This article is based on a presentation at the International Conference on the Toxicology of Fumonisin held 28-30 June 1999 in Arlington, Virginia, USA.
Address correspondence to K.A. Voss, Toxicology and Mycotoxin Research Unit, Agricultural Research Service, USDA, Richard Russell Agricultural Research Center, 950 College Station Rd., Athens, GA 30605 USA. Telephone: (706) 546-3315. Fax: (706) 546-3116. E-mail: kvoss@ars.usda.gov
The expert technical assistance of N. Brice, P. Malcom, M. Nelms, J. Showker, P. Stancel, E. Wray, and many others are gratefully acknowledged. Special thanks to W. Chamberlain. The consultations and contributions of A. Merrill Jr. and W. Marasas are appreciated.
Received 10 April 2000; accepted 1 December 2000.
Fumonisins are produced by
Fusarium moniliforme Sheldon (=
F. verticillioides),
F. proliferatum, and other
Fusarium species (
1-4). They were discovered by Gelderblom et al. (
5) in 1988, and their natural occurrence in corn was demonstrated soon thereafter (
6-10). Fumonisin B
1 (FB
1) is the most common homologue (Figure 1); however, a growing number of other homologues and derivatives have been described. Fumonisins have worldwide distribution in corn and occur in corn-based feeds and foods. A comprehensive review of this subject by Dutton has been published (
11). Equine leukoencephalomalacia (ELEM) and porcine pulmonary edema, fatal toxicoses associated with the consumption of (
F. moniliforme) moldy feed by horses (
12,13) and swine (
13), respectively, have been experimentally reproduced using purified FB
1 (
14-18).
 |
Figure 1. Chemical structure of FB1.
|
The impact of fumonisins on human health remains unclear but is of concern. Consumption of F. moniliforme-molded, home-grown corn has been correlated with high esophageal cancer rates in areas of southern Africa (19-21) and central China (22), and comparatively high fumonisin concentrations are found in the corn from these high esophageal cancer areas (4,23-28). It has also been suggested that fumonisins are a risk factor for liver cancer (29), and FB1, like some F. moniliforme isolates (30,31), was hepatocarcinogenic when fed (50 ppm) to male BD IX rats (32). Studies are limited, but hepatotoxicity and atherogenic serum lipid profiles, perhaps secondary to liver dysfunction, were found in nonhuman primates fed diets containing fumonisin (13,33,34). Finally, a possible link between fumonisin exposure and neural tube defects in humans has been proposed (35).
In vivo investigations using rodents and rabbits have contributed significantly to F. moniliforme and fumonisin research. Fumonisins were discovered using an in vivo liver bioassay (5). Data from subchronic toxicity studies have been used in preliminary risk evaluations (36,37), have been useful for developing protocols for chronic studies, and have otherwise increased our understanding of these compounds. An overview of toxicity and other important data obtained during in vivo investigations follows.
Fumonisins are poorly absorbed and rapidly eliminated; small amounts accumulate in liver and kidneys (Table 1). Norred et al. (
38) recovered 80% of the radiolabel from feces within 48 hr and
3% from urine within 96 hr after giving a single oral dose of [
14C]FB
1 (0.045 µCi) to rats. Small but relatively constant amounts of radiolabel were found in liver (about 0.4% of the dose) and kidney (about 0.1% of the dose) up to 96 hr postdosing. After administering the same dose for 3 consecutive days to rats, more than 75% of the [
14C] was excreted in feces and about 4% in urine within 72 hr of the last dose. Liver- and kidney-specific activities peaked 24 hr after the last dose, but persisted for another 48 hr. Like FB
1, fumonisin B
2 (FB
2) is also rapidly cleared from plasma and excreted (82% within 72 hr, mostly during the first 24 hr), predominantly in the feces (
39). Only about 1% of the dose was recovered in the urine.
Liver and kidney accumulated relatively high amounts of [14C]FB1 following intraperitoneal (ip) or intravenous (iv) dosing to rats (Table 1). Up to 66% of the radiolabel appeared in feces, suggesting that FB1 (or possibly a metabolite) is excreted in bile. This was confirmed by Shephard et al. (40) who, within 4 hr of giving 7.5 mg/kg body weight (bw) [14C]FB1 ip to cannulated rats, recovered about 67% of the dose as unchanged FB1 in the bile. In contrast, only 0.2% of the radiolabel was recovered in bile following oral administration of the same dose (7.5 mg/kg bw [14C]FB1), further suggesting that gastrointestinal absorption of FB1 by rats is low.
Little pharmacokinetic data is available. Shephard et al. calculated time of plasma maximum concentration (Tmax) of about 20 min, peak plasma concentration (Cmax) of 8.6 µg/mL, and a serum elimination half-life (T1/2) of approximately 18 min for rats following a single ip injection of 7.5 mg/kg FB1 (41). Tmax, Cmax, and T1/2 of FB2 are similar (Table 1). There have been no reports of fumonisin metabolism by the liver, kidney, or other tissues, although the intestinal flora of the rat, like that of the nonhuman primate (42), hydrolytically removes the tricarballylic acid groups from fumonisin's hydrocarbon backbone (43).
Fumonisins, F. moniliforme, and in Vivo Toxicity
Fumonisins are fungal products. Therefore, the relationship between fumonisin toxicity and toxicity of the fungi should be kept in perspective. Not all fungi identified as F. moniliforme are toxic. For example, culture material (0, 4, 8, or 16% w/w in the diet) of isolate MRC 826 caused significant dose-related toxicity and liver pathology (kidney was not examined) when fed to rats for 4 weeks, whereas isolate RRC 415 culture material was without effect (44). Similarly, only 3 of 11 F. moniliforme isolates induced 
-glutamyl transpeptidase (GGT)-positive liver foci in rats (45). MRC 826 culture material (0.5% in the diet), but not a 10-fold higher dietary concentration of isolate MRC 1069 culture material, caused hepatocarcinomas in rats (30). It has been shown that MRC 826 is a fumonisin producer (46), but that both MRC 1069 (30) and RRC 415 (47) produce predominantly fusarin C.
Additionally, F. moniliforme produces other biologically active, potentially toxic compounds including fusariocins (48), the mutagen fusarin C, other fusarins (49,50), and fusaric acid (51). None of these have reproduced the in vivo effects of toxic F. moniliforme isolates (30,52-54). Conversely, the link between F. moniliforme and fumonisin has been independently established by several research groups; that is, the in vivo toxicities of corn (involved in ELEM outbreaks) naturally contaminated with F. moniliforme (9,55), culture materials of (toxic) F. moniliforme isolates, polar culture material extracts, and purified FB1 are qualitatively the same (5,32,45,56-61). FB2, fumonisin B3 (FB3), and probably also hydrolyzed FB1 (HFB1) exert the same in vivo effects (62-64).
