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PubMed1980

In vivo covalent binding of aflatoxin B1 and aflatoxin M1 to liver DNA of rat, mouse and pig.

[14C]Aflatoxin B1 (AFB1) was isolated from cultures of Aspergillus parasiticus grown on [1-14C]sodium acetate. Covalent binding of AFB1 to liver DNA of rat and mouse was determined 6-8 h after oral administration. The effectiveness of covalent binding, expressed as DNA binding per dose in the units of a 'Covalent Binding Index' (CBI), (micromol aflatoxin/mol DNA nucleotides)/(mmol aflatoxin/kg animal), was found to be 10 400 for rats and 240 for mice. These CBI partly explain the different susceptibility of the two species for the incidence of hepatic tumors. The corresponding values for pig liver DNA, 24 and 48 h after oral administration, were found to be as high as 19 100 and 13 300. DNA-binding has not so far been reported for this species although it could represent an appropriate animal model for studies where a human-like gastrointestinal tract physiology is desirable. Aflatoxin M1 (AFM1) is a metabolite found in the milk of cows that have been fed AFB1-contaminated diet. [14C]AFM1 was also found to be produced by cultures of A. parasiticus giving a yield of about 0.3% of the total aflatoxins. A test for covalent binding to rat liver DNA revealed a CBI of 2100 showing that AFM1 must also be regarded as a strong hepatocarcinogen. It is concluded that AFB1 contaminations should be avoided in dairy feed.

Aflatoxin B1↗

PubMed1987

Carcinogenicity of dietary aflatoxin M1 in male Fischer rats compared to aflatoxin B1.

Aflatoxin M1 (AFM), an hydroxy metabolite of the potent carcinogenic mycotoxin aflatoxin B1 (AFB) is frequently found in milk and other dairy products. Sufficient amounts of AFM were produced to study the carcinogenicity of this compound. AFM was fed to male Fischer rats starting at 7 weeks up to 21 months of age. Agar-based semisynthetic diets contained 0.0, 0.5, 5.0, and 50.0 micrograms/kg of AFM or 50 micrograms/kg of AFB. Hepatocellular carcinomas were detected in two of 37 rats and neoplastic nodules were found in six of 37 rats fed 50 micrograms/kg AFM between 19 and 21 months. No nodules or carcinomas were observed in the lower AFM dose groups. Nineteen of 20 rats fed a diet containing 50 micrograms/kg of AFB developed hepatocellular carcinomas by 19 months of age. Carcinogenic potency of the aflatoxins was reflected by morphometric quantitation of foci detected in hematoxylin and eosin stained sections. Three rats fed the diet containing 50 micrograms/kg AFM developed intestinal carcinomas. None were observed in other groups. Under the conditions of this experiment AFM was found to be a weak hepatic carcinogen compared to AFB and to possess intestinal carcinogenicity.

Aflatoxin B1↗

PubMed1988

The genetics of aflatoxin B1 metabolism. Association of the induction of aflatoxin B1-4-hydroxylase with the transcriptional activation of cytochrome P3-450 gene.

The association between murine cytochrome P3-450 and hepatic aflatoxin B1-4-hydroxylase, a cytochrome P-450-dependent enzyme which converts aflatoxin B1 (AFB1) to aflatoxin M1 (AFM1), was examined by (a) purification of the cytochrome P-450 which preferentially metabolizes AFB1 to AFM1; (b) isolation of the specific cDNA clone; and (c) correlating induction of transcriptional activation of the specific message with the enzyme activity in the hepatic microsomes. Isolation of cytochromes P-450 from C57BL/6 mice, an Ah-responsive strain, pretreated with a 150 mg/kg dose of beta-naphthoflavone resulted in the partial purification of the cytochrome P-450 with preference for the metabolism of AFB1 to AFM1. Antibodies raised against this cytochrome P-450 were used to enrich hepatic mRNA for cDNA cloning. A cDNA library screened with a rat cytochrome P-450c gene probe yielded only two types of cDNA clones that contained inserts corresponding to cytochrome P1-450 and cytochrome P3-450. Specific restriction fragments of near full-length P1-450 cDNA and full-length P3-450 cDNA, hybridizing only with their respective messages, were isolated and used to assess transcriptional activation of these messages in liver and extrahepatic tissues from C57BL/6 mice treated with 3-methylcholanthrene, beta-naphthoflavone, indolylacetonitrile, and Aroclor-1254. Dose-dependent induction of the two messenger RNAs, when compared with the induction of specific enzyme activities, demonstrated the association of cytochrome P1-450 with aryl hydrocarbon hydroxylase activity and the association of cytochrome P3-450 with AFB1-4-hydroxylase activity. This supports our earlier hypothesis that AFB1-4-hydroxylase and aryl hydrocarbon hydroxylase, although regulated by the Ah locus, are the products of two separate genes (Gurtoo, H.L., Dahms, R.P., Kanter, P., and Vaught, J.B. (1978) J. Biol. Chem. 253, 3952-3961).

