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PubMed1998

Use of aflatoxin adducts as intermediate endpoints to assess the efficacy of chemopreventive interventions in animals and man.

Clinical cancer prevention studies that use disease as an endpoint are of necessity, large, lengthy, and extremely costly. Development of the field of cancer chemoprevention is being accelerated by the application of intermediate markers to preclinical and clinical studies. Sensitive and specific analytic methods have been developed for detecting and quantifying levels of covalent adducts of aflatoxins with cellular DNA and blood proteins at ambient levels of exposure. Such biomarkers can be applied to the preselection of exposed individuals for study cohorts, thereby reducing study size requirements. Levels of these aflatoxin-DNA and albumin adducts can be modulated by chemopreventive agents such as oltipraz and chlorophyllin in experimental models. Overall, a good concordance is seen between diminution of biomarkers and reductions in tumor incidence and/or multiplicity in these settings. Thus, these markers can also be used to rapidly assess the efficacy of preventive interventions. However, the successful application of these biomarkers to clinical prevention trials will be dependent upon prior determination of the associative or causal role of the marker to the carcinogenic process, establishment of the relationship between dose and response, and appreciation of the kinetics of adduct formation and removal. The general approach that has been utilized for the development, validation and application of aflatoxin-DNA and protein adduct biomarkers to cancer chemoprevention trials is summarized.

Aflatoxins↗

PubMed2002

Promoter elements in the aflatoxin pathway polyketide synthase gene.

PksA catalyzes the formation of the polyketide backbone necessary for aflatoxin biosynthesis. Based on reporter assays and sequence comparisons of the nor1-pksA intergenic region in different aflatoxin-producing Aspergillus species, cis-acting elements for the aflatoxin pathway-specific regulatory protein, AflR, and the global-acting regulatory proteins BrlA and PacC are involved in pksA promoter activity.

Aflatoxins↗

PubMed2003

Development of a method for direct visual determination of aflatoxin production by colonies of the Aspergillus flavus group.

This report describes a simple, rapid and reliable method for screening the aflatoxin production by moulds of the Aspergillus flavus group. Strains were cultivated on yeast extract agar to which methylated beta-cyclodextrin derivative plus sodium desoxycholate was added. Production of aflatoxins was readily detectable by direct visualisation of a beige ring surrounding colonies after an incubation time of 3 days at 28 degrees C. When this ring was examined under UV light, it exhibited blue fluorescence. The presence of aflatoxins was confirmed by extracting the medium with chloroform and examining the extracts by HPLC with fluorescence detection.

Aflatoxins↗

PubMed1993

Point mutations of the P53 gene, human hepatocellular carcinoma and aflatoxins.

The tumor suppressor p53 exerts important protective functions towards DNA-damaging agents. Its inactivation by allelic deletions or point mutations within the P53 gene as well as complex formation of wildtype p53 with cellular or viral proteins is a common and crucial event in carcinogenesis. Mutations increase the half-life of the p53 protein allowing the immunohistochemical detection and anti-p53 antibody formation. Distinct G to T point mutations in codon 249 leading to a substitution of the basic amino acid arginine by the neutral amino acid serine are responsible for the altered functionality of the mutant gene product and were originally identified in 8 of 16 Chinese and 5 of 10 African HCC patients. Both groups are frequently exposed to mycotoxin contaminations of their food. Today an average P53 gene mutation rate of 25% is assumed for high-aflatoxin B1-exposure regions. This is double the rate observed in low-aflatoxin B1-exposure countries. Although many HCC patients displaying P53 mutations also suffer from HBV infection, which itself can lead to rearrangements of P53 coding regions or induce the synthesis of viral proteins possibly interacting with p53, the specific G to T transversion within codon 249 of the P53 gene seems to directly reflect the extent of aflatoxin B1 exposure.

Aflatoxins↗

PubMed1978

Alterations of brain and intestine serotonin levels in hamsters pretreated with dietary aflatoxin.

Male Syrian hamsters were fed 30.3 ppm mixed aflatoxins (AFT) for a 45-day period followed by a 123-day recovery period. Tests made at the end of the recovery period indicated a reduction in whole brain and duodenal serotonin and a slight but not statistically significant elevation in brain 5-hydroxyindoleacetic acid. There was a high incidence of liver cell hyperplasia in the aflatoxin fed animals. Following toxin withdrawal, the experimental animals showed significant gains in body weight but they never attained a body weight equal to the controls. Aflatoxin apparently interferes with serotonin production and the return to normal body weight even after withdrawal of the animal from the contaminated diet.