Hepatotoxicity
Histopathologic effects in rats, which have been referred to by various terms such as hepatopathy, hepatosis, or toxic hepatitis, have been reported by several research groups. Their descriptions are consistent, differing only in detail and nomenclature (5,56-58,61,65-67). The initial finding is small, rounded, eosinophilic hepatocytes that appear to have pulled away from neighboring cells. The chromatin of these cells is irregularly condensed and marginated or may be fragmented. Inflammatory response is absent to minimal. Although their appearance is consistent with apoptosis, these cells were commonly described as single-cell necrosis until their apoptotic nature was histochemically confirmed by Tolleson et al. (61) and Howard et al. (68,69). This does not mean, however, that necrosis (oncotic necrosis in the traditional sense, as opposed to programmed cell death or apoptosis) does not play a role in fumonisin-induced hepatotoxicity. Necrotic hepatocytes are also present early-on. Serum chemical indications of hepaocellular injury, including increased alanine and aspartate transaminase, alkaline phosphatase, and lactate dehydrogenase activities, as well as increased cholesterol and triglyceride concentrations (Figure 2), are routine, early findings. As tissue injury progresses, both apoptotic and necrotic cells increase in number, mitotic figures appear with increasing frequency, hepatocellular cytoplasm becomes increasingly vacuolated, and cytomegaly with variability in cell and nuclear size becomes obvious. Bile duct and oval cell proliferation, foci of cellular alteration, cholangiomatous lesions, and fibrosis occur in long-standing or advanced lesions, giving a picture of nodular regeneration or cirrhosis (32). Females are generally more sensitive than males (Table 2). Along with the aformentioned clinical chemical indicators, which continue to rise, serum GGT activity and bilirubin concentration increase as liver injury becomes more severe.
Figure 2. Selected serum chemical effects of FB1. Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. Serum ALT and AST activities, international units/deciliter cholesterol, and milligrams per deciliter triglycerides were significantly increased (p < 0.05) in male Sprague-Dawley rats fed 150 ppm FB1 for 4 weeks. Data from Voss et al. (58).
Fumonisins induced both GGT and the placental form of glutathione S-transferase (GSTP)-positive foci in BD IX and Fischer rats (5,62,70,71). Foci induction in diethylnitrosamine-pretreated Fischer rats was dose related, and GSTP was a more sensitive marker than GGT (Figure 3) (70). From these and other data, Gelderblom et al. (72) proposed that FB1 was a tumor promoter at doses not causing significant liver pathology, but when given at overtly hepatotoxic doses, it was also a weak initiator. FB1 (50 ppm) caused marked nonneoplastic changes (cirrhosis) and hepatocellular carcinomas when fed to BD IX males for 20 months or more (32). Relatively (marginally deficient) low dietary lipotrope levels may have contributed to the neoplastic response. Nonetheless, these results demonstrated carcinogenicity by FB1 and the need for further studies. One such study, the recently completed chronic bioassay by the National Center for Toxicological Research of the U.S. Food and Drug Administration (73), showed that FB1 was a kidney carcinogen in rats and a liver carcinogen in mice, respectively.
Figure 3. Dose-related induction of GGT and the placental form of GSTP-positive foci in liver of male Fischer 344 rats (n = 5/group). The animals were fed diets with up to 500 ppm FB1 for 3 weeks, beginning 2 weeks after pretreatment with 200 mg/kg diethylnitrosamine (ip injection). The number of GGT and GSTP foci per square centimeter was significantly increased (p < 0.05) at >= 250 ppm and >= 100 ppm FB1, respectively; the percent area involved per liver section was significantly increased (p < 0.05) at >= 100 ppm and >= 500 ppm FB1, respectively. Figure adapted from the data of Gelderblom et al. (70).
Nephrotoxicity
The kidney was the most sensitive target organ in Sprague-Dawley and Fischer 344 rats fed FB1 for up to 90 days (Table 2) (57,58,61,74) or given FB1 by gavage or ip injection for 4-11 days (65-67,75). Males were more sensitive than females. In contrast, Gelderblom et al. (5,32) described hydropic degeneration, occasional necrosis, and a few other renal abnormalities in their studies in BD IX rats, but did not refer to the kidney as a target organ. This suggests that significant differences in response to fumonisins may exist among various rat strains.
As in liver, apoptosis is the initial microscopic finding in kidney. Apoptotic cells are initially found almost exclusively in tubules of the outer medulla (designated "corticomedullary junction" in some publications). Many of the apoptotic cells appear rounded and detached from adjacent cells and the basement membrane. Mitotic figures appear, and the number of apoptotic cells increases in the tubule epithelium as injury progresses. Cytoplasmic vacuolation and basophilia, decreased cellular height, and alterations in nuclear size and staining become evident. At this point, lesions may extend deeper into the medulla or into the cortex, and epithelial cells are sloughed into the tubular lumina. Thus, there is simultaneous cell loss and replacement revealed on three levels: on the cellular level by apoptosis and mitosis, on the histologic level by tubular atrophy and hyperplasia (regeneration), and grossly by decreased kidney weight (Figure 4). The failure of regeneration to keep pace with cell loss may be quite important, as imbalances between cell loss and replacement in tissues may be a significant contributor to carcinogenesis (76-78).
Figure 4. Relative (% bw) kidney weight was significantly (p < 0.05) decreased in male Sprague-Dawley rats (n = 5/group) fed 15, 50, or 150 ppm FB1 for 4 weeks. Significant differences in relative kidney weight were not found in females; however, absolute kidney weight (g) of females fed 150 ppm was significantly lower than control values (not shown). Data from Voss et al. (58).
Increased serum creatinine, decreased CO2 and, less often, increased urea nitrogen occur in FB1-treated rats (57,58,79). Increased activities of N-acetyl-ß-glucosaminidase, GGT, and lactate dehydrogenase have been found in urine, giving further clinical evidence of tubular injury (65,75). Proteinuria may also occur and, because of the presence of high-molecular-weight proteins in the urine, it has been suggested that FB1 may also cause glomerular injury (75). Alternatively, sloughed tubule cells, which can be numerous in urine, are a more likely cause of proteinuria (80).
There is little data on renal function in fumonisin-treated animals. Urinary output and water consumption were increased in male rats fed F. moniliforme culture material (64). These observations were consistent with those of Bondy et al. (65,67) and Suzuki et al. (75), who studied renal function in rats given daily ip doses (7.5-10 mg/kg for 4 days) or oral doses (1-75 mg/kg for 11 days) of FB1. Signs of renal dysfunction in these animals included increased output of hypoosmotic urine, increased urinary enzyme levels, proteinuria, increased serum Mg2+ and Ca2+ concentrations, and decreased anion (p-aminohippurate, up to 80% reduction) and cation (tetraethylammonium, up to 40% reduction) transport by renal cortex slices. Interestingly, some indications of renal dysfunction peaked on days 6-8 of the 11-day exposure period (67), suggesting that fumonisin-damaged kidneys have some functional adaptive capacity.
Other in Vivo Toxicologic Findings
in Rats
There are indications that the immune system may be a target. Bondy et al. (66) found disseminated thymic necrosis with decreased thymic weight and increased serum IgM concentrations in FB1-exposed rats. Others found that the immune responses to sheep red blood cells and to splenic clearance of Listeria monocytogenes were slightly decreased in rats given 15 (L. monocytogenes) or 25 (sheep red blood cells) mg/kg bw FB1 for 14 days (81).
Testicular tubule epithelial degeneration (59), decreased heart weight (54), adrenal cortex hypertrophy, and cytoplasmic vacuolation (consistent with Zona fasciculata lipoidosis and probably a nonspecific stress response) (64), cytoplasmic vacuolation of myeloid precursor cells in bone marrow, and other hematologic findings (66) have been found in rats given fumonisins or F. moniliforme culture materials. Little toxicologic importance has yet been given to any of these observations.