Aflatoxin B1↗

PubMed1994

Quantitative carcinogenesis and dosimetry in rainbow trout for aflatoxin B1 and aflatoxicol, two aflatoxins that form the same DNA adduct.

Two exposure protocols were used to establish complete dose-response relationships for the hepatic carcinogenicity and DNA adduction in vivo of aflatoxin B1 (AFB1) and aflatoxicol (AFL) in rainbow trout. By passive egg exposure, AFL was taken up less well than AFB1, but was more efficiently sequestered into the embryo itself, to produce an embryonic DNA binding curve that was linear with carcinogen dose and with a DNA binding index three-fold greater than AFB1. Both aflatoxins produced the same phenotypic response, predominantly mixed hepatocellular/cholangiocellular carcinoma. Tumor responses as logit [incidence] vs. In [dose] were parallel-offset, non-linear responses showing a three-fold greater carcinogenic potency for AFL at all doses examined (i.e. 3 times more AFB1 than AFL required to produce an equivalent liver tumor incidence). By molecular dosimetry analysis (logit [incidence] vs. In [DNA adducts]), the two data sets were coincident, indicating that, per DNA adduct formed in vivo in total embryonic DNA, these two aflatoxins were equally efficient in tumor initiation. By dietary fry exposure, both carcinogens produced linear DNA binding dose responses in liver, but with an AFL target organ DNA binding index only 1.14 times that of AFB1 by this exposure route. The tumor dose-response curves also did not exhibit the three-fold difference shown by embryo exposure, but were closely positioned non-linear curves. Since the DNA binding indices differed by only 14%, the resulting molecular dosimetry curves for AFL and AFB1 by dietary exposure were similar to the tumor response curves. These results indicate that differing exposure routes produced differing relative carcinogenicity estimates based on doses applied, as a result of protocol-dependent differences in AFL and AFB1 pharmacokinetic behaviors, but that potency comparisons based on molecular dose received were similar for the two protocols. By comparison with standard DNA adducts produced in vitro using the dimethyloxirane-produced 8,9-epoxides of AFB1 and AFL, we conclude that > 99% of AFL-DNA adducts produced in vivo were identical to those produced by AFB1. Thus similar molecular dosimetry responses should be expected under all exposure protocols in which the two parent carcinogens do not exhibit differing toxicities to the target organ.

Aflatoxin B1↗

PubMed2005

Aflatoxin occurrence in foodstuff supplied to dairy cattle and aflatoxin M1 in raw milk in the North of Paraná state.

Moulds occur in a great variety of foods, including the concentrated and roughage destined for animal feeding, and can produce mycotoxins under certain conditions. The ingestion of mycotoxin AFB(1) by dairy cattle leads to the biotransformation of that substance, which is eliminated via milk as AFM(1), and also causes damage to human health. The present study aimed to analyze the presence of aflatoxins in foodstuff destined for dairy cattle and in the milk produced by these animals. The contamination of the foodstuff by aflatoxins happened mainly in the feeds and the silages did not present contamination by aflatoxins. Out of the 42 samples of milk analyzed, 10 (24%) were contaminated by AFM(1), and 3 (7%) were above the 0.5 microg/l limit.

