Mycotoxin research in South Africa.
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Aflatoxins↗
Biomedical subjects
M F Dutton
Publications and source records attributed to M F Dutton.
Antibodies to oxidised low-density lipoproteins and cardiolipin in pre-eclampsia and eclampsia.
The objective of this study was to test the hypothesis that autoantibodies to phospholipids and to oxidised low-density lipoprotein (ox-LDL) are increased in pre-eclamptic and eclamptic women compared with normal pregnancy. Serum concentrations of autoantibodies to ox-LDL and to cardiolipin were measured in 21 non-pregnant controls, 29 pregnant controls, 21 pre-eclamptic and six eclamptic women. Concentrations of IgG antibodies to ox-LDL and to cardiolipin were not significantly different in women with eclampsia as compared with the non-pregnant controls, pregnant controls and pre-eclampsia. Concentrations of IgM antibodies to cardiolipin were significantly lower in women with pre-eclampsia compared with non-pregnant controls and eclampsia. All three pregnant states differ markedly from the non-pregnant controls, of whom only 5% (1 of 21) had "high positive" IgG antibodies. These results suggest that ACAs rise as a result of the pregnant state rather than as a result of preeclampsia or eclampsia. According to these results, there is no evidence of increased production of serum autoantibodies against modified LDL in African women with pre-eclampsia, which may reflect reduced lipid peroxidation involving lipoproteins or no link at all. In addition, IgG and IgM anticardiolipin antibodies have no diagnostic value in preeclampsia and eclampsia.
Adolescent↗
Cytotoxicity of aflatoxin B1 and its chemically synthesised epoxide derivative on the A549 human epithelioid lung cell line.
Aflatoxin B1 (AFB1 ) is a carcinogenic mycotoxin found in feeds and in airborne grain dusts. Aflatoxin B1 requires biotransformation to the AFB1-8,9 epoxide (AFBO) by a bioactivation system and subsequent covalent binding to DNA or proteins, to exert its carcinogenic potential. The lung contains cytochrome P450, prostaglandin-H-synthase, lipoxygenase, epoxide hydrolase and other bioactivation enzymes, and is thus a potential target for the effects of AFB1 via the routes of inhalation and ingestion. The A549 human epithelioid lung cell line and the methylthiazol tetrazolium (MTT) bioassay were used to investigate the cytotoxicity of AFB1 and its chemically synthesised epoxide (AFBO) in vitro. Statistical analysis of the MTT results indicated that there were overall significant differences between the control and both the AFB1-treated (p < 0.0001) and AFBO-treated cells (p = 0.002). However, there was no significant difference between AFB1 and AFBO-treated cells, when the entire range of concentrations were assessed against each other (p = 0.2877). When analysed at each concentration, only at 0.01 mM was there a significant difference between the effects of AFB1 and AFBO (p = 0.0358). The results of this investigation show that AFB1 and AFBO are both cytotoxic in the A549 cell line.
Aflatoxin B1↗
Oxidative stress in pre-eclampsia.
BACKGROUND: The objective of this study was to test the hypothesis that maternal plasma, cord plasma and placental tissue lipid peroxidation products are increased and antioxidants are decreased in women with pre-eclampsia. METHODS: Placenta, maternal and cord plasma were collected at delivery from 29 normal, 21 pre-eclamptic and six eclamptic women. Plasma was collected from 21 non-pregnant matched controls. The analyses were measured by HPLC and colorimetric assay. RESULTS: Plasma maternal concentrations of uric acid, LPO, MDA, ascorbic acid, vitamin E and cholesterol were not significantly different in pre-eclampsia as compared with normal pregnancy. Plasma concentrations of ascorbic acid and vitamin E were not significantly different in normal pregnancy as compared with the non-pregnant controls. Cord plasma concentrations of MDA were significantly higher in eclampsia (1.16+/-0.26 micromol/l) as compared with normal pregnancy (0.79+/-0.05 micromol/l, p<0.02) and pre-eclampsia (0.83+/-0.05 micromol/l, p<0.05). Cord plasma concentrations of vitamin E were significantly higher in eclampsia (21.3+/-7.5 micromol/l) as compared with normal pregnancy (10.2+/-1.1 micromol/l, p<0.01) and pre-eclampsia (10.4+/-1.8 micromol/l, p<0.04). Placental concentrations of LPO, MDA and ascorbic acid were not significantly different in pre-eclampsia as compared with normal pregnancy. Plasma cord concentrations of LPO and placental concentrations of vitamin E were undetected for normal pregnant, pre-eclamptic and eclamptic women respectively. Uric acid concentrations were significantly increased in eclampsia as compared with the non-pregnant controls (p<0.0001), normal pregnant controls (p<0.0001) and pre-eclampsia (p<0.008). CONCLUSIONS: The findings in this study do not show any evidence of deficiency in the maternal protective antioxidant systems or increased production of lipid peroxidation products, LPO and MDA in African women with pre-eclampsia as compared with normal pregnancy. However, there was evidence of increased cord plasma concentrations of MDA and vitamin E in eclampsia as compared with normal pregnancy and pre-eclampsia. The placenta may be effective in removing MDA. The antioxidant uric acid serves as a protective role whilst the antioxidant and oxidant capacity in the different study groups remained unchanged.
