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PubMed1991

Reliability of a short-term test for hepatocarcinogenesis induced by aflatoxin B1.

The reliability of a short-term test for hepatocarcinogenesis induced by aflatoxin B1 (AFB1) was tested by comparing the early appearance of gamma-glutamyl transpeptidase (GGT)-positive foci with the occurrence of primary liver cancer at a later stage. All rats received a basic short-term treatment with AFB1 intraperitoneally, during which three experimental groups received Chinese green tea or 2000 or 5000 ppm butylated hydroxyanisole in the diet and a control group received basic diet. Some of the rats in each group were sacrificed at the end of the short-term procedure, and the remainder were observed up to 92 weeks. The livers of all animals were examined for GGT-positive foci or primary liver tumours. The GGT-positive foci were most numerous and largest and the incidence of liver tumours was highest in the control group. These findings suggest that GGT-positive foci are a valuable preneoplastic marker for AFB1-induced hepatocarcinogenesis, that the short-term model is fairly reliable, and that both Chinese green tea and butylated hydroxyanisole inhibit AFB1-induced hepatocarcinogenesis.

Aflatoxin B1↗
PubMed1989

Effects of aflatoxin B1 on murine lymphocytic functions.

We recently reported on the immunotoxic effects of Aflatoxin B1 (AFB1), a secondary fungal metabolite of Aspergillus flavus in mice. The present paper describes the effect of AFB1 on cellular functions in lymphocytes after in vivo or in vitro exposures. Male BALB/c mice received 0, 0.03, 0.145 or 0.7 mg/kg body weight of AFB1 for 4 weeks. A dose-related decrease in DNA synthesis in lymphocyte cultures with or without the mitogens (lipopolysaccharide, phytohemagglutinin, pokeweed mitogen and concanavalin A) was observed. No effects on protein or ribonucleic acid synthesis were observed. There were dose-dependent decreases in peripheral leucocyte counts and natural killer cell function. Splenic lymphocytes from normal mice cultured with 10(-6) to 10(-4) M AFB1 had decreased DNA synthesis at greater than 1 X 10(-5) M, a decreased protein synthesis at 10(-4) M and decreased RNA synthesis at greater than 2.5 X 10(-5) M. In vitro addition of AFB1 (greater than 50 microM) reduced generation of concanavalin A-induced suppressor cells. The results suggest that AFB1 had a direct and complex effect on lymphocytes and there is a differential sensitivity of various subpopulations.

Administration, Oral↗
PubMed2006

Study of aflatoxin B1 and ochratoxin A production by natural microflora and Aspergillus parasiticus in black and green olives of Greek origin.

Aflatoxin B1 (AFB1) is a carcinogenic metabolite produced by certain Aspergillus species. Ochratoxin A (OTA) is classified as "possible carcinogen" and it is a metabolite of Aspergillus ochraceus and Penicillium verrucosum. Fungi contaminate natural and processed olives which support AFB1 and OTA production. The aim of this study was to compare and investigate AFB1 and OTA production in three different varieties of damaged olives. For each variety two different treatments were applied: (1) olives with natural microflora and (2) olives inoculated with A. parasiticus after natural microflora elimination. AFB1 and OTA have been extracted simultaneously from olives, purified with immunoaffinity columns and quantitated by HPLC using fluorescence detector. The recoveries and detection limits of AFB1 and OTA were 94% and 0.15 ng AFB1 g(-1) and 102.7%, 0.41 ng OTA g(-1) respectively. Results showed that, meanwhile OTA was not found in any olive sample, AFB(1) production within the three varieties of olives with natural microflora was significantly (P< or =0.05) different regarding their substrate and time of incubation (18 days). AFB1 production in two different varieties of black olives after inoculation by A. parasiticus was not significantly higher compared with control samples. On the contrary, AFB1 production in green olives was stimulated after the 12th day. Additionally, investigation on the occurrence of AFB1 and OTA in 30 samples of olives and olive pasta from Athens market showed OTA's presence in two samples of olives contaminated at the levels of 1.18 and 1.86 ng OTA g(-1). Aflatoxin B1 was found at levels 0.15-1.13 ng AFB1 g(-1) in all samples tested.