Aflatoxins↗

PubMed1999

Aflatoxin B1 is an inhibitor of cyclic nucleotide phosphodiesterase activity.

Aflatoxin B1 (AFB1) action on cyclic nucleotide phosphodiesterase (PDE) activity has been tested on tissue extracts of various organs. In the presence of 100 microM AFB1 a significant inhibition of cAMP and cGMP hydrolytic activity is observed in all tested tissue extracts. However, cGMP hydrolytic activity appears more sensitive to AFB1 inhibition than cAMP hydrolytic activity and a considerably higher inhibition is observed in lung and spleen, than in liver, brain, kidney, and heart. When cGMP is used as substrate, the inhibitory response reaches 72% in lung and spleen extracts. We have also tested AFB1 effects on lung and liver PDE activity peaks separated by DEAE-cellulose chromatography. These data confirm the poor sensitivity to the toxin of all PDE activities present in liver, while the lung peak (where PDE V in present) shows a higher sensitivity to AFB1. In order to establish whether PDE V is in fact more sensitive to AFB1, we have used mouse neuroblastoma cells, in which cGMP hydrolytic activity has been shown to be due to PDE V only. In this case, the calculated IC50 is 24 microM and Dixon plot analysis shows a competitive inhibitory effect with a Ki of 16.7 microM. We have also used aflatoxin B2 and M2, and they proved to be much less effective than AFB1: AFB2 inhibits PDE V with an IC50 of 117 microM, while AFM2 does not show any effect. These results provide the first evidence of a competitive inhibition of AFB1 on an enzymatic activity and suggest that an alteration of cellular cyclic nucleotide levels may play a role in the mechanism of aflatoxin action.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed1996

Hydrated sodium calcium aluminosilicate (HSCAS), acidic HSCAS, and activated charcoal reduce urinary excretion of aflatoxin M1 in turkey poults. Lack of effect by activated charcoal on aflatoxicosis.

In one experiment, the effect of inorganic sorbents on the metabolic fate of aflatoxin B1 (AFB1) was studied in turkey poults. At 5 weeks of age, female poults were surgically colostomized and 9 days later orally dosed with 0.75 mg AFB1/kg BW. Hydrated sodium calcium aluminosilicate (HSCAS), acidic HSCAS, and activated charcoal (AC) were tested, by concomitant administration with AFB1. Urine was collected up to 48 h post-dosing and analyzed for aflatoxin M1 (AFM1) which was the major metabolite found in all treatment groups. Hydrated sodium calcium aluminosilicate, previously proven beneficial in alleviating aflatoxicosis in farm animals, reduced urinary AFM1 output when orally dosed simultaneous with AFB1. Also, acidic HSCAS and AC significantly decreased AFM1 excretion when administered concomitantly with AFB1. A second experiment was conducted to evaluate the ability of two types of AC to modify aflatoxicosis when added to aflatoxin (AF)-contaminated (from culture material) diets of turkey poults. Although AC was able to decrease AFM1 excretion in the first experiment, no protective effects from AF toxicity were observed in the feeding study.

Aflatoxin M1↗

PubMed1997

Experimental induction of liver fibrosis in young guinea pigs by combined application of copper sulphate and aflatoxin B1.

Aflatoxin B1 alone (0.05 mg resp. 0.037 mg/kg/d), copper alone (6.6 mg/kg/d or 200 mg/l drinking water) or a combination of both was administered orally for 6 months to young guinea pigs from the first/second day of life. In the copper group there were no pathomorphological changes. For the aflatoxin B1 group, liver damage was established. In the combined group, liver injury was more frequent and more severe compared to the aflatoxin B1 group and biliary copper excretion was diminished compared with the copper group. Histologically, only the livers of this group exhibited degeneration, atrophy and steatosis of liver cells, inflammatory processes and a more or less prominent fibrosis. For childhood cirrhosis (ICC and ICT) a combined etiology--a liver damaging agent plus elevated alimentary copper--is a plausible hypothesis.

