEM and people in certain regions with high incidence of esophageal cancer led to more research on F.verticillioides. Soon they found experimentally that F.verticillioides caused ELEM in horses and porcine pulmonary edema
in pigs. It was found to be highly hepatotoxic and cardiotoxic in rats. In 1984 it was shown that the fungus was hepatocarcinogenic in rats . The chemical nature of the metabolite(s) causing all this had still not been discovered in 1984. After discovery of the carcinogenicity of the fungus, isolation and chemical characterization of the mycotoxin(s) and carcinogen(s) produced by F.verticillioides was urgent. It wasn't until 1988 that the chemical nature of the carcinogen was unraveled. Fumonisin B1 and fumonisin B2 were isolated from cultures of F.verticillioides at PROMEC (Programme on Mycotoxins and Experimental Carcinogenesis) . The structures were elucidated in collaboration with the CSIR(Council for Scientific and Industrial Research) . Now approximate 15 different fumonisins are discovered, the most important ones being fumonisin B1, B2 and B3 .
Absorption of orally administered fumonisin B1 (10 mg/kg body weight) to rats is low (3.5% of dose) but rapid (Tmax = 1.02h).
Plasma distribution of the absorbed dose conformed to a two-compartment open model
and the tissue (liver, kidney) concentration time results were consistent with a one-compartment open model
.
However, FB1 is rapidly excreted mostly in its original form. Small amounts are excreted in urine; the most are excreted in feaces.
-sphinganin-transferases and ceramide
synthases and are therefore competitive
inhibitors of sphingolipid
biosynthesis and metabolism.
Figure 2 shows the sphingolipid metabolism (schematic) and the inhibition caused by fumonisins. Fumonisin B1 inhibits the enzyme ceramide synthase (sphingosine N-acyltransferase), which acylates sphingoid bases. This blocks the formation of ceramide via two pathways: It inhibits de formation via de novo sphinganine and fatty acyl-CoA
and via sphingosine produced by the breakdown of ceramide by ceramidase.
The inhibition results in increased concentrations of sphinganine, sphingosine and their 1-phosphate metabolites and in decreased concentrations of complex sphingolipids.
The accumulation of sphinganine and sphingosine is a primary cause of the toxicity of fumonisin B1 Spinganine and sphingosine are cytotoxic, and have growth inhibitory effects. Also, these sphingoid bases induce apoptosis. Increased apoptosis seems to play an important role in the toxic effects including tumor induction .
However, it should be mentioned that the reduced concentration of ceramide and the increased concentration of sphingosine-1-phosphate (as a result of FB1 intake) cause an inhibition of apoptosis and promote mitosis and regeneration . The balance between the intracellular concentration of compounds that inhibit apoptosis and those that induce apoptosis will determine the cellular response.
Also, the decreased concentrations of complex sphingolipids appear to play a role in the abnormal behavior and altered morphology of the affected cells .
Because FB1 also occupies the fatty acyl-CoA space, it isn’t acylated, since acyl-CoA is necessary for the acylation; FB1 only inhibits ceramide synthase. However, when the tricarbillic acid groups are removed from FB1 by hydrolysis, the resulting product (aminopentol, AP1) doesn’t only act as an inhibitor, but also as a substrate for ceramide synthase; aminopentol is acylated by ceramide synthase to form N-palmitoyl-AP1 . This supports the suggestion that the aminopentol part of FB1 occupies the space of sphinganine in the enzyme. N-palmitoyl-AP1 is an even more potent inhibitor of ceramide synthase and may therefore play a role in the toxicity of nixtamalized fumonisins .
Until now, nothing about the kinetics and metabolism of fumonisin B1 in humans have been reported. On other animals much research has been done, but it might not be comparable to humans. In mice the elimination of FB1 is very rapid, but in humans it could be much slower considering their body weight .
There are several possible pathways that cause toxic effects of Fumonisin B1. Most toxic effects are due to altered sphingolipid metabolism by inhibition of ceramide synthase.