Aflatoxin B1↗
PubMed1994

Shuttle-vector mutagenesis by aflatoxin B1 in human cells: effects of sequence context on the supF mutational spectrum.

Rat-liver microsomes were used to activate aflatoxin B1 for in vitro modification of the pS189 shuttle vector and the related signature vector pSP189, both of which carry the Escherichia coli supF gene as a mutational target. Plasmid degradation was minimized by carrying out the in vitro incubations in the absence of Mg2+ ions. Modified plasmids were transfected into human Ad293 cells, then recovered and electroporated into E. coli MBM7070 for mutant identification. Point mutation frequencies for in vitro modified plasmids were dramatically increased over the spontaneous background level. Mutant plasmids were characterized by DNA-sequence analysis. The vast majority of aflatoxin B1-induced mutations were base substitutions, mostly G:C to T:A transversions. The spectrum of aflatoxin B1-induced mutations in the pS189 supF gene was very similar to that observed previously for the pS189 supF gene with aflatoxin B1 activated by cytochrome P450 1A2 (CYP1A2) synthesized from a cDNA expression vector within transfected Ad293 cells. However, the spectrum for pSP189, which carries the same supF gene as pS189, but with different surrounding sequences, exhibited some notable differences from that of pS189; this suggests that sequence context effects on mutagenic specificity can operate over distances of tens of base pairs.

Aflatoxin B1↗
PubMed1983

Mutation of Chinese Hamster V79 cells and transformation and mutation of mouse fibroblast C3H/10T1/2 clone 8 cells by aflatoxin B1 and four other furocoumarins isolated from two Nigerian medicinal plants.

Mutation by aflatoxin B1 (AFB1), imperatorin, marmesin, chalepin, and 8-methoxypsoralen (MOP), with and without black light (BL; long-wavelength ultraviolet light) activation, was determined at the hypoxanthine-guanine phosphoribosyltransferase locus (8-azaguanine resistance) in Chinese hamster V79 cells and at the ouabain locus in mouse C3H/1OT1/2 cells. Transformation by these furocoumarins under the same activation conditions was also investigated in C3H/1OT1/2 cells. In V79 cells, AFB1 induced a 4-fold maximum mutation frequency over controls under BL activation at a concentration of 5 micrograms/ml; marmesin induced a 2-fold increased mutation frequency at 1.5 micrograms/ml; MOP induced a 19-fold increase at 10 micrograms/ml; chalepin induced a 3-fold increase at 5 micrograms/ml; and imperatorin induced a 20-fold increase at 10 micrograms/ml. Essentially no mutation was observed at the ouabain-resistant (Ouar) locus in C3H/1OT1/2 cells with any of these compounds. In the transformation assays, type II and type III foci were observed at a 1-microgram/ml addition of AFB1 with or without BL activation; while with MOP and imperatorin, these types of foci were observed only with BL activation. Marmesin, although relatively more cytotoxic than the other furocoumarins studied, with a 50% lethal dose of less than 0.5 micrograms/ml, was not as mutagenic or potentially carcinogenic as were AFB1, imperatorin, or MOP with BL activation. These furocoumarins are considered to be involved in the etiology of the high incidence of skin cancer in Nigeria. Our experiments reinforce that concept and suggest that exposure to these furocoumarins may constitute a real carcinogenic hazard.

Aflatoxin B1↗
PubMed1986

Protection of mitochondrial genetic system against aflatoxin B1 binding in animals resistant to aflatoxicosis.