Because of the human health implications, esophageal effects of fumonisins are of special interest. Marasas et al. (31) found basal cell hyperplasia of the esophagus in rats fed F. moniliforme culture material. Others have noted a transient increase in the 5-bromo-2´-deoxyuridine labeling index in esophageal epithelium 3 days following an iv injection of 1.25 mg/kg bw (82), which suggests that FB1 may be mitogenic under some conditions. However, there is no evidence from subchronic (5,57,58,61) or chronic (32,73) feeding studies of purified FB1 that the esophagus is a target organ. Furthermore, FB1 (5 mg/kg bw/day for 5 weeks) had no effect on the number of esophageal papillomas produced in rats concurrently given the esophageal carcinogen N-methylbenzylnitrosamine (83). Thus, there is no evidence from rodent studies that FB1 is an esophageal carcinogen, and the possibility that F. moniliforme produces other potentially (esophageal) carcinogenic compounds should not be dismissed.
Hepatic and Renal Toxicity in Other Laboratory Species
Liver and kidney are also targets in mice (74,84,85). The pathology is similar to that seen in rats, and females are more sensitive to hepatotoxicity than males. Apoptosis, hepatocellular hyperplasia, bile canaliculi hyperplasia, and Kupffer cell hyperplasia were the principal findings in females (B6C3F1) fed >= 99 ppm FB1 and males fed 484 ppm FB1 for 4 weeks (68,73). A hepatocellular cytoplasmic alteration described as reduced cytoplasm, basophilia, and loss of cytoplasmic vacuoles was found in both sexes fed >= 99 ppm. Histopathology findings (hepatopathy) in female B6C3F1 mice fed 81 ppm FB1 for 90 days (57) were characterized by apoptosis (= single-cell necrosis), cytomegaly, increased mitotic figures, scant inflammatory infiltrates, and pigmented macrophages. Serum chemical indications of hepatic injury of the same type found in rats also occurred.
Compared to rats, mice are resistant to nephrotoxicity. No kidney lesions were found in mice fed diets with 81 ppm FB1 for 90 days (57) or diets with 484 ppm FB1 for 28 days (68). However, when given at relatively high doses by oral or parenteral routes, FB1 is nephrotoxic, as illustrated by the findings of Sharma et al. (84). They found terminal deoxynucleotidyl transferase-mediated nick-end labeling (TUNEL)-positive cells in the renal tubules of males (females were not examined) given subcutaneous injections of FB1 for 5 consecutive days (Figure 5). Findings were corroborated by the dose-related increase in apoptotic cells, which was found during routine microscopic examinations (hematoxylin and eosin sections). Bondy et al. (85) found slight increases in single-cell necrosis (= apoptosis) in the renal tubules of female but not male B6C3F1 mice given 15-75 mg/kg FB1 by gavage for 14 days.
Figure 5. Daily subcutaneous injection of FB1 for 5 consecutive days increased the number of renal tubular cells stained in situ by TUNEL, a technique marking apoptotic nuclei. Values indicate group mean; n = 5. The difference was statistically significant (p < 0.05) at 6.25 mg/kg FB1 but, because of a large standard deviation, not at 2.25 mg/kg FB1. Microscopic examination of hematoxylin and eosin-stained kidney specimens yielded similar results: apoptosis was found in all mice given 2.25 or 6.25 mg/kg FB1, 2-3 mice/group given 0.25-0.75 mg/kg FB1, and none of the controls. Figure adapted from the data of Sharma et al. (84).
Rabbits are quite sensitive to FB1 (86). As in male rats, the kidney is a more sensitive target organ than liver. Morphologic, serum chemical, and tissue sphingolipid findings were similar to those seen in rodents.
The preponderance of experimental evidence, including evaluations of unscheduled DNA synthesis,
Salmonella typhimurium mutagenicity, SOS response in
Escherichia coli, mitotic index, and micronucleus formation [reviewed by Howard (
87)], suggests that fumonisins exert their effects through a nongenotoxic mode of action. A significant breakthrough in understanding these compounds occurred when Wang et al. (88) discovered that fumonisins inhibit the enzyme ceramide synthase [sphinganine (sphingosine)-
N-acetyltransferase], leading to disruption of
de novo sphingolipid biosynthesis. The immediate consequences thereof are accumulation of the sphingoid bases sphinganine (Sa) and sphingosine (So), an increase in the Sa to So ratio (Sa/So), and depletion of complex sphingolipids (CSLs) in tissues (Figure 6). Recognizing the importance of sphingolipids in cell regulatory processes, including those related to proliferation and apoptosis (
76,89-91), investigators have proposed that ceramide synthase inhibition is the critical mechanistic step in fumonisin toxicity, starting a cascade of molecular events eventually leading to cytotoxicity or neoplasia.
Figure 6. Simplified depiction of the de novo synthesis of sphingolipids. Abbreviations: CSL, complex sphingolipids FBx, fumonisins B; SM, sphingomyelin. FBx inhibit incorporation of the sinto ceramide (Cer), thus increasinphingoid bases Sa and So g cellular Sa and So, depleting CSL, and otherwise disrupting sphingolipid metabolism. Data from Yoo et al. (124).
Fumonisin exposure, sphingolipid effects, and toxicity are correlated in vivo. Liver and kidney Sa, So, and Sa/So were increased in rats fed 15-150 ppm FB1 for 4 weeks (Figure 7) (80), and increases occurred at doses equal to or less than those causing microscopic lesions (apoptosis). Importantly, liver and kidney Sa/So increases were correlated with the severity of hepatopathy and nephropathy in rats fed F. moniliforme culture material (71 ppm FB1), water-extracted culture material (11 ppm FB1), or an alkali-treated (nixtamalized) culture material containing 58 ppm HFB1 but no measureable FB1 (92,93).
Figure 7. Tissue Sa/So, a biomarker of fumonisin exposure, was increased in Sprague-Dawley rats (n = 5/group) fed 15, 50, or 150 ppm FB1 for 4 weeks, primarily because of increased Sa. Differences in liver Sa/So were significant (p < 0.05) at 150 ppm in males and >= 50 ppm in females, and differences in kidney Sa/So were significant at >= 15 ppm in both sexes, doses that for both organs were equal to or less than the lowest dose causing microscopic lesions (arrows). Data from Voss et al. (58) and Riley et al. (80).
The role of sphingolipids as mediators of fumonisin toxicity has not yet been proven, and other mechanisms may come into play. For example, several groups have presented data suggesting that fumonisins cause compositional or oxidative damage to cellular lipids, which in turn causes molecular events culminating in oxidative damage to DNA and other critical macromolecules (94-99). A more detailed discussion of molecular mechanism is beyond the purpose of this review but can be found elsewhere in this issue (87,100-102).
Javed et al. (
103) found that FB
1 was embryotoxic and caused malformations when injected into chicken eggs. FB
1 and HFB
1 also inhibited growth of rat embryos exposed
in vitro on gestation day (GD) 9.5 (
104). Under similar conditions, 100 or 300 µM HFB
1 caused neural tube and other malformations (
105). Although useful as screens,
in vitro methods allow direct fetal exposure and avoid maternal gastrointestinal absorption, pharmacokinetics, placental transfer, and other potential barriers of
in utero exposure.
To assess the reproductive effects of F. moniliforme, male and female Sprague-Dawley rats were fed culture material of isolate MRC 826 providing 0, 1, 10 or 55 ppm FB1 (106). The culture material was minimally toxic to males (>= 10 ppm) and females (55 ppm), as indicated by serum chemistry findings and kidney pathology. All reproductive end points in males, which included testicular morphology, sperm morphology, and sperm motility, were unaffected. One half of the mated females from each group were examined on GD 15, at which time no differences among groups were found in the number of corpora lutea, implantation sites, resorptions, dead fetuses, and live fetuses per dam. The remaining females gave birth and were observed, along with their litters, for 21 days postpartum. Other than a slight decrease in weight gain (but not absolute weight) of litters from groups given 10 and 55 ppm FB1, no differences were found in maternal reproductive or offspring development variables. Although liver Sa/So of the dams fed 55 ppm FB1 was significantly increased, no differences in the Sa/So of control and high-dose (55 ppm) fetuses were found on GD 15 (abdominal slices containing liver and kidney), indicating that fumonisins did not cross the placenta. This was corroborated in a second study in which no radiolabel (< 0.02% of the dose) was found in the fetuses following iv injection of [14C]FB1 to pregnant females on GD 15 (106).
