History
In 1970, an outbreak of leukoencephalomalacia in horses in South Africa was associated with the contamination of corn with the fungus ''Toxicokinetics
Regarding toxicokinetics there is 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 = 1.02 h). FB1 does not significantly permeate through the human skin and hence has no significant systemic health risk after dermal exposure.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 and the tissue (liver, kidney) concentration time results were consistent with a one-compartment open model.Excretion
Elimination half-life in rats is 3.15 h for plasma, 4.07 h for liver, and 7.07 h for kidney. However, FB1 is rapidly excreted mostly in its original form. Small amounts are excreted in urine; the most are excreted in feces.Toxicodynamics
Because of their similarity, fumonisins are able to inhibitMechanism 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 and the Scientific Committee on Food of the European Commission. They determined a tolerable daily intake 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 could occur. This increases oxidative stress and induce lipid peroxidation and could damage cells. In agreement with this some studies showed decreased levels of glutathione in liver, but other studies showed even elevated levels of glutathione. 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.Toxic effects in humans
Neural tube defects
Neural tube defect are abnormalities 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 neural tube defects. FB1 disrupts sphingolipid metabolism and therefore this could affect folate uptake and cause neural tube defects. In 1990 and 1991 a 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. Regions in China and South Africa with high corn consumption also have a high prevalence of neural tube defects.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 varied diet, that mainly consists of corn and wheat, is associated with the appearance of esophageal cancer. This derives from epidemiologic studies in various countries. Other studies show that higher 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 didn’t show any significant relationship between serum sphingolipids and risk of esophageal cancer. This is quite remarkable, because elevated levels of sphingolipids sphinganine and sphingosine 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. InCarcinogenic effects
In rats and mice that were exposed to FB1 tumor formation occurred. Several studies on this subject have been done. Depending on the strain of mice being used different carcinomas were shown. 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 (production of reactive oxygen species) 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, kidney 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 parts per million). Doses of 10 parts per million caused a milder form of pulmonary edema.Equine leukoencephalomalacia
Leukoencephalomalacia 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 leukoencephalomalacia.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 indicated no mutagenetic effects. Although fumonisin could damage DNA directly by production of reactive oxygen species. Mouse embryos were exposed to FB1 and they showed inhibited sphingolipid synthesis and growth. It caused neural tube defects. Folic acid uptake was dramatically inhibited. Treatment after exposure with folic acid reduced neural tube defects 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 and the Scientific Committee on Food of the European Commission. They determined a tolerable daily intake 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 andReferences
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