Administration of a single dose of aflatoxin B1 (AFB1) (6 mg/kg) to Sprague-Dawley rats results in a high level of modification of hepatic mitochondrial DNA (2.1 nmol of AFB1 adducts per mumol DNA-phosphate) and long-term inhibition of mitochondrial transcription and translation activities (N. Bhat et al., Cancer Res., 42: 1876-1880, 1982). Similar doses of AFB1 given to ICR mice and Syrian golden hamsters result in negligible to very low levels (0-06 nmol) of adducts in hepatic mitochondrial DNA. Intact mitochondria from rat liver can metabolize significant amounts of AFB1 (0.29 nmol/mg of protein) without externally added reduced nicotinamide adenine dinucleotide phosphate, and the metabolic activity is stimulated nearly 3-fold by Kreb's cycle intermediates (glutamate and malate), which support intramitochondrial reduced nicotinamide adenine dinucleotide phosphate production. Intact mitochondria from mice and hamsters, on the other hand, metabolize negligible or very low levels of AFB1 (0-0.1 nmol of AFB1 per mg of protein) even when intramitochondrial reduced nicotinamide adenine dinucleotide phosphate production is stimulated by the addition of Kreb's acids. Detergent-solubilized mitoplasts containing less than 1% microsome contamination from all three sources can catalyze the metabolic activation of AFB1 to electrophilic reactive forms as determined in an in vitro DNA binding assay at comparable levels (1.2-2.2 nmol of AFB1 bound per mumol of cytochrome P-450), suggesting that the low levels of AFB1 metabolism by intact mouse and hamster mitochondria and the relative resistance of macromolecular synthesis in these particles to added AFB1 may be due to mitochondrial membrane impermeability. In support of this possibility, AFB1 transported into mouse liver mitochondria through a liposome delivery system causes about 80% inhibition of protein synthesis.

Aflatoxin B1↗
PubMed1986

Influences of glutathione status on different cytocidal responses of monolayer rat hepatocytes exposed to aflatoxin B1 or acetaminophen.

In short-term primary monolayer cultures of rat hepatocytes, aflatoxin B1 (AFB1) causes a characteristic prelethal cytomorphological response in which peripheral attached cytoplasm contracts segmentally to form finger-like blebs. This response precedes lethal injury as detected by release of lactate dehydrogenase (LDH) into culture medium. We compared the influences of various modifiers of cellular glutathione (GSH) status on cytocidal responses of Fischer 344 rats hepatocytes exposed to AFB1 or acetaminophen (AAP), a hepatotoxin which does not produce segmental cytoplasmic contraction. N-Acetylcysteine (4 mM) reduced the degree of LDH release by AAP (4 to 16 mM) but was not protective against cell killing by AFB1, although it slightly reduced the percentage of hepatocytes with segmental cytoplasmic contraction at 6 hr. BCNU (1,3-bis(2-chloroethyl)-1-nitrosourea) at 40 microM markedly inhibited glutathione reductase and also strongly potentiated cell killing by AAP but did not significantly influence segmental cytoplasmic contraction or LDH release in response to AFB1. Diethylmaleate (40 to 160 microM), a depletor of hepatocellular GSH, and buthionine-D,L-sulfoximine (4 mM), an inhibitor of GSH synthesis, each did not alter hepatocyte killing by AFB1 but were strong potentiators of toxicity of AAP. AAP inhibited glutathione reductase but AFB1 did not. Total GSH concentrations at 6 and 18 hr were reduced by AAP and to a lesser extent by AFB1 in comparison with control cultures. These findings demonstrate that, in contrast to AAP toxicity, the characteristic mode of hepatocyte killing by AFB1 in monolayer cultures is substantially independent of induced alterations in GSH. These results indicate that GSH-dependent detoxification mechanisms do not play a major role in removing necrogenic metabolites of AFB1 in Fischer 344 rat hepatocytes. They further suggest that prelethal responses of AFB1-injured hepatocytes are not affected by GSH-dependent cytoprotective mechanisms.

Acetaminophen↗
PubMed1985

Effects of the irreversible ornithine decarboxylase inhibitor, alpha-difluoromethylornithine, aflatoxin B1, and choline deficiency on hepatocarcinogenesis.