Production of reactive oxygen species (ROS) could occur. This increases oxidative stress and induce lipid peroxidation and could damage cells. In agreement with this some studies showed decreased levels of gluthation(GSH) in liver, but other studies showed even elevated levels of GSH . Cytotoxic effects have also been reported .
Another effect of exposure to FB1 is apoptosis. This has been observed in a number of different cells and tissues. Inhibition of ceramide synthase is not responsible for this effect. The main factors could be DNA fragmentation and caspase-3 activation .
FB1 has also immunotoxic effects, but much more research is necessary to get a clear overview of the effects on the immune system.
In 1990 and 1991 an sudden outbreak of neural tube defects occurred along the Texas-Mexico border. It is believed that this outbreak might have been due to high levels of FB1 that were observed in corn during previous years . Also regions in China and South Africa with high corn consumption show a high prevalence of NTD .
Another study on the relationship between sphingolipid levels and cancer incidence dind’t show any significant relationship between serum shpingolipids and risk of esophageal cancer. This is quite remarkable, because elevated levels of spingolipids shinganine and shingosine are believed to be biomarkers for exposure of FB1 .
Based on all these animal studies FB1 is classified by The International Agency for Research on Cancer (IARC) as possibly carcinogenic to humans (Group 2B) .
Alteration in sphingolipid biosynthesis are reported, especially in lung, heart, kindey and liver tissue. Lethal pulmonary edema was developed within 4–7 days after exposure to feed with concentrations of FB1 >16 mg/kg body weight (>92 ppm). Doses of 10ppm developed a milder form of pulmonary edema .
Mice don’t seem to be very sensitive to nephrotoxic effects in comparison with rats. In mouse kidneys little histological changes were seen by high dose exposure. The liver was also the main target organ in mice. Pathology is similar as in rats, with apoptosis and hepatocellular hyperplasia .
Fumonisin B1 is possibly embryotoxic if the dose is maternally toxic. A number of studies on genotoxicity inidicated no mutagenetic effects. Although fumonisin could damage DNA directly by production of reactive oxygen species(ROS) .
Mouse embryos were exposed to FB1 and they showed inhibited sphingolipid synthesis and growth. It caused NTD. Folic acid uptake was dramatically inhibited. Treatment after exposure with folic acid reduced NTD by 50-65% .
The information on metabolism and biotransformation
of FB1 is very sparse. However, metabolism most likely occurs in the gut since partially hydrolysed and fully hydrolysed FB1 were recovered in faeces but not in bile of Vervet monkeys.
Bioavailability of FB1 can be reduced by treating fumonisin-contaminated corn with glucomannans extracted from the cell wall of the yeast Saccharomyces cerevisiae. These polysaccharides are able to bind certain mycotoxins and have a 67% binding capacity for fumonisins.
Fusarium
Fusarium is a large genus of filamentous fungi widely distributed in soil and in association with plants. Most species are harmless saprobes, and are relatively abundant members of the soil microbial community. Some species produce mycotoxins in cereal crops that can affect human and animal health...
mold
Mold
Molds are fungi that grow in the form of multicellular filaments called hyphae. Molds are not considered to be microbes but microscopic fungi that grow as single cells called yeasts...
s, such as Fusarium verticillioides, which occur mainly in maize (corn), wheat and other cereals. Fumonisin B1 contamination of maize has been reported worldwide at mg/kg levels. Human exposure occurs at levels of micrograms to milligrams per day and is greatest in regions where maize products are the dietary staple.
Fumonisin B1 is hepatotoxic and nephrotoxic in all animal species tested. The earliest histological change to appear in either the liver or kidney of fumonisin-treated animals is increased apoptosis followed by regenerative cell proliferation. While the acute toxicity of fumonisin is low, it is the known cause of two diseases which occur in domestic animals with rapid onset: equine leukoencephalomalacia and porcine pulmonary oedema syndrome. Both of these diseases involve disturbed sphingolipid metabolism and cardiovascular dysfunction.