Aflatoxin B1↗

PubMed2000

Effects of aflatoxin B(1) on the liver and kidney of broiler chickens during development.

Aflatoxin B(1) (AFB(1)) negatively affects chicken (Gallus domesticus) growth. This effect is more severe during development. We studied the influence of age on the toxic effects of AFB(1) on plasma, renal and hepatic enzymes, under two protocols, in adult and in developing Arbor-Acres chickens. Protocol A: 100 male 4-week-old chickens (640 g), received AFB(1), 0.5, 1.0, or 2.0 microg/g of feed (daily p.o.), a fourth group received an aflatoxin-free diet. Five birds/group were slaughtered at 7, 14, 21 and 28 days of treatment. Body, hepatic and renal weights, succinate-dehydrogenase (SDH) and glutamate-dehydrogenase (GluDH) in plasma and liver were measured. Hepatic SDH and GluDH decreased (P<0.05). Protocol B: two groups of 24 male 1-week-old chickens (106 g) received either aflatoxin-free feed (n=24) or AFB(1) feed (2.0 microg/g). At days 7, 14, 21 and 28, the same parameters of Protocol A were measured. AFB(1) markedly reduced body weight gain (20-30%), plasma proteins, albumin, renal and hepatic protein content (P<0.05) and increased absolute and relative weights of the kidney (P<0.05). SDH and GluDH were reduced (P<0.05), while total renal gamma-glutamyltranspeptidase (GGT) increased (P<0.05). Results suggest that serum proteins, SDH and GluDH are sensitive early indicators of this toxicity that was more severe in developing chickens. Decrease in serum albumin might be used as an early and suitable indicator of the deleterious effect of this mycotoxin in developing chickens.

Aflatoxin B1↗

PubMed2001

Amelioration of cytotoxic effects of aflatoxin by vitamin A: an in vitro study on erythrocytes.

We have evaluated the ameliorative role of vitamin A on aflatoxin-induced cytotoxicity in vitro. Aflatoxin (1.95 microM)-induced hemolysis was found to be significantly reduced on addition of vitamin A (125--1250 IU/ml) in incubation medium. The decrease in hemolysis was almost dose dependent. The kinetics of reduction of AFB(1) to B(2) and AFG(1) to G(2) by vitamin A has been investigated in dilute aqueous solution at 37 degrees C. The rate of the reduction was found to be first order with respect to the concentration of vitamin A and aflatoxin concentration.

Aflatoxins↗

PubMed2000

Oxidative stress as a prerequisite for aflatoxin production by Aspergillus parasiticus.

The relevance of free radical generation and oxidative stress with regard to aflatoxin production was examined by comparing the oxygen requirement and antioxidant status of a toxigenic strain of Aspergillus parasiticus with that of a nontoxigenic strain at early (trophophase) and late logarithmic (idiophase) growth phases. In comparison to the nontoxigenic strain, wherein the oxygen requirements were relatively unaltered at various growth phases, the toxigenic strain exhibited greater oxygen requirements at trophophase coinciding with onset of aflatoxin production. The activities of antioxidant enzymes such as xanthine oxidase, superoxide dismutase, and glutathione peroxidase and the mycelial contents of thiobarbituric acid-reactive substances as well as of reduced glutathione were all enhanced during the progression of toxigenic strain from trophophase to idiophase. The combined results suggest that aflatoxin production by the toxigenic strain may be a consequence of increased oxidative stress leading to enhanced lipid peroxidation and free radical generation.

Aflatoxins↗

PubMed1998

Liver fibrosis in guinea pigs experimentally induced by combined copper and aflatoxin application.

Aflatoxin B1 alone (0.05 mg resp. 0.037 mg/kg/d), copper alone (6.6 mg/kg/d or 200 mg/l drinking water) or a combination of both was administrated orally for 6 months to young guinea pigs from the first/second day of life. In the copper group there were no pathomorphological changes. For the aflatoxin B1 group liver damage was established. In the combined group liver injury was more frequent and more severe compared to the aflatoxin B1 group. Compared with the copper group biliary copper excretion was diminished and the kidney copper content was elevated in the Afl. B1 + Cu group. While copper concentrations in bile and kidney correlated with other parameters, notably the pathological lesions of the liver, no such correlation was found for liver copper. Therefore in this experiment the degree of Cu accumulation was not decisive for the liver lesions. The livers' capacity for excreting Cu by bile seems to be a much more important factor. Histologically only the livers of the combined group exhibited degeneration, atrophy and steatosis of liver cells, and a fibrosis more or less pronounced. For childhood cirrhosis (ICC and ICT), a combined etiology--a liver damaging agent plus elevated alimentary copper--is a plausible hypothesis.