Liver carcinogenesis was induced in rats by aflatoxin B1 (AFB1) enhanced by a choline-deficient diet. In Experiment 1, the ornithine decarboxylase inhibitor, alpha-difluoromethylornithine (DFMO), was administered by gavage to one group only during AFB1 administration; another group received DFMO during AFB1 administration and for 2 months after carcinogen administration. These two groups were compared to two control groups, one given AFB1 and fed the choline-deficient diet and another fed the deficient diet only. In a second experiment, DFMO was administered at a concentration of 2% in the water for 3 weeks and then at 1% for the remainder of the study. Rats from each group in Experiment 1 were killed at 2, 8, and 10 months after AFB1 administration and the development of tumors was followed by histology; autoradiography of [3H]thymidine incorporation into DNA; enzyme histochemistry; and alpha-fetoprotein determination. The group given DFMO during AFB1 administration was not significantly different from the AFB1-treated control group at 2 and 8 months after AFB1 administration. However, at 10 months following AFB1 and DFMO administration, the [3H]thymidine-labeling index and glucose-6-phosphatase staining were significantly increased. This group had three animals bearing hepatocellular carcinomas as compared to none in the controls. The group given DFMO for 2 months after AFB1 administration had a significantly depressed growth rate 2 months later, but this difference was not apparent after 8 months. After 10 months, there was a significantly increased [3H] thymidine-labeling index and increased volume fraction of gamma-glutamyltranspeptidase in the AFB1-DFMO-treated group as compared to the controls. DFMO appeared to inhibit growth under some conditions, but if administration was discontinued after AFB1 exposure, it appeared to enhance tumorigenesis. In Experiment 2, where a larger dose of AFB1 was used and DFMO was administered in the water from start to finish of the experiment, DFMO inhibited tumor induction and depressed the appearance of markers examined during carcinogenesis. These data indicate that the regimen used for DFMO administration can markedly affect tumor induction.

Aflatoxin B1↗
PubMed1976

Cecal coccidiosis in poultry as affected by prior exposure to aflatoxin B1.

Young New Hampshire and broiler chickens were given feed containing 2 concentrations of aflatoxin B1 (0.2 or 2.0 ppm). The larger concentration caused severe toxicosis and death in the New Hampshire chicks, but did not cause gross signs in the broiler chicks. However, temporary stunting was seen on both New Hampshire and broiler chicks during periods of aflatoxin feeding, along with persisting decreased weight gains in the broiler chicks; the latter apparently recovered during the next 21 days of feeding the starter ration. New Hampshire and broiler chicks which were given feed containing aflatoxin B1 at concentrations of 0.2 and 2.0 ppm for 28 days followed by a 21-day "recovery period" and which were not given a coccidiostat were more susceptible to severe cecal coccidiosis and had more persisting hepatic and cecal lesions than did chicks not given aflatoxin. The coccidiostat was protective against both cecal damage and losses in checks challenge exposed at 49 days of age to 100,000 infective Eimeria tenella oocysts.

Aflatoxins↗
PubMed1978

A diploid rat liver cell culture. IV. Malignant transformation by aflatoxin B1.

Chronic exposure of a cloned rat hepatocyte culture (RL-PR-C) to a subtoxic, sublethal dose of aflatoxin B1 resulted in malignant transformation. Continuous exposure to aflatoxin B1 caused increasing tumorigenic potential as tested by back injection into isogenic animals. Control cultures exhibited spontaneous transformation, although approximately 20 passages beyond the chemically induced event. Neither aflatoxin-treated nor control cultures exhibited cytopathological morphology, formation of cell foci, growth in soft agar, or irregular fibroblast-like growth patterns that could be specifically related to the onset of tumorigenic potential. In general, those parameters commonly used to monitor fibroblast cultures for transformation in vitro were not applicable for assessing the tumorigenic potential of these epithelial cells. Karyotypic analyses revealed no specific chromosomal aberrations associated with aflatoxin treatment; however, chromosomal instability was a property of the tumorigenic cell populations. Injection of both aflatoxin-treated and control cultures at passage 56 resulted in tumors indicative of both carcinoma and sarcoma indicating to us the multipotency of these epithelial cells transformed in vitro.