History
In 1970 an outbreak of Leukoenchephalomalacia (ELEM) in horses in South Africa was associated with the contamination of corn with the fungus Fusarium verticillioides . It is one of the most prevalent seed-borne fungi associated with corn . Another study was been done on the possible role of fungal toxins in the etiologyEtiology
Etiology is the study of causation, or origination. The word is derived from the Greek , aitiologia, "giving a reason for" ....
of human esophageal cancer
Esophageal cancer
Esophageal cancer is malignancy of the esophagus. There are various subtypes, primarily squamous cell cancer and adenocarcinoma . Squamous cell cancer arises from the cells that line the upper part of the esophagus...
in a region in South Africa. The diet of the people living in this area was homegrown corn and F. verticillioides was the most prevalent fungus in the corn consumed by the people with high incidence of esophageal cancer . Further outbreaks of ELEM and people in certain regions with high incidence of esophageal cancer led to more research on F.verticillioides. Soon they found experimentally that F.verticillioides caused ELEM in horses and porcine pulmonary edema
Pulmonary edema
Pulmonary edema , or oedema , is fluid accumulation in the air spaces and parenchyma of the lungs. It leads to impaired gas exchange and may cause respiratory failure...
in pigs. It was found to be highly hepatotoxic and cardiotoxic in rats. In 1984 it was shown that the fungus was hepatocarcinogenic in rats . The chemical nature of the metabolite(s) causing all this had still not been discovered in 1984. After discovery of the carcinogenicity of the fungus, isolation and chemical characterization of the mycotoxin(s) and carcinogen(s) produced by F.verticillioides was urgent. It wasn't until 1988 that the chemical nature of the carcinogen was unraveled. Fumonisin B1 and fumonisin B2 were isolated from cultures of F.verticillioides at PROMEC (Programme on Mycotoxins and Experimental Carcinogenesis) . The structures were elucidated in collaboration with the CSIR(Council for Scientific and Industrial Research) . Now approximate 15 different fumonisins are discovered, the most important ones being fumonisin B1, B2 and B3 .
Toxicokinetics
Regarding toxicokinetics there are no human data available, but research on animals has been done.Absorption
FB1 is taken orally via food. Overall FB1 is poorly absorbed, less than 6%.Absorption of orally administered fumonisin B1 (10 mg/kg body weight) to rats is low (3.5% of dose) but rapid (Tmax = 1.02h).
Distribution
After absorption, some appears to be retained in liver and kidneys. For rats that were fed diets containing fumonisins for several weeks, the concentrations of the fumonisins in the kidneys were approximately 10-fold higher than in the liver..Plasma distribution of the absorbed dose conformed to a two-compartment open model
Multi-compartment model
A multi-compartment model is a type of mathematical model used for describing the way materials or energies are transmitted among the compartments of a system. Each compartment is assumed to be a homogenous entity within which the entities being modelled are equivalent...
and the tissue (liver, kidney) concentration time results were consistent with a one-compartment open model
One compartment kinetics
Refer brahmankarOne-compartment kinetics for a chemical compound specifies that the uptake in the compartment is proportional to the concentration outside the compartment, and the elimination is proportional to the concentration inside the compartment...
.
Excretion
Elimination half-life in rats is 3.15h for plasma, 4.07h for liver, and 7.07h for kidney.However, FB1 is rapidly excreted mostly in its original form. Small amounts are excreted in urine; the most are excreted in feaces.
Toxicodynamics
Because of their similarity, fumonisins are able to inhibit sphingosineSphingosine
Sphingosine is an 18-carbon amino alcohol with an unsaturated hydrocarbon chain, which forms a primary part of sphingolipids, a class of cell membrane lipids that include sphingomyelin, an important phospholipid.-Functions:...