Pregnant rats were given 1.875-15 mg/kg bw purified FB1 on GD 3-16 (107) and examined on GD 17 and GD 20. FB1 had no effect on maternal reproductive variables. The high dose (15 mg/kg FB1) was maternally toxic, causing decreased weight gain on GD 17, decreased kidney weights, and increased Sa/So of liver, kidney, and serum. Sa/So was also increased in livers of dams given 7.5 mg/kg, kidneys of dams given >= 1.875 mg/kg, and serum of dams given 7.5 mg/kg FB1. Decreased length and weight of female fetuses were noted on GD 20. Otherwise, there was no evidence of fetal toxicity or teratogenicity. The study was repeated at doses ranging from 6.25 to 50 mg/kg FB1 (108). Apoptosis and other microscopic findings typical of fumonisins were found in kidney (>= 6.25 mg/kg) and liver (25 or 50 mg/kg). Increased Sa/So was found in maternal liver (>= 25 mg/kg), kidney (>= 6.25 mg/kg), and serum (>= 25 mg/kg). Fetal deaths were increased at 25 and 50 mg/kg, and the number of viable fetuses/dam (12.0 ± 1.1 vs control value of 14.0 ± 0.5), fetal length, and fetal weight were decreased at 50 mg/kg. The incidence of hydrocephalic fetuses and skeletal anomalies such as wavy ribs and reduced ossification was increased somewhat at 50 mg/kg, but no teratogenic effects were found. Sa/So of fetal tissues were unchanged at any of the doses studied, suggesting that the fetal effects were indirect and secondary to maternal toxicity.
Results of other developmental toxicity studies (Table 3) generally agree and likewise suggest that FB1 is not teratogenic but may be embryotoxic at maternally toxic doses (109,110). In contrast, Floss et al. (111,112) concluded that FB1 was a developmental toxin in hamsters at dosages that were not maternally toxic. It is possible that there are species-related differences in maternal response. However, detailed serum chemical, histopathologic, or fetal and maternal tissue sphingolipid evaluations, which may have revealed maternal toxicity in the hamsters, were not undertaken. Collins et al. (107,108), LaBorde et al. (110), and Voss et al. (106) have shown significant organ weight, pathology, and sphingolipid effects in dams that otherwise appear unaffected by FB1.
FB
1 does not occur alone. Co-exposure undoubtedly occurs with other mycotoxins and mycotoxin products formed during grain handling or food preparation. As illustrated below,
F. moniliforme culture material can be a useful, cost-effective tool for studying how co-exposure to other mycotoxins or mycotoxin products influences FB
1 toxicity. However, such experiments should be carefully designed and results interpreted with caution. Not all
F. moniliforme strains are toxic, and culture materials are complex mixtures containing biologically active compounds (both known and unknown) that may confound results.
To determine the potential in vivo toxicity of FB2 and FB3, Voss et al. (64) studied three genetically related F. moniliforme isolates. Isolate M3125 produced FB1, FB2, and FB3 in the approximate ratio of 1:0.35:0.15. Isolate 107-R-7 produced FB2 (no detectable FB1 or FB3), and isolate 397-R-74 produced FB3 (no FB1 or FB2). Low (4.6-6.9 ppm), mid (32-53 ppm), and high (219-303 ppm) levels of culture materials of each isolate were fed to rats for 3 weeks. All were toxic. Their effects were qualitatively indistinguishable, consisting of decreased weight gain, decreased kidney weights, increased serum chemical indications of hepatotoxicity, increased Sa/So, and apoptosis in the liver and kidneys. All findings were consistent with the effects of FB1 (57,58), and elevated tissue Sa/So was correlated with various toxicologic end points. Thus, hepato- and nephrotoxicities can be induced by FB1 nonproducing fungi, and toxicity studies of purified FB2 and FB3 are warranted.
It has been suggested that fusaric acid, another mycotoxin commonly produced by F. moniliforme (51,113), exacerbates fumonisin toxicity (114,115). Bacon et al. (116) demonstrated synergistic embryotoxicity by simultaneous injection of FB1 and fusaric acid in ovo. Diets containing F. moniliforme MRC 826 culture material providing low (3.4 ppm), slightly higher (18 ppm), or very high (437 ppm) amounts of FB1 and, at each fumonisin level, 0, 20, 100, or 400 ppm fusaric acid were fed to rats for 4 weeks (54). Dose-related body weight, serum chemical, liver and kidney pathologies, and renal sphingolipid effects typical of fumonisins were caused by the culture material. No evidence of synergism was found. Fusaric acid alone up to 400 ppm in the diet was not toxic, and its presence did not modify the response of the animals to the culture material.
Masa flour is made from nixtamalized corn. During nixtamalization, corn is boiled under alkaline conditions sufficient to convert fumonisins to their hydrolyzed forms (117,118). A study by Hendrich et al. (63) showed that nixtamalization did not reduce hepatotoxicity or cancer-promoting activity of F. proliferatum culture material, even though FB1 and FB2 were converted to HFB1 and HFB2. However, others reported that although cytotoxic in vitro, purified HFB1 had no effect in vivo, and they proposed that it was not gastrointestinally absorbed (62). To further study nixtamalization and in vivo toxicity, Voss (92) fed rats F. moniliforme culture material providing 71 ppm FB1, water-extracted culture material providing about 11 ppm FB1, or a nixtamalized culture material providing 58 ppm HFB1, but no measurable FB1. After 4 weeks the culture material and the nixtamalized culture material caused the hepatic and renal lesions typical of fumonisins, though the nixtamalized material was somewhat less potent. The water-extracted culture material elicited a noticeably lesser nephrotoxic response and was not hepatotoxic. Sa and Sa/So increases in liver and kidney were increased in all three groups, and the increases were correlated with the severity of liver and kidney injury (93). These results agree with the in vitro findings of Norred et al. (119), who reported that HFB1 inhibited ceramide synthase in precision-cut rat liver slices, but less potently than FB1. The consequences of chronic HFB1 exposure remain unknown, and, given the popularity of masa-based food products, additional investigations on its occurrence in foods and its toxicity are needed.
In vivo studies of
F. moniliforme and fumonisins in rodents have shown that FB
1 and probably FB
2, FB
3, and HFB
1 cause the toxic and pathologic effects of
F. moniliforme. These studies have provided other important data including the following:
a) Gastrointestinal absorption is low, absorbed fumonisins are rapidly eliminated, and only minor amounts are retained in liver and kidney.
b) Liver and kidneys are the two major target organs, although differences in response occur between sexes, strains, and species.
c) Fumonisins may have other, more subtle organ-specific effects; however, there is no compelling evidence that the esophagus is a target organ.
d) Apoptosis is the initial and presumably critical event in the pathogenesis of liver and kidney lesions characterized by simultaneous cell loss and regeneration.
e) A key molecular event in fumonisin cytotoxicity is inhibition of ceramide synthase, leading to disruption of sphingolipid metabolism and probably of sphingolipid regulatory function.
f) FB
1 does not cross the placenta and is not teratogenic in laboratory species; however, fumonisins may be embryotoxic at maternally toxic doses.
g) The use of culture materials provides a cost-effective means of studying
F. moniliforme and fumonisins, as long as caution is exercised in study design and data interpretation. The relationships between
F. moniliforme, fumonisins, and human health remain unresolved. Undoubtedly,
in vivo investigations in rodents will continue to provide insight into the effects and modes of action of these important mycotoxins.