Aflatoxin B1↗

PubMed1990

Properties of aflatoxin-DNA adducts formed by photoactivation and characterization of the major photoadduct as aflatoxin-N7-guanine.

Aflatoxin-DNA adducts were formed by microsomal and photoactivation, using nick-translated DNA labelled with 14C in each of the DNA bases [3H]AFB1 and [3H]AFB2. DNA adducts were analysed by HPLC of DNA hydrolysates, and were characterized as double labelled peaks with specific retention times. The only AF-DNA adducts which were detected in significant amounts were guanine adducts, irrespective of the type of aflatoxin used or the mode of its activation. No stable adduct with adenine, cytosine or thymine was detected. UV spectra, proton NMR spectroscopy and mass spectrometry are consistent with the notion that the major AFB1-DNA photoadduct is the N7-guanine adduct. This report provides direct evidence for the existence of aflatoxin photoadducts formed on DNA.

Aflatoxin B1↗

PubMed1991

Identification of an aflatoxin G1-serum albumin adduct and its relevance to the measurement of human exposure to aflatoxins.

A major aflatoxin G1 (AFG1)-albumin adduct has been identified and characterized in rats following exposure to AFG1. The product isolated from a Pronase digest of in vivo-modified albumin was identical by chromatographic retention time to the synthetic product obtained by the acylase-catalysed deacetylation product of N alpha-acetyl-L-lysine with 8,9-dihydro-8,9-dibromo-AFG1. The in vitro product, AFG1-lysine, was characterized by UV, fluorescence, 1H- and 13C-NMR spectroscopy and fast atom bombardment MS. A competitive enzyme-linked immunoassay for this adduct was established using polyclonal antibodies to AFB1 and this was used together with an HPLC-fluorescence technique to quantitate the in vivo formation of AFG1-albumin adducts in comparison to AFB1. A linear dose-response relationship was observed in rats following single exposures to 0.1-3 mg AFG1/kg body wt. The levels of AFG1-albumin adducts were determined to be 5.7- and 2.8-fold lower than with equivalent doses of AFB1 as determined by immunoassay and HPLC fluorescence respectively. The lower binding of AFG1 and the lower levels in the human food supply compared to AFB1 suggest that the newly identified adduct could be added as an internal standard for methods using the measurement of aflatoxin-albumin adducts to quantitate human exposure to aflatoxin.

Aflatoxin B1↗

PubMed1983

Histochemical analysis of liver cells from short term, aflatoxin-dosed and nondosed Coturnix coturnix japonica. 1. Aflatoxin-sensitive quail.

Although aflatoxicosis in Coturnix coturnix japonica has been described, the histochemical localization of liver chemicals and the occurrence of ingested aflatoxins within blood, feces, and liver have not been described. Six to 8-week-old quail, which were intubated with a carrier with or without .3 mg mixed aflatoxins (AFB1, AFB2, AFG1, AFG2)/kg body weight were sacrificed within .25 to 5 days of intubation. Deparaffinized sections of livers were stained for lipids, nucleic acids, polysaccharides, and proteins. Other livers and excrement were homogenized and filtered homogenates as well as blood partitioned against chloroform. The aqueous phase was treated with pepsin and then partitioned, but the organic phase was analyzed directly. Organic phases of .25 to 5 day blood, feces, and liver lacked aflatoxins. Pepsin digesta of blood from males and females dosed 6 hr appeared to contain aflatoxicol (disappeared by 24 hr) and an unknown fluorescent compound, respectively. Whereas an unidentified fluorescent compound was observed within excrement of males dosed 6 hr, female excrement contained a fluorescent compound with an AFB1 Rf (disappeared by 24 hr). Although the liver of males dosed 6 hr had three fluorescent compounds (Rfs for AFB1 and AFB2a), only one was seen within dosed females. Ultra violet absorption spectra of presumed AFB2a and aflatoxicol failed to yield their reported absorption maxima. Livers from dosed quail exhibited bile duct proliferation, cellular necrosis, vacuolization, congestion, fatty changes and mild hepatitis. Sinusoidal membranes were thickened and contained abundant periodic acid-Schiff's (PAS)-positive substances. Although livers of nondosed quail abounded with regularly shaped and uniformly distributed, Sudan IV-positive droplets, livers of dosed quail accommodated few, irregularly-shaped and positioned droplets. Hepatocyte nuclei and nucleoli of dosed quail displayed marked affinities for the Feulgen reagent and toluidine blue O, respectively. Lobules of dosed quail possessed concentrations of cells in which their entire cytoplasm was PAS positive. Treatment of sections with alpha-amylase reduced staining suggesting the presence of glycogen. Ninhydrin-positive substances were distributed throughout the liver in both DQ and non DQ with no apparent difference in intensities between the two livers. Generally the DQ showed mild hepatitis due to aflatoxicosis and the toxin altered liver histochemistry for the major classes of cellular chemicals.