-sphinganin-transferases and ceramide
Ceramide
Ceramides are a family of lipid molecules. A ceramide is composed of sphingosine and a fatty acid. Ceramides are found in high concentrations within the cell membrane of cells. They are one of the component lipids that make up sphingomyelin, one of the major lipids in the lipid bilayer...
synthases and are therefore competitive
Competitive inhibition
Competitive inhibition is a form of enzyme inhibition where binding of the inhibitor to the active site on the enzyme prevents binding of the substrate and vice versa.-Mechanism:...
inhibitors of sphingolipid
Sphingolipid
Sphingolipids are a class of lipids containing a backbone of sphingoid bases, a set of aliphatic amino alcohols that includes sphingosine. They were discovered in brain extracts in the 1870s and were named for the mythological Sphinx because of their enigmatic nature. These compounds play...
biosynthesis and metabolism.
Figure 2 shows the sphingolipid metabolism (schematic) and the inhibition caused by fumonisins. Fumonisin B1 inhibits the enzyme ceramide synthase (sphingosine N-acyltransferase), which acylates sphingoid bases. This blocks the formation of ceramide via two pathways: It inhibits de formation via de novo sphinganine and fatty acyl-CoA
Acyl-CoA
Acyl-CoA is a group of coenzymes involved in the metabolism of fatty acids. It is a temporary compound formed when coenzyme A attaches to the end of a long-chain fatty acid inside living cells. The compound undergoes beta oxidation, forming one or more molecules of acetyl-CoA...
and via sphingosine produced by the breakdown of ceramide by ceramidase.
The inhibition results in increased concentrations of sphinganine, sphingosine and their 1-phosphate metabolites and in decreased concentrations of complex sphingolipids.
The accumulation of sphinganine and sphingosine is a primary cause of the toxicity of fumonisin B1 Spinganine and sphingosine are cytotoxic, and have growth inhibitory effects. Also, these sphingoid bases induce apoptosis. Increased apoptosis seems to play an important role in the toxic effects including tumor induction .
However, it should be mentioned that the reduced concentration of ceramide and the increased concentration of sphingosine-1-phosphate (as a result of FB1 intake) cause an inhibition of apoptosis and promote mitosis and regeneration . The balance between the intracellular concentration of compounds that inhibit apoptosis and those that induce apoptosis will determine the cellular response.
Also, the decreased concentrations of complex sphingolipids appear to play a role in the abnormal behavior and altered morphology of the affected cells .
Mechanism of action
The proposed mechanism of action is depicted in figure 3. Fumonisin B1 occupies the space and electrostatic interactions of both sphinganine (or sphingosine) and fatty acyl-CoA in ceramide synthase. The part of FB1 that has structural similarity with sphingoid bases (the aminopentol part) may interact with the sphinganine binding site, whereas the negatively charged tricarbyllic acid groups may interact with the fatty acyl-CoA binding site .Because FB1 also occupies the fatty acyl-CoA space, it isn’t acylated, since acyl-CoA is necessary for the acylation; FB1 only inhibits ceramide synthase. However, when the tricarbillic acid groups are removed from FB1 by hydrolysis, the resulting product (aminopentol, AP1) doesn’t only act as an inhibitor, but also as a substrate for ceramide synthase; aminopentol is acylated by ceramide synthase to form N-palmitoyl-AP1 . This supports the suggestion that the aminopentol part of FB1 occupies the space of sphinganine in the enzyme. N-palmitoyl-AP1 is an even more potent inhibitor of ceramide synthase and may therefore play a role in the toxicity of nixtamalized fumonisins .
Toxic effects
The risks of fumonisin B1 have been evaluated by The World Health Organization’s International Programme on Chemical Safety(IPCS) and the Scientific Committee on Food(SCF) of the European Commission. They determined an tolerable daily intake(TDI) for FB1, FB2, FB3, alone or in combination of 2 µg/kg body weight .Until now, nothing about the kinetics and metabolism of fumonisin B1 in humans have been reported. On other animals much research has been done, but it might not be comparable to humans. In mice the elimination of FB1 is very rapid, but in humans it could be much slower considering their body weight .