Aflatoxins↗
PubMed1999

The p53 tumor suppressor protein reduces point mutation frequency of a shuttle vector modified by the chemical mutagens (+/-)7, 8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene, aflatoxin B1 and meta-chloroperoxybenzoic acid.

p53 has been postulated to be the guardian of the genome. However, results supporting the prediction that point mutation frequencies are elevated in p53-deficient cells either have not been forthcoming or have been equivocal. To analyse the effect of p53 on point mutation frequency, we used the supF gene of the pYZ289 shuttle vector as a mutagenic target. pYZ289 was treated in vitro by ultraviolet irradiation, aflatoxin B1, (+/-)7,8-dihydroxy-9, 10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene and meta-chloroperoxybenzoic acid and then transfected into p53-deficient cells with or without a p53 expression vector. p53 reduced the mutant frequency up to fivefold when pYZ289 was treated with aflatoxin B1, (+/-)7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene or meta-chloroperoxybenzoic acid but not when it was ultraviolet-irradiated. The p53-dependent mutation frequency reduction was higher at a higher level of premutational lesions for aflatoxin B1 and (+/-)7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene and at a lower level of lesions for meta-chloroperoxybenzoic acid. This suggests that the chemical mutagens produce, in a dose-dependent fashion, two kinds of DNA damage, one subject to p53-dependent mutation frequency reduction and the other not. These results indicate that p53 can reduce the point mutation frequency in a shuttle vector treated by chemical mutagens and suggest that p53 can act as guardian of the genome for at least some kinds of point mutations.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1978

Thin layer chromatographic determination of aflatoxin B1 in eggs: collaborative study.

The thin layer chromatographic method of Trucksess et al. for aflatoxin B1 in eggs was collaboratively studied. Each collaborator analyzed 3 known practice samples and 9 unknown samples containing added aflatoxin B1 at 0, 0.05, 0.10, and 0.30 ng/g. For 9 collaborators, recoveries for the 3 positive levels were: 0--0.13 ng/g (average 98%, coefficient of variation (C.V.) 83%), 0.05--0.18 ng/g (average 102%, C.V. 36%, and 0.11--0.42 ng/g (average 93%, C.V. 31%), respectively. The method has been adopted as official first action.

Aflatoxins↗
PubMed1993

Exposure to aflatoxin B1 in animal-feed production plant workers.

The exposure to aflatoxin B1 (AFB) in animal-feed processing plants was assessed using binding of AFB to serum albumin. The albumin fraction was digested with pronase, and the digest was purified on a C18 Sepak column and an aflatest affinity column before quantification by ELISA. The level of detectability was 5 pg/mg albumin. The workers served as their own controls, as blood samples were taken upon return from vacation and after 4 weeks of work. A total of 7 of 45 samples were positive for AFB, with an estimated average daily intake of 64 ng AFB/kg body weight. The exposed workers had been disembarking cargos contaminated with AFB or working at places where the dust contained detectable amounts of AFB. The sera from the exposed workers had a significantly higher titer against an aflatoxin B1-epitope than a nonexposed Danish control group. The level of exposure could partly explain the increased risk of liver cancer in workers in the animal-feed processing industry.

Adult↗
PubMedDate not supplied

Influence of aflatoxin B1 on gas production by lactic acid bacteria.

The main characteristic of homofermentative lactic acid bacteria is that they do not produce gas from glucose and other sugars. However, in these experiments Lactobacillus casei, Lb. plantarum and Streptococcus lactis in broth media with glucose, galactose, lactose and sucrose, and aflatoxin B1 produces acid and also a significant amount of gas. In the control media without aflatoxin, these bacteria did not produce gas. The data suggest that lactic acid bacteria, known until now as homofermentative, become heterofermentative because of the influence of aflatoxin B1. The results of these investigations are of practical value because they may explain the defect of cheese "blowing," which can appear in Trapist cheese vacuum packed in foil. This type of unusual "blowing" occurs approximately one month after cheese manufacture. This defect can be characterized by very large holes and cracks inside the cheese. The flavor is similar to that of young cheese, which can be very undesirable for a ripened, Trapist, aged cheese.