Aflatoxins↗

PubMed1990

Detection and detoxification of aflatoxins: prevention of aflatoxicosis and aflatoxin residues with hydrated sodium calcium aluminosilicate.

Our recent findings demonstrate that HSCAS can prevent aflatoxicosis in chickens and swine and significantly decreases the level of aflatoxin M1 residues in the milk of lactating dairy cattle. The basic mechanism for this action appears to involve sequestration of aflatoxin in the gastrointestinal tract and chemisorption (i.e., tight binding) to HSCAS which results in a reduction in aflatoxin bioavailability. Research is in progress to elucidate the specificity of HSCAS action and to construct a series of selective chemisorbents for mycotoxin control in livestock and poultry.

Aflatoxins↗

PubMed1993

[Study on the relationship between dietary aflatoxin B1 levels in foods and aflatoxin M1 excretion levels in children's urine in Guangxi].

617 children in high and low liver cancer incidence areas of Guangxi were observed for a study on the relationship between the dietary Aflatoxin B1 (AFB1) levels and Aflatoxin M1 (AFM1) excretion amounts in urine. The average amount of Aflatoxin B1 absorbed by children within 24 hours was 0.0883 x 10(-9) micrograms, (0.1232 x 10(-9)) in high liver cancer incidence area (LCIA), and 0.0306 x 10(-9) in low LCIA (P < 0.001). The average amount of AFM1 excreted in the children's urine within 24 hours was 0.0020 x 10(-9) micrograms, (0.0027 x 10(-9) in high LCIA, and 0.0010 x 10(-9) in low LCIA (P < 0.001). The conversion ratio from AFB1 to AFM1 excreted from urine was 2.27% in 24 hours after the children consumed AFB1 from foods. The ratio of conversion was 2.19% and 3.27% for the children who life in high and low LCIA respectively, it was 1.75% for the boys, 2.97% for the girls.

Adolescent↗

PubMed1996

High incidence of Aspergillus flavus and aflatoxins in stored groundnut in Ghana and the use of a microbial assay to assess the inhibitory effects of plant extracts on aflatoxin synthesis.

Groundnut samples from 21 selected markets in the 10 regions of Ghana yielded high levels of the aflatoxigenic fungus Aspergillus flavus on half-strength potato dextrose agar. The fungus was associated with 31.7 and 12.8%, respectively, of all damaged and undamaged kernels assayed. Only 0.24% of total kernels assayed yielded A. parasiticus. Other fungi detected from total kernels assayed were A. niger (34%), A. candidus (1.45%), A. tamarii (3.93%), A. ochraceous (5.26%), Fusarium spp. (1.7%) Penicillium spp. (5.19%), a Mucor sp. (2.3%), a Trichoderma sp. (0.2%), Rhizopus stolonifer (12%) and certain unidentifiable fungi (11.72%). Total aflatoxin levels ranging from 5.7 to 22, 168 ppb were identified with damaged kernel samples. The mycotoxin was not detected in 50% of undamaged kernel samples tested and very low levels mostly ranging from 0.1 to 12.2 ppb were associated with the undamaged samples that tested positive for aflatoxins. In a novel in vitro microbial assay to determine the effectiveness of certain plant extracts against aflatoxin synthesis, extracts from Xylopia aethiopica, Monodera myristica, Cinnamomum verum and Piper nigrum permitted fungal growth in 1.5% potato-dextrose broth while completely suppressing NOR formation. These extracts, however, could not suppress NOR formation in a yeast extract sucrose medium.