Aflatoxin B1↗

PubMed2005

Aflatoxin screening by MALDI-TOF mass spectrometry.

Efficient detection of aflatoxins B1, B2, G1, and G2 has been performed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry using a UV-absorbing ionic liquid matrix to obtain "matrix-free" mass spectra and addition of NaCl to enhance sensitivity via Na+ cationization. Using ionic alpha-cyano-4-hydroxycinnamic acid (Et3N-alpha-CHCA) as the matrix, matrix-free mass spectra in the m/z range of interest are acquired, and the B1, B2, G1, and G2 aflatoxins are readily detected with an LOD as low as 50 fmol. The technique is fast, requires little sample preparation and no derivatization or chromatographic separation, and seems therefore to be suitable for high-throughput aflatoxin screening. It should be easily extended to other micotoxins and provide an attractive technique to control the quality of major crops subjected to huge world commercial trades such as peanuts, corn, and rice as well as to monitor bioterrorism threats by micotoxin poisoning.

Aflatoxins↗

PubMed2002

Mispairing of the 8,9-dihydro-8-(N7-guanyl)-9-hydroxy-aflatoxin B1 adduct with deoxyadenosine results in extrusion of the mismatched dA toward the major groove.

The G --> T transversion is the dominant mutation induced by the cationic trans-8,9-dihydro-8-(N7-guanyl)-9-hydroxy-aflatoxin B(1) adduct. The structure of d(ACATC(AFB)GATCT).d(AGATAGATGT), in which the cationic adduct was mismatched with deoxyadenosine, was refined using molecular dynamics calculations restrained by NOE data and dihedral restraints obtained from NMR spectroscopy. Restrained molecular dynamics calculations refined structures with pairwise rmsd <1 A and a sixth root R1x factor between the refined structure and NOE data of 10.5 x 10-2. The mismatched duplex existed in a single conformation at neutral pH. The aflatoxin moiety intercalated above the 5' face of the modified (AFB)G. The mismatched dA was in the anti conformation about the glycosyl bond. It extruded toward the major groove and did not participate in hydrogen bonding with (AFB)G. The structure was compared with that of d(ACATCGATCT).d(AGATAGATGT) containing the corresponding unmodified G.A mismatch and with d(ACATC(AFB)GATCT).d(AGATCGATGT) containing the aflatoxin lesion in the correctly paired (AFB)G.C context. The correctly paired oligodeoxynucleotide exhibited Watson-Crick-type geometry at the (AFB)G.C pair. It melted at higher temperature than the mismatched (AFB)G.A duplex. The unmodified mismatched G.A duplex exhibited spectral line broadening at neutral pH, suggesting a mixture of conformations. It exhibited a lower melting temperature than did the mismatched (AFB)G.A duplex. These differences correlated with replication bypass experiments performed in vitro utilizing DNA polymerase I exo- [Johnston, D. S., and Stone, M. P. (2000) Chem. Res. Toxicol. 13, 1158-1164]. Those experiments showed that correct insertion of dC opposite (AFB)G blocked replication by the enzyme, whereas incorrect insertion of dA opposite (AFB)G allowed full-length replication of the adducted template strand.

Aflatoxin B1↗

PubMed2000

Distribution of aflatoxin in pistachios. 7. Sequential sampling.

Sequential sampling for aflatoxin testing in pistachios is evaluated using the aflatoxin distribution and Monte Carlo results previously obtained (J. Agric. Food Chem. 1999, 47, 3771-3775). The sequential protocol is modeled on the current EU test protocol by applying a three-step sampling, using 10, 20, and 30 kg sample averages. An acceptance level of 15 ng/g of total aflatoxin, under consideration for U.S. standards, is applied. Optimization leads to indifference regions of 2-30 ng/g for the first two steps. The resulting OC curve approximates that for a single 50 kg sample. The sequential protocol is applied to the results for a set of 1293 lots of the 1998 crop year, each tested with a single 10 kg sample. Ninety-five percent of the lots would have been accepted on the basis of the single test and 1.5% would have been rejected, whereas 3.5% of the lots would have required retesting.