REFERENCES AND NOTES
1. Nelson PE, Desjardins AE, Plattner RD. Fumonisins, mycotoxins produced by Fusarium species: biology, chemistry and significance. Ann Rev Phytopathol 31:233-252 (1993).
2. Nelson PE, Plattner RD, Shackelford DD, Desjardins AE. Fumonisin B1 production by Fusarium species other than F. moniliforme in section Liseola and by some related species. Appl Environ Microbiol 58:984-989 (1992).
3. Nelson PE, Plattner RD, Shackelford, DD, Desjardins AE. Production of fumonisins by Fusarium moniliforme strains from various substrates and geographic areas. Appl Environ Microbiol 57:2410-2412 (1991).
4. Marasas WFO. Fumonisins: history, world-wide occurrence and impact. Adv Exp Med Biol 392:1-17 (1996).
5. Gelderblom WCA, Jaskiewicz K, Marasas WFO, Thiel PG, Horak RM, Vlaggar R, Kriek NPJ. Fumonisin--novel mycotoxins with cancer-promoting activity produced by Fusarium moniliforme. Appl Environ Microbiol 54:1806-1811 (1988).
6. Bacon CW, Bennett RM, Hinton DM, Voss KA. Scanning electron microscopy of Fusarium moniliforme within asymptomatic corn kernels and kernels associated with equine leukoencephalomalacia. Plant Dis 76:144-148 (1992).
7. Norred WP, Plattner RD, Voss KA, Bacon CW, Porter JK. Natural occurrence of fumonisins in corn associated with equine leukoencephalomalacia (ELEM) [Abstract]. Toxicologist 9:258 (1989).
8. Plattner RD, Norred WP, Bacon CW, Voss KA, Peterson R, Shackelford DD, Weisleder D. A method of detection of fumonisins in corn samples associated with field cases of leukoencephalomalacia. Mycologia 82:698-702 (1990).
9. Voss KA, Norred WP, Plattner RD, Bacon CW. Hepatotoxicity and renal toxicity in rats of corn samples associated with field cases of leukoencephalomalacia. Food Chem Toxicol 27:89-96 (1989).
10. Sydenham EW, Gelderblom WCA, Thiel PG, Marasas WFO. Evidence for the natural occurrence of fumonisin B1, a mycotoxin produced by Fusarium moniliforme, in corn. J Agric Food Chem 38:285-290 (1990).
11. Dutton MF. Fumonisins, mycotoxins of increasing importance: their nature and their effects. Pharmacol Ther 70:137-161 (1996).
12. Wilson BJ, Maronpot RR. Causative fungus agent of leukoencephalomalacia in equine animals. Vet Record 88:484-486 (1971).
13. Kriek NPJ, Kellerman TS, Marasas WFO. Comparative study of the toxicitiy of Fusarium verticillioides (= F. moniliforme) to horses, primates, pigs, sheep and rats. Onderstepoort J Vet Res 48:129-131 (1981).
14. Alberts JF, Gelderblom WCA, Marasas WFO. Evaluation of the extraction and purification procedures of the maleyl derivatization HPLC technique for the quantification of the fumonisin B mycotoxins in corn cultures. Mycotoxin Res 8:2-12 (1993).
15. Kellerman TS, Marasas WFO, Thiel PG, Gelderblom WCA, Cawood M, Coetzer JAW. Leukoencephalomalacia in two horses induced by oral dosing of fumonisin B1. Onderstepoort J Vet Res 57:269-275 (1990).
16. Marasas WFO, Kellerman TS, Gelderblom WCA, Coetzer JAW, Thiel PG, van der Lugt JJ. Leukoencephalomalacia in a horse induced by fumonisin B1 isolated from Fusarium moniliforme. Onderstepoort J Vet Res 55:197-203 (1988).
17. Harrison LR, Colvin BM, Greene JT, Newman LE, Cole JR Jr. Pulmonary edema and hydrothorax in swine produced by fumonisin B1, a toxic metabolite of Fusarium moniliforme. J Vet Diagn Invest 2:217-221 (1990).
18. Haschek WM, Motelin G, Ness DK, Harlin KS, Hall WF, Vesonder RF, Peterson RE, Beasley VR. Characterization of fumonisin toxicity in orally and intravenously dosed swine. Mycopathologia 117:83-96 (1992).
19. Marasas WFO. Mycotoxicological investigations on corn produced in esophageal cancer areas in Transkei. In: Cancer of the Esophagus, Vol I (Pfeiffer, CJ ed).Boca Raton, FL:CRC Press, 1978;29-40.
20. Marasas WFO, Jaskiewicz K, Ventor FS, van Schalkwyk DJ. Fusarium moniliforme contamination of maize in oesophageal cancer areas in Transkei. S A Med J 74:110-114 (1988).
21. Marasas WFO, Kriek NPJ, Wiggins VM, Steyn PS, Towers DK, Hastie TJ. Incidence, geographic distribution, and toxigenicity of Fusarium species in South African corn. Phytopathol 69:1181-1185 (1979).
22. Yang CS. Research on esophageal cancer in China: a review. Cancer Res 40:2633-2644 (1980).
23. Marasas WFO. Fumonisins: their implications for human and animal health. Nat Toxins 3:193-198 (1995).
24. Rheeder JP, Marasas WFO, Thiel PF, Sydenham EW, Shephard GS, van Schalkwyk DJ. Fusarium moniliforme and fumonisins in corn in relation to human esophageal cancer in Transkei. Phytopathol 82:353-357 (1992).
25. Thiel PG, Marasas WFO, Sydenham EW, Shephard GS, Gelderblom WCA. The implications of naturally occurring levels of fumonisins in corn for human and animal health. Mycopathologia 117:3-10 (1992).
26. Chu FS, Li GY. Simultaneous occurrence of fumonisin B1 and other mycotoxins in moldy corn collected from the People's Republic of China in regions with high incidences of esophageal cancer. Appl Environ Microbiol 60:847-852 (1994).
27. Yoshizawa T, Yamashita A, Luo Y. Fumonisin occurrence in corn from high- and low-risk areas for human esophageal cancer in China. Appl Environ Microbiol 60:1626-1629 (1994).
28. Yoshizawa T, Yamashita A, Luo Y, Jin Y-Z, Yamakura S. Natural occurrence of Fusarium toxins (fumonisins, trichothecenes and zearalenone) in corn from China. Proc. Jpn Assoc Mycotoxicol 36:49-51 (1992).
29. Ueno Y, Iijima K, Wang S-D, Sugiura Y, Sekijima M, Tanaka T, Chen C, Yu S-Z. Fumonisins as a possible contributory risk factor for primary liver cancer: a 3-year study of corn harvested in Haimen, China, by HPLC and ELISA. Food Chem Toxicol 35:1143-1150 (1997).
30. Jaskiewicz K, van Rensburg SJ, Marasas WFO, Gelderblom WCA. Carcinogenicity of Fusarium moniliforme culture material in rats. J Natl Cancer Inst 78:321-325 (1987).