Aflatoxins↗

PubMed1982

Aflatoxin and aflatoxicosis. I. Fungal flora of some food and animal feeds with special references to aflatoxin-producing abilities.

A wide range of fungi, amounting to fifty-six species belonging to twenty-two genera, have been recovered from animal feeds and foodstuffs. The most frequent fungi were Aspergillus niger, and A. flavus, followed by Mucor racemosus, Alternaria alternata. Rhizopus stolonifer, Penicillium corylophilum and P. notatum. Three genera were found to be of moderate occurrence, namely, Mucor, Rhizopus and alternaria. The three following genera were of low occurrence: cladosporium, Fusarium, and Neurospora. The fluorescence method of detecting aflatoxin-producing strains demonstrated that only one is isolated of A. flavus possesses this property. Certain species of Penicillium and Aspergillus produced fluorescent substances (metabolites) similar in color to B and G aflatoxin. These substances were subsequently proved not to be aflatoxin by (TLC) chromatography. The animal and public health significance from such toxins was also discussed.

Aflatoxins↗

PubMed1979

Comparison of aflatoxin B1 and aflatoxin G1 binding to cellular macromolecules in vitro, in vivo and after peracid oxidation; characterisation of the major nucleic acid adducts.

A comparison between [14C]aflatoxin B1 (AFB1) and [14C]aflatoxin G1 (AFG1) binding to rat liver and kidney cellular macromolecules has shown AFG1-DNA and-ribosomal RNA binding to be lower in both organs. For both mycotoxins more was bound to nucleic acids than to protein. Two hours after intraperitoneal injection (60 microgram/100 g) of [14C] AFB1, 40 ng, 151 ng/mg. Loss of radioactivity bound to liver DNA for both [14C]AFB1 and protein respectively and for [14C]AFG1 the respective figures were 10, 7 and 1 ng/mg. Loss of liver bound radioactivity to DNA for both [14C]AFG1 and [14C]AFG1 appeared to be biphasic indicating that an enzymic DNA repair process may be operating. In vitro binding studies also showed less AFG1 was bound to exogenous DNA after microsomal activation than AFB1. This difference was not a result of differences in the chemical reactivity of the "ultimate" electrophilic species, the respective expoxides, since chemical activation studies using 3-chloroperbenzoic acid showed similar amounts of AFG1 and AFB1 to be converted to the epoxides and to bind to DNA. Studies on the distribution coefficients of the two mycotoxins showed AFB1 to be more lipophilic than AFG1 and this may be an important factor in determining the weaker carcinogenicity of the latter compound. Characterisation of the major AFG1-DNA adduct formed in vitro, in vivo and after peracid oxidation showed it to have the structure trans-9,10-dihydro-9-(7-guanyl)-10-hydroxy-aflatoxin G1. This adduct is similar to that obtained from AFB1 by activation in vivo, in vitro and after peracid oxidation.

Aflatoxins↗

PubMed2005

Yellow pigments used in rapid identification of aflatoxin-producing Aspergillus strains are anthraquinones associated with the aflatoxin biosynthetic pathway.