There are several possible pathways that cause toxic effects of Fumonisin B1. Most toxic effects are due to altered sphingolipid metabolism by inhibition of ceramide synthase.
Production of reactive oxygen species (ROS) could occur. This increases oxidative stress and induce lipid peroxidation and could damage cells. In agreement with this some studies showed decreased levels of gluthation(GSH) in liver, but other studies showed even elevated levels of GSH . Cytotoxic effects have also been reported .
Another effect of exposure to FB1 is apoptosis. This has been observed in a number of different cells and tissues. Inhibition of ceramide synthase is not responsible for this effect. The main factors could be DNA fragmentation and caspase-3 activation .
FB1 has also immunotoxic effects, but much more research is necessary to get a clear overview of the effects on the immune system.
Neural tube defects
Neural tube defect (NTD) are defects of the brain and spinal cord in the embryo resulting from failure of the neural tube to close . Epidemiological studies and clinical trials have pointed out folate deficiency as a major risk factor for NTD . FB1 disrupts sphingolipid metabolism and therefore this could affect folate uptake and cause NTD .In 1990 and 1991 an sudden outbreak of neural tube defects occurred along the Texas-Mexico border. It is believed that this outbreak might have been due to high levels of FB1 that were observed in corn during previous years . Also regions in China and South Africa with high corn consumption show a high prevalence of NTD .
Esophageal cancer
It is thought that there is a relationship between the occurrence of F.verticillioides and human esophageal cancer. A low socioeconomic status and a less variated diet, that mainly exists of corn and wheat, is associated with the appearance of esophageal cancer . This derives from epidemiologic studies in various countries. Other studies show that a higher level of concentrations of FB1, FB2 and F. verticillioides are present in corn growing in regions with a high percentage of esophageal cancer. This in contrast with regions with low levels of F.verticillioides, FB1 and FB2 in corn . On top of this it seems that people with a high corn intake are at higher risk to develop esophageal cancer than people with low corn intake. This is observed by people in regions in Italy, Iran, Kenia, Zimbabwe, United States and Brazil with high incidence of esophageal cancer .Another study on the relationship between sphingolipid levels and cancer incidence dind’t show any significant relationship between serum shpingolipids and risk of esophageal cancer. This is quite remarkable, because elevated levels of spingolipids shinganine and shingosine are believed to be biomarkers for exposure of FB1 .
Acute mycotoxicosis
Acute mycotoxicosis is food poisoning by food products contaminated by fungi. In 1995 an outbreak of disease characterized by diarrhea and abdominal pain occurred in 27 villages in India. This was the result of consumption of moldy sorghum and corn due to rain damage. This outbreak was studied and the mycotoxicosis was connected to consumption of unleavened bread. Corn and sorghum samples were collected from the households and examined. The corn and sorghum were contaminated by Fusarium and Aspergillus and contained high levels of FB1 compared with samples of unaffected households .Toxic effects in animals
Much research has been done on toxic effects of FB1 in animals. In vivo studies indicate that liver and kidneys are the main target organs . Fumonisins are poorly absorbed, rapidly eliminated and not metabolized in animals . In pigs and rats there is a wide distribution of FB1 and small amounts have been found to accumulate only in liver and kidneys. In vervet monkeys, some FB1 is partially hydrolyzed in the gut .Carcinogenic effects
In rats and mice that were exposed to FB1 tumor formation occurred. Several studies on this subject have been done. Depending on de strain of mice being used different carcinomas were showed . FB1 is shown to be nongenotoxic. Therefore the mechanisms responsible for cancer development should lie elsewhere. Important mechanisms for cancer development due to fumonisin B1 could be oxidative damage (ROS-production) and lipid peroxidation. Hepatic and renal tumors could also be due to apoptosis by FB1. As a response to this there could be continuous regeneration of cells, causing cancer. It seems to be that disrupted sphingolipid metabolism is the causative factor for FB1-induced carcinogenicity, as is the case with the toxic effects .Based on all these animal studies FB1 is classified by The International Agency for Research on Cancer (IARC) as possibly carcinogenic to humans (Group 2B) .