31. Marasas WFO, Kriek NPJ, Fincham JE, van Rensburg SJ. Primary liver cancer and oesophageal basal cell hyperplasia in rats caused by Fusarium moniliforme. Int J Cancer 34:383-387 (1984).
32. Gelderblom WCA, Kriek NPJ, Marasas WFO, Thiel PG. Toxicity and carcinogenicity of the Fusarium moniliforme metabolite, fumonisin B1 in rats. Carcinogenesis 12:1247-1251 (1991).
33. Fincham JE, Marasas WFO, Taljaard JJF, Kriek NPJ, Badenhorst CJ, Gelderblom WCA, Seier JV, Smuts CM, Faber M, Weight MJ, et al. Atherogenic effects in a non-human primate of Fusarium moniliforme cultures added to a carbohydrate diet. Atherosclerosis 94:13-25 (1992).
34. Jaskiewicz K, Marasas WFO, Taljaard JJF. Hepatitis in vervet monkeys caused by Fusarium moniliforme. J Comp Pathol 97:281-291 (1987).
35. Stevens VL, Tang J. Fumonisin B1-induced sphingolipid depletion inhibits vitamin uptake via the glycosylphosphatidylinositol-anchored folate receptor. J Biol Chem 272:18020-18025 (1997).
36. Kuiper-Goodman T, Scott PM, McEwen NP, Lombaert GA, Ng W. Approaches to the risk assessment of fumonisins in corn-based foods in China. Adv Exp Med Biol 392:369-393 (1996).
37. Humphreys SH, Carrington C, Bolger PM. Risk assessment for fumonisin [Abstract]. Toxicologist 30:148 (1996).
38. Norred WP, Plattner RD, Chamberlain WJ. Distribution and excretion of [14C]fumonisin B1 in male Sprague-Dawley rats. Nat Toxins 1:341-346 (1993).
39. Shephard GS, Thiel PG, Sydenham EW, Snijman PW. Toxicokinetics of the mycotoxin fumonisin B2 in rats. Food Chem Toxicol 33:591-595 (1995).
40. Shephard GS, Thiel PG, Sydenham EW, Alberts JF. Biliary excretion of the mycotoxin fumonisin B1 in rats. Food Chem Toxicol 32:489-491 (1994).
41. Shephard GS, Thiel PG, Sydenham EW. Initial studies on the toxicokinetics of fumonisin B1 in rats. Food Chem Toxicol 30:277-279 (1992).
42. Shephard GS, Thiel PG, Sydenham EW, Savard ME. Fate of a single dose of 14C-labelled fumonisin B1 in vervet monkeys. Natural Toxins 3:145-150 (1995).
43. Ross PF. Personal communication.
44. Voss KA. Unpublished data.
45. Gelderblom WCA, Marasas WFO, Jaskiewicz K, Combrinck S, van Schalkwyk DJ. Cancer promoting potential of different strains of Fusarium moniliforme in a short-term cancer initiation/promotion assay. Carcinogenesis 9:1405-1409 (1988).
46. Thiel PG, Marasas WFO, Sydenham EW, Shephard GS, Gelderblom WCA, Nieuwenhuis JJ. Survey of fumonisin production by Fusarium species. Appl Environ Microbiol 57:1089-1093 (1991).
47. Marijonovic DR, Holt P, Norred WP, Bacon CW, Voss KA, Stancel PC. Immunosuppressive effects of Fusarium moniliforme cultures in chickens. Poultry Sci 70:1895-1901 (1991).
48. Arai Y, Ito T. Cytotoxicity and antitumor activity of fusariocins, mycotoxins from Fusarium moniliforme. In: Progress in Antimicrobial and Anticancer Therapy (Umezi H, ed). Tokyo:Tokyo Press, 1970;870-892.
49. Amra HA, Miller J, Shahab AF, Naguib K. Unpublished data.
50. Gelderblom WCA, Marasas WFO, Steyn PS, Thiel PG, van der Merwe KJ, van Rooyan PH, Vleggaar R, Wessels PL. Structure elucidation of fusarin C, a mutagen produced by Fusarium moniliforme. J Chem Soc Chem Comm 122-124 (1984).
51. Bacon CW, Porter JK, Norred WP, Leslie JF. Production of fusaric acid by Fusarium species. Appl Environ Microbiol 62:4039-4043 (1996).
52. Gelderblom WCA, Thiel PG. The role of rat liver microsomal enzymes in the metabolism of the fungal metabolite fusarin C. Food Chem Toxicol 26:31-36 (1988).
53. Gelderblom WCA, Thiel PG, van der Merwe KJ. The chemical and enzymatic interaction of glutathione and the fungal metabolite fusarin C. Mutat Res 199:207-214 (1988).
54. Voss KA, Porter JK, Bacon CW, Meredith FI, Norred WP. Fusaric acid and modification of the subchronic toxicity to rats of fumonisins in F. moniliforme culture material. Food Chem Toxicol 37:853-861 (1999).
55. Nelson PE, Wilson TM. Hepatocarcinogenicity of corn screenings naturally contaminated with Fusarium moniliforme. In: Mycotoxins and Phycotoxins (Steyn PS, Vleggaar R, ed). Amsterdam:Elsevier, 1986;535-544.
56. Laurent D, Pellegrin F, Kohler F, Lambert C, Fouquet L, Domenech J, Boccas B. Fusarium moniliforme du maize en New Caledonia: toxicologie animale [in French]. Microbiol Aliments Nutr 6:159-164 (1988).
57. Voss KA, Chamberlain WJ, Bacon CW, Herbert RA, Walters DB, Norred WP. Subchronic feeding study of the mycotoxin fumonisin B1 in B6C3F1 mice and Fischer 344 rats. Fundam Appl Toxicol 24:102-110 (1995).
58. Voss KA, Chamberlain WJ, Bacon CW, Norred WP. A preliminary investigation on renal and hepatic toxicity in rats fed purified fumonisin B1. Nat Toxins 1:222-228 (1993).
59. Voss KA, Norred WP, Bacon CW. Subchronic toxicological investigations of F. moniliforme-contaminated corn, culture material and ammoniated culture material. Mycopathologia 117:97-104 (1992).
60. Voss KA, Plattner RD, Bacon CW, Norred WP. Comparative studies of hepatotoxicity and fumonisin B1 and B2 content of water and chloroform/methanol extracts of Fusarium moniliforme strain MRC 826 culture material. Mycopathologia 112:81-92 (1990).
61. Tolleson WH, Dooley KL, Sheldon WG, Thurman JD, Bucci TJ, Howard PC. The mycotoxin fumonisin induces apoptosis in cultured human cells and in livers and kidneys of rats. Adv Exp Med Biol 392:237-250 (1996).
62. Gelderblom WCA, Cawood ME, Snyman SD, Vleggaar R, Marasas WFO. Structure-activity relationships of fumonisins in short-term carcinogenesis and cytotoxicity assays. Food Chem Toxicol 31:407-414 (1993).
63. Hendrich S, Miller KA, Wilson TM, Murphy PA. Toxicity of Fusarium proliferatum-fermented nixtamalized corn-based diets fed to rats. Effect of nutritional status. J Agric Food Chem 41:1649-1654 (1993).
64. Voss KA, Plattner RD, Riley RT, Meredith FI, Norred WP. In vivo effects of fumonisin B1-producing and fumonisin B1-nonproducing Fusarium moniliforme isolates are similar: fumonisins B2 and B3 cause hepato- and nephrotoxicity in rats. Mycopathologia 141:45-58 (1998).