Aflatoxin B1↗
PubMed1987

Aflatoxin B1-4-hydroxylase is associated with cytochrome P3-450 in C57BL/6 mouse liver.

Messenger RNA from the livers of Aroclor 1254 treated mice was used to produce a cDNA library. cDNA clones corresponding to cytochromes P1-450 and P3-450 were isolated from this library by screening with a probe for the rat cytochrome P-450c gene. Specific non-cross hybridizing probes for P1-450 and P3-450 were prepared from unique restriction fragments. The radiolabeled probes were hybridized to RNA from mice treated with a low (15 mg/kg) and high (150 mg/kg, 400 mg/kg) doses of beta-naphthoflavone. The low dose of beta-naphthoflavone was found to induce only P3-450 mRNA, whereas higher doses induced both P1-450 and P3-450 mRNA. Similarly, a low dose of beta-naphthoflavone induced aflatoxin B1-4-hydroxylase, whereas higher doses induced both aflatoxin B1-4-hydroxylase and aryl hydrocarbon hydroxylase activities. These results suggest that P3-450 mRNA codes for the cytochrome that is associated with aflatoxin B1-4-hydroxylase activity.

Animals↗
PubMedDate not supplied

Genotoxicity of aflatoxin B1 and its ammonium derivatives.

Aflatoxin (AF) B1 is a main contaminant in diverse agricultural products. In an attempt to reduce this problem and the hazards to human health, an AFB1 inactivating system with ammonia has been developed. In this work we evaluated the efficiency of the system in mice using micronucleus (MN) and sister chromatid exchange (SCE) analysis. Four groups of animals were fed for 8 weeks with a special diet mainly composed of maize: (1) uncontaminated; (2) uncontaminated/inactivated; (3) contaminated/inactivated; and (4) contaminated. We evaluated MN at weekly intervals in peripheral blood, and in weeks 4 and 8 SCE frequencies were quantified in bone marrow cells. The results shows that animals fed with AFB1 contaminated/inactivated maize had a 45% lower level of induced cytogenetic damage than those animals fed with AFB1 contaminated but not inactivated maize. A residual amount of AFB1 after the inactivating treatment and reconversion back to AFB1 in the organism may account for the remaining increased levels of SCE and MN.

Aflatoxin B1↗
PubMed1984

Metabolism, DNA binding, and cytotoxicity of aflatoxin B1 in tracheal explants from Syrian hamster.

Metabolism, DNA binding and cytopathological effects of aflatoxin B1 (AFB1) were studied in isolated tracheal explants from Syrian golden hamsters. Explants were exposed to 0.1, 0.5 and 1.0 microM [14C]AFB1 in Dulbeccos's modified Eagle medium for 24 h, then analyzed for AFB1-DNA binding and AFB1 metabolism. Binding (pmol AFB1/mg DNA) was dose-related (16.3 +/- 1.9 to 180.8 +/- 16.1) and analysis of the culture medium revealed the metabolic conversion products aflatoxicol (AFL) and aflatoxin Q1 (AFQ1). Ultrastructural analysis of sections of tracheal epithelium revealed degenerative changes primarily in the non-ciliated epithelial cells. Autoradiographic analysis of the same treated explants, however, showed no discernible distribution of label with respect to either cell type or cell location, with the exception of increased grain densities overlying vacuoles containing dark droplets. In addition, S9 prepared from hamster trachea was shown to activate AFB1 to mutagens detectable by Salmonella typhimurium TA 98, but was approximately 70 times less active on a per mg protein basis than was S9 prepared from hamster liver. These results demonstrate the metabolic capabilities of tracheal epithelial cells in the activation of AFB1, thus indicating that AFB1 present in respiratory particles may be activated by pulmonary mixed-function oxidases, posing a hazard to those exposed.

Aflatoxin B1↗