Studies on biological control of aflatoxin production in crops by pre-infection with non-toxigenic Aspergillus flavus strains have created a need for improved methods to screen isolates for aflatoxigenicity. We have evaluated two empirical aflatoxigenicity tests: (i) yellow pigment production, and (ii) the appearance of a plum-red color in colonies exposed to ammonium hydroxide vapor. Yellow pigments from aflatoxigenic A. flavus were shown to function as pH indicator dyes. Seven pigments representing most of the pigmentation in extracts have been isolated using color changes when chromatography spots were exposed to ammonium hydroxide vapor to guide fractionation. Their structures have been shown to be norsolorinic acid, averantin, averufin, versicolorin C, versicolorin A, versicolorin A hemiacetal and nidurufin, all of which are known anthraquinone pigments on, or associated with, the aflatoxin biosynthetic pathway in Aspergillus spp. Thus, the basis of both empirical tests for aflatoxigenicity is detecting production of excess aflatoxin biosynthetic intermediates.

Aflatoxins↗

PubMed1996

Characterization of monoclonal antibodies to aflatoxin M1 and molecular modeling studies of related aflatoxins.

Aflatoxin M1 (AFM1) and seven structural analogs were used to investigate the correlation between antibody binding and the conformational and electronic properties of these molecules. Mice were immunized with AFM1-BSA and hybridomas secreting anti-AFM1 antibodies were isolated and characterized. The cross-reactivities of seven structurally similar aflatoxins were determined by competition enzyme-linked immunosorbent assay (cELISA). In an effort to correlate antibody binding with three-dimensional properties of the analogs, all of the aflatoxins (and the immunogen) were modeled and global energy minima were determined using molecular, mechanical and quantum mechanical methods. The results demonstrate that, for these molecules, loss of optimum structure and introduction of steric hindrance in the portion of the molecule that would fit into the antibody binding site are more important to binding than simply loss of a determinant group. Molecular computational techniques can give reasons for the wide variation in IC50 values observed between structural analogs and can be used as a tool for determining which conformational and electronic properties of molecules are most important for antibody binding.

Aflatoxin M1↗

PubMed2005

Several physical properties of aflatoxin-contaminated pistachio nuts: application of BGY fluorescence for separation of aflatoxin-contaminated nuts.

The primary objective was to evaluate and find a proper method for visual identification of aflatoxin-contaminated pistachio nuts. The feasibility of using bright greenish yellow fluorescence (BGYF) in pistachio nut as a discriminating factor for identification of Aspergillus flavus-infested nuts, at harvest and in post-harvest, is investigated. Results show a strong relationship between BGYF and aflatoxin content at harvest. The factors affecting the application of this method in post-harvest stages are also discussed. The relationship between inside-brown kernels and aflatoxin presence is confirmed. At harvest, the brown kernels are a subdivision of fluorescent fraction. The share of different pistachios based on hull types (with sound hull, growth split and early-split) in contamination is studied. The early-split nuts are the most contaminated nuts, growth split nuts are less contaminated, and pistachios with sound hulls are almost clean. The effect of inappropriate handling on the percentage of fluorescent nuts is studied. The percentage of visible mould in samples is observed which shows a good relationship with the presence of BGY fluorescence.

Aflatoxins↗

PubMed1986

Regulation of aflatoxin biosynthesis: effect of adenine nucleotides, cyclic AMP and N6-O2' -dibutyryl cyclic AMP on the incorporation of (1-14C)-acetate into aflatoxins by Aspergillus parasiticus NRRL-3240.

Adenosine triphosphate (ATP) was found to inhibit the incorporation of labelled acetate into aflatoxins while adenosine diphosphate (ADP) and adenosine monophosphate (AMP) stimulated the process. Exogenous cyclic AMP and its derivative, N6-O2' -dibutyryl cyclic AMP produced efficient (1-14C)-acetate incorporation into aflatoxins at all the concentrations tried (0.1, 0.5 and 1 mM). The stimulation of incorporation of labelled acetate into aflatoxins was significant at 0.1 and 1 mM concentration of the cyclic nucleotide but was found to be maximum at 0.5 mM concentration.

Acetates↗

PubMed1971

Aflatoxin P-1: a new aflatoxin metabolite in monkeys.

A new phenolic derivative of aflatoxin B(1), appearing mainly in conjugated form, was identified as the principal urinary metabolite of aflatoxin B(1) in rhesus monkeys. Its identification in human urine might facilitate estimation of aflatoxin exposure in human populations.

Aflatoxins↗