65. Bondy G, Barker M, Mueller R, Fernie S, Miller JD, Armstrong C, Hierlihy SL, Rowsell P, Suzuki C. Fumonisin B1 toxicity in male Sprague-Dawley rats. Adv Exp Med Biol 392:251-264 (1996).
66. Bondy G, Suzuki C, Barker M, Armstrong C, Fernie S, Hierlihy L, Rowsell P, Meuller R. Toxicity of fumonisin B1 administered intraperitoneally to male Sprague-Dawley rats. Food Chem Toxicol 33:653-665 (1995).
67. Bondy GS, Suzuki CAM, Mueller RW, Fernie SM, Armstrong CL, Hierlihy SL. Gavage administration of the fungal toxin fumonisin B1 to female Sprague-Dawley rats. J Environ Health (Part A) 53:135-151 (1998).
68. Howard PC, Muskhelishvili L, Dooley KL, Bolon B, Warbritton A, Voss KA, Lorentzen RJ, Bucci TJ. Hepatic and renal apoptosis and sphingolipid changes in F344 rats and B6C3F1 mice chronically fed the corn fungal toxin fumonisin B1. Proc Am Assoc Cancer Res 37:371 (1996).
69. Howard PC, Thurman JD, Lorentzen RJ, Voss KA, Bucci TJ, Dooley KL. The induction of apoptosis in the liver and kidneys of male and female F344 rats fed diets for 28 days containing the mycotoxin fumonisin B1 [Abstract]. Proc Am Assoc Cancer Res 36:785 (1995).
70. Gelderblom WCA, Snyman SD, Lebepe-Mazur S, van der Westhuizen L, Kriek NPJ, Marasas WFO. The cancer-promoting potential of fumonisin B1 in rat liver using diethylnitrosamine as a cancer initiator. Cancer Lett 109:101-108 (1996).
71. Mehta R, Lok E, Rowsell PR, Miller JD, Suzuki CAM, Bondy GS. Glutathione S-transferase-placental form expression and proliferation of hepatocytes in fumonisin B1-treated male and female Sprague-Dawley rats. Cancer Lett 128:31-39 (1998).
72. Gelderblom WCA, Cawood ME, Snyman SD, Marasas WFO. Fumonisin B1 dosimetry in relation to cancer initiation in rat liver. Carcinogenesis 15:209-214 (1994).
73. Howard PC, Eppley RM, Stack ME, Warbritton A, Voss KA, Lorentzen RJ, Kovach RM, Bucci TJ. Fumonisin B1 carcinogenicity in a two-year feeding study using male and female F344 and B6C3F1 mice. Environ Health Perspect 109(suppl 2):277-282 (2001).
74. Bucci TJ, Howard PC, Tolleson WH, LaBorde JB, Hansen DK. Renal effects of fumonisin mycotoxins in animals. Toxicol Pathol 26:160-164 (1998).
75. Suzuki CAM, Hierlihy L, Barker M, Curran I, Mueller R, Bondy GS. The effects of fumonisin B1 on several markers of nephrotoxicity in rats. Toxicol Appl Pharmacol 133:207-214 (1995).
76. Hunnan YA, Obeid LM. Ceramide: an intracellular signal for apoptosis. Trends Biochem Sci 20:73-77 (1995).
77. Goldsworthy TL, Conolly RB, Fransson-Steen R. Apoptosis and cancer risk assessment. Mutat Res 365:71-90 (1996).
78. Majno G, Joris I. Apoptosis, oncosis, and necrosis: an overview of cell death. Am J Pathol 146:3-15 (1995)
79. Voss KA, Chamberlain WJ, Bacon CW, Riley RT, Norred WP. Subchronic toxicity of fumonisin B1 to male and female rats. Food Addit Contam 12:473-478 (1995).
80. Riley RT, Hinton DM, Chamberlain WJ, Bacon CW, Wang E, Merrill AH Jr, Voss KA. Dietary fumonisin B1 induces disruption of sphingolipid metabolism in Sprague-Dawley rats: a new mechanism of nephrotoxicity. J Nutr 124:594-603 (1994).
81. Tryphonas H, Bondy G, Miller JD, Lacroix F, Hodgen M, McGuire P, Fernie S, Miller D, Hayward S. Effects of fumonisin B1 on the immune system of Sprague-Dawley rats following a 1-day oral (gavage) exposure. Fundam Appl Toxicol 39:53-59 (1997).
82. Lim CW, Parker HM, Vesonder RF, Haschek WM. Intravenous fumonisin B1 induces cell proliferation and apoptosis in the rat. Nat Toxins 4:34-41 (1996).
83. Wild CP, Castegnaro M, Ohgaki H, Garren L, Galendo D, Miller JD. Absence of a synergistic effect between fumonisin B1 and N-nitromethylbenzylamine in the induction of oesophageal papillomas in the rat. Nat Toxins 5:126-131 (1997).
84. Sharma RP, Dugyala RR, Voss KA. Demonstration of in-situ apoptosis in mouse liver and kidney after short-term repeated exposure to fumonisin B1. J Comp Pathol 117:371-381 (1997).
85. Bondy GS, Suzuki CAM, Fernie SM, Armstrong CL, Hierlihy SL, Savard ME, Barker M. Toxicity of fumonisin B1 to B6C3F1 mice: a 14-day gavage study. Food Chem Toxicol 35:981-989 (1997).
86. Gumprecht LA, Marcucci A, Weigel RM, Vesonder RF, Riley RT, Showker JL, Beasley VR, Haschek WM. Effects of intravenous fumonisin B1 in rabbits: nephrotoxicity and sphingolipid alterations. Nat Toxins 3:395-403 (1995).
87. Howard PC, Warbritton A, Voss KA, Lorentzen RJ, Thurman D, Kovach RM, Bucci TJ. Compensatory regeneration as a mechanism for renal tubule carcinogenesis of fumonisin B1 in the F344/N/Nctr BR rat. Environ Health Perspect 109(suppl 2):309-314 (2001).
88. Wang E, Norred WP, Bacon CW, Riley RT, Merrill AH. Inhibition of sphingolipid biosynthesis by fumonisins. J Biol Chem 266:14486-144490 (1991).
89. Merrill AH Jr, Schmelz E-M, Dillehay DL, Spiegel S, Shayman JA, Schroeder JJ, Riley RT, Voss KA. Sphingolipids--the enigmatic lipid class: biochemistry, physiology, and pathophysiology. Toxicol Appl Pharmacol 142:208-225 (1997).
90. Riley RT, Voss KA, Yoo H-S, Gelderblom WCA, Merrill AH Jr. Mechanism of fumonisin toxicity and carcinogenesis. J Food Protect 57:638-645 (1994).
91. Merrill AH Jr. Cell regulation by sphingosine and more complex sphingolipids. J Bioenerg Biomembr 23:83-104 (1991).
92. Voss KA, Bacon CW, Meredith FI, Norred WP. Comparative subchronic toxicity studies of nixtamalized and water-extracted Fusarium moniliforme culture material. Food Chem Toxicol 34:623-632 (1996).
93. Voss KA, Riley RT, Bacon CW, Meredith FI, Norred WP. Toxicity and sphinganine levels are correlated in rats fed fumonisin B1 (FB1) or hydrolyzed FB1. Environ Toxicol Pharmacol 5:101-104 (1998).
94. Gelderblom WCA, Smuts CM, Abel S, Snyman SD, Cawood ME, van der Westhuizen L, Swanevelder S. Effect of fumonisin B1 on protein and lipid synthesis in primary rat hepatocytes. Food Chem Toxicol 34:361-369 (1996).