Aflatoxins↗

PubMed2001

Monitoring the preventive effect of hydrogen peroxide and gamma-radiation of aflatoxicosis in growing rabbits and the effect of cooking on aflatoxin residues.

The objective of the present study was the prevention of aflatoxicosis of growing rabbits fed aflatoxin (AF)-contaminated diet (833 microg of aflatoxins/kg) using 5% hydrogen peroxide (H2O2) and gamma-radiation at a dose level of 500 krad (5 kGy) and fed to growing rabbits. A total of 24 New Zealand white rabbits were divided into three groups. The experimental diets included AF-contaminated diet; AF-decontaminated diet, and AF-free diet (control). The obtained data showed significant reduction (p < 0.05) in live body weight and body weight gain of rabbits that fed on AF-contaminated diet as well as AF-decontaminated diet relative to control. There were no differences in feed consumption among the three groups; feed efficiency reduced significantly for AF-contaminated and AF-decontaminated groups. Mortality percentage was 25% for AF-contaminated and AF-decontaminated groups. Relative weight of the liver increased in animals fed AF-contaminated and AF-decontaminated diets, whereas the relative weight of kidneys decreased for both. There was no difference in total protein, but the levels of albumin and globulin were altered in rabbits receiving AF-contaminated diet. Serum enzymes (alanine amino transferase and aspartate amino transferase) activity increased significantly in rabbits that received AF-contaminated as well as AF-decontaminated diets. Histopathological examination revealed particularly alteration in liver and kidneys of rabbits fed AF-decontaminated diet. Results showed that the percentage of aflatoxin reduction ranged between 67 and 80% in boiled liver and between 79 and 90.5% in fried liver, whereas complete reduction in AF was found after boiling followed by frying. These findings indicate that the use of H2O2 and gamma-radiation for the destruction of aflatoxins in contaminated diet induces adverse effects in the animals.

Aflatoxins↗

PubMed2002

Rapid, non-destructive selection of peanuts for high aflatoxin content by soaking and tandem mass spectrometry.

Peanut lots are subject to aflatoxin levels high enough to cause concern to health agencies and trade channels. A possible solution would be to mechanically sort out high aflatoxin nuts from the process stream. Only highly contaminated nuts would need to be removed. However, there exists at present no sorting mechanism which meets commercial needs of adequate reduction and product preservation. To build such a sorter requires knowledge of the properties that can be used for sorting. The first step in the design is to select on the order of one hundred undamaged contaminated nuts which can be compared with noncontaminated ones. Because contaminated nuts are rare, a very large number of nuts needs to be examined nondestructively. We present a method to rapidly carry out such a selection. The method is based on dipping nuts into extraction fluid and examining the resulting fluid by tandem MS without preliminary cleanup. This method has been applied to examine over 65,000 nuts, yielding approximately 120 nuts, each containing more than 250-43000 ng/g aflatoxin (depending on process stream).

Aflatoxins↗

PubMed2002

Incidence, level, and behavior of aflatoxins during coffee bean roasting and decaffeination.

Screening for aflatoxins (Afs), isolation and identification of Aspergillus flavus, and the effect of decaffeination and roasting on the level of contamination in coffee beans are studied. The percent frequency of A. flavus ranged between 4 and 80% in green coffee beans (GCB), whereas in ground roasted coffee beans (GRCB), it ranged between 1 and 71%. Aflatoxins were detected in 76.5 and 54.6% of the infected samples with averages of 4.28 and 2.85 microg/kg of GCB and GRCB, respectively. Roasting was demonstrated to lower the concentration of Afs in GCB. The Afs levels were reduced by approximately 42.2-55.9% depending on the type and temperature of roasting. The highest yields of Afs were detected in the decaffeinated green coffee beans (24.29 microg/kg) and roasted coffee beans (16.00 microg/kg). The growth of A. flavus in liquid medium containing 1 or 2% caffeine was reduced by 50%, and the level of aflatoxin in the medium was undetectable.

Aflatoxins↗