Porcine pulmonary edema
Porcine pulmonary edema due to FB1 is intensively studied after the first report in 1981 of swine with pulmonary edema after exposure to corn contaminated with F.verticillioides.Alteration in sphingolipid biosynthesis are reported, especially in lung, heart, kindey and liver tissue. Lethal pulmonary edema was developed within 4–7 days after exposure to feed with concentrations of FB1 >16 mg/kg body weight (>92 ppm). Doses of 10ppm developed a milder form of pulmonary edema .
Equine leukoencephalomalacia
Leukoenchephalomalacia (ELEM) is a neurotoxic disease of horses. Outbreaks of this disease in the 20th century resulted in a number of studies. Apparently FB1 was the cause for this disease. There were shown elevated levels of serum enzyme levels that indicate liver damage. They were normally observed by an elevation of the sphinganine/sphingosine ratio. FB1 possibly induces cardiovascular function, because of the elevated sphinganine/sphingosine ratio. This could be one of the main factors that causes ELEM ..Toxicity in laboratory animals
Effects of feeding rats with FB1 for up to 90 days were usually nephrotoxicity. Between different strains of rats, sensitivity to FB1 varied. In the kidneys the main effect was apoptosis. Also tubular atrophy and regeneration as well as decreased kidney weight was reported . Histopathologic effects on rat liver were reported after both short- and long-term exposure. The main cause was apoptosis.Mice don’t seem to be very sensitive to nephrotoxic effects in comparison with rats. In mouse kidneys little histological changes were seen by high dose exposure. The liver was also the main target organ in mice. Pathology is similar as in rats, with apoptosis and hepatocellular hyperplasia .
Fumonisin B1 is possibly embryotoxic if the dose is maternally toxic. A number of studies on genotoxicity inidicated no mutagenetic effects. Although fumonisin could damage DNA directly by production of reactive oxygen species(ROS) .
Mouse embryos were exposed to FB1 and they showed inhibited sphingolipid synthesis and growth. It caused NTD. Folic acid uptake was dramatically inhibited. Treatment after exposure with folic acid reduced NTD by 50-65% .
Tolerable Daily Intake
The risks of fumonisin B1 have been evaluated by The World Health Organization’s International Programme on Chemical Safety(IPCS) and the Scientific Committee on Food(SCF) of the European Commission. They determined an tolerable daily intake(TDI) for FB1, FB2, FB3, alone or in combination of 2 µg/kg body weight.Detoxification
The inhibition of ceramide synthase by FB1 is thought to be reversible, since the binding is formed by noncovalent interactions. Factors that will probably induce this reversibility are reduction of cellular FB1-concentration and increasing of cellular concentrations of the substrates for ceramide synthase. Also, the rate of removal of the accumulated sphinganine and sphingosine will affect the detoxification.The information on metabolism and biotransformation
Biotransformation
Biotransformation is the chemical modification made by an organism on a chemical compound. If this modification ends in mineral compounds like CO2, NH4+, or H2O, the biotransformation is called mineralisation....
of FB1 is very sparse. However, metabolism most likely occurs in the gut since partially hydrolysed and fully hydrolysed FB1 were recovered in faeces but not in bile of Vervet monkeys.
Bioavailability of FB1 can be reduced by treating fumonisin-contaminated corn with glucomannans extracted from the cell wall of the yeast Saccharomyces cerevisiae. These polysaccharides are able to bind certain mycotoxins and have a 67% binding capacity for fumonisins.
External links
- Detailed information about mycotoxins
- International Agency for Research on Cancer (IARC)- Good review on Fumonisin B11
- Fumonisin Toxicosis, Merck Veterinary ManualMerck Veterinary ManualThe Merck Veterinary Manual is a reference manual of animal health care. It is published by Merck & Co., Inc. and Merial Limited. The Merck Veterinary Manual is available as a reference manual or as an online resource for veterinarians, veterinary students, and others involved in animal health...