95. Gelderblom WCA, Smuts CM, Abel S, Snyman SD, van der Westhuizen L, Huber WW, Swanevelder S. Effect of fumonisin B1 on the levels and fatty acid composition of selected lipids in rat liver in vivo. Food Chem Toxicol 35:647-656 (1997).
96. Abado-Becognee K, Mobio TA, Ennamany R, Fleurat-Lessard F, Shier WT, Badria F, Creppy EE. Cytotoxicity of fumonisin B1: implication of lipid peroxidation and inhibition of protein and DNA synthesis. Arch Toxicol 72:233-236 (1998).
97. Abel S, Gelderblom WCA. Oxidative damage and fumonisin B1-induced toxicity in primary rat hepatocytes and rat liver in vitro. Toxicology 131:121-131 (1998).
98. Yin J-J, Smith MJ, Eppley RM, Page SW, Sphon JA. Effects of fumonisin B1 on lipid peroxidation in membranes. Biochim Biophys Acta 1371:134-142 (1998).
99. Sahu SC, Eppley RM, Page SW, Gray GC, Barton CN, O'Donnell MW. Peroxidation of membrane lipids and oxidative DNA damage by fumonisin B1 in isolated rat liver nuclei. Cancer Lett 125:117-121 (1998).
100. Merrill AH Jr. Sphingolipid biosynthetic pathways and their role in signal transduction. Environ Health Perspect 109(suppl 2):283-289 (2001).
101. Riley RT, Voss KA, Norred WP, Sharma RP, Merrill AH Jr. Sphingolipid perterbations as mechanisms for fumonisin carcinogenesis. Environ Health Perspect 109(suppl 2):301-308 (2001).
102. Gelderblom WCA, Abel S, Smuts CM, Marnewick J, Marasas WFO, Lemmer ER, Ramljak D. Fumonisin-induced hepatocarcinogenesis: mechanisms related to cancer initiation and promotion. Environ Health Perspect 109(suppl 2):291-300 (2001).
103. Javed T, Richard JL, Bennett GA, Dombrink-Kurtzman MA, Bunte RM, Koelkebeck KW, Cote LM, Buck WB. Embryopathic and embryocidal effects of purified fumonisin B1 or Fusarium proliferatum culture material extract on chicken embryos. Mycopathologia 123:185-193 (1993).
104. Flynn TJ, Pritchard D, Bradlaw JA, Eppley R, Page S. In vitro embryotoxicity of fumonisin B1 evaluated with cultured postimplantation staged embryos. Toxicol in Vitro 9:271-279 (1996).
105. Flynn TJ, Stack ME, Troy AL, Chirtel SJ. Assessment of the embryotoxic potential of the total hydrolysis product of fumonisin B1 using organogenesis-staged rat embryos. Food Chem Toxicol 35:1135-1141 (1997).
106. Voss KA, Bacon CW, Norred WP, Chapin RE, Chamberlain WJ, Plattner RD, Meredith FI. Studies on the reproductive effects of Fusarium moniliforme culture material in rats and the biodistribution of [14C]fumonisin B1 in pregnant rats. Nat Toxins 4:24-33 (1996).
107. Collins TFX, Shackelford ME, Sprando RL, Black TN, LaBorde JB, Hansen DK, Eppley RM, Trucksess MW, Howard PC, Bryant MA, et al. Effects of fumonisin B1 in pregnant rats. Food Chem Toxicol 36:697-408 (1998).
108. Collins TFX, Sprando RL, Black TN, Shackelford ME, LaBorde JB, Hansen DK, Eppley RM, Trucksess MW, Howard PC, Bryant MA, et al. Effects of fumonisin B1 in pregnant rats. Part 2. Food Chem Toxicol 36:673-685 (1998).
109. Reddy RV, Johnson G, Rottinghaus GE, Casteel SW, Reddy CS. Developmental effects of fumonisin B1 in mice. Mycopathologia 134:161-166 (1996).
110. LaBorde JB, Terry KK, Howard PC, Chen JJ, Collins TFX, Shackelford ME, Hansen DK. Lack of embryotoxicity of fumonisin B1 in New Zealand white rabbits. Fundam Appl Toxicol 40:120-128 (1997).
111. Floss JL, Casteel SW, Johnson GC, Rottinghaus GE, Krause GF. Developmental toxicity in hamsters of an aqueous extract of Fusarium moniliforme culture material containing known quantities of fumonisin B1. Vet Hum Toxicol 36:5-10 (1994).
112. Floss JL, Casteel SW, Johnson GC, Rottinghaus GE, Krause GF. Developmental toxicity of fumonisin in Syrian hamsters. Mycopathologia 128:33-38 (1994).
113. Porter JK, Bacon CW, Wray EM, Hagler WM Jr. Fusaric acid in Fusarium moniliforme cultures, corn, and feeds toxic to livestock and the neurochemical effects in the brain and pineal gland of rats. Nat Toxins 3:91-100 (1995).
114. Porter JK, Wray EM, Rimando AM, Stancel PC, Bacon CW, Voss KA. Lactational passage of fusaric acid from the feed of nursing dams to the neonate rat and effects on pineal neurochemistry in the F1 and F2 generations at weaning. J Toxicol Environ Health 49:161-175 (1996).
115. Rimando AM, Porter JK. Fusaric acid increases melatonin levels in the weanling rat and in pineal cell cultures. J Toxicol Environ Health 50:275-284 (1997).
116. Bacon CW, Porter JK, Norred WP. Toxic interaction of fumonisin B1 and fusaric acid measured by injection into fertile chicken eggs. Mycopathologia 129:29-35 (1995).
117. Doko MB, Canet C, Brown N, Sydenham EW, Mpuchane S, Siame BA. Natural co-occurrence of fumonisins and zearalenone in cereals and cereal-based foods from eastern and southern Africa. J Agric Food Chem 44:3240-3243 (1996).
118. Sydenham EW, Stockenstrom S, Thiel PG, Shephard GS, Koch KR, Marasas WFO. Potential of alkaline hydrolysis for the removal of fumonisins from contaminated corn. J Agric Food Chem 43:1198-1201 (1995).
119. Norred WP, Plattner RD, Dombrink-Kurtzman MA, Meredith FI, Riley RT. Mycotoxin-induced elevation of free sphingoid bases in precision-cut rat liver slices: specificity of the response and structure activity relationships. Toxicol Appl Pharmacol 147:63-70 (1997).
120. Shephard GS, Thiel PG, Sydenham EW, Alberts JF, Gelderblom WCA. Fate of a single dose of the 14C-labelled mycotoxin fumonisin B1, in rats. Toxicon 30:768-770 (1992).
121. Shephard GS, Thiel PG, Sydenham EW, Alberts JF, Cawood ME. Distribution and excretion of a single dose of the mycotoxin fumonisin B1 in a non-human primate. Toxicon 32:435-541 (1994).
122. Lebepe-Mazur S, Bal H, Hopmans E, Murphy P, Hendrich S. Fumonisin B1 is fetotoxic in rats. Vet Hum Toxicol 37:126-130 (1995).
123. Gross SM, Reddy RV, Rottinghaus GE, Johnson G, Reddy CS. Developmental effects of fumonisin B1-containing Fusarium moniliforme culture extract in CD1 mice. Mycopathologia 128:111-118 (1995).
124. Yoo H-S, Norred WP, Showker J, Riley RT. Elevated sphingoid bases and complex sphingolipid depletion as contributing factors in fumonisin-induced cytotoxicity. Toxicol Appl Pharmacol 138:211-218 (1996).
Last Updated: April 20, 2001