Adolescent↗
Systemic inflammatory indices in pre-eclampsia and eclampsia.
The objective of this study was to test the hypothesis that TNF-alpha, TNFp55 receptor and sICAM-1 are markers of immune activation, protective response to concentrations of TNF-alpha and endothelial cell activation, respectively, in pre-eclampsia. In addition, MPO and sL-selectin were selected as blood discriminators of neutrophil activation. This was a cross-sectional study comparing 21 non-pregnant controls, 29 normal pregnant controls, 21 pre-eclamptic and six eclamptic women. Blood concentrations of TNF-alpha, sTNFp55 receptor, sICAM-1, sL-selectin, myeloperoxidase, leucocyte count, neutrophil count, C-reactive protein and gamma-glutamyl transferase were estimated. The neutrophil count was significantly decreased in pre-eclampsia compared with normal pregnancy (9.12+/-0.95 vs. 12.52+/-0.80 x 10(9)/l, P<0.01). Serum concentrations of sL-selectin were significantly higher in non-pregnant controls compared with pregnant controls (P<0.0001), pre-eclampsia (P<0.0001) and eclampsia (P<0.0001). Serum concentrations of TNF-alpha, sTNFp55 receptor, sICAM-1, sL-selectin and MPO were not significantly different in women with pre-eclampsia compared with normal pregnancy. Serum concentrations of TNF-alpha, sTNFp55, sICAM-1, sL-selectin and MPO did not discriminate between normal and pre-eclamptic pregnancies. The high neutrophil count in normal and eclamptic pregnancies and the lack of shedded L-selectin suggests that neutrophil exudation to inflammatory sites was increased in women with an accompanying inflammatory response.
Journal Article↗
Fumonisin B1: an aetiological role in pre-eclampsia.
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Journal Article↗
Exposure of rural and urban populations in KwaZulu Natal, South Africa, to fumonisin B(1) in maize.
We surveyed households in rural and urban areas of KwaZulu Natal, South Africa, to assess the exposure of the inhabitants to fumonisin B(1) (FB(1)), a mycotoxin produced by Fusarium verticillioides. In southern African regions maize, used as a staple food by the population, is prone to F. verticillioides infection. Furthermore, high levels of FB(1) in maize have been associated with esophageal cancer in South Africa. We assessed exposure of the population to FB(1) at three levels, namely, by analyzing stored maize, plate-ready food, and feces. The positions of participating households in the rural area were recorded using geographic information systems (GIS) for ease and accuracy of follow-up. Of the 50 rural maize samples examined, 32% had levels of FB(1) ranging from 0.1-22.2 mg/kg, whereas 29% of the 28 cooked maize (phutu) samples contained FB(1) ranging from 0.1-0.4 mg/kg. The incidence and levels of FB(1) in feces were 33% and 0.5-39.0 mg/kg, respectively. Of the 49 urban maize samples analyzed 6.1% had a range of 0.2-0.5 mg/kg FB(1), whereas 3 of 44 fecal samples (6%) ranged between 0.6 and 16.2 mg/kg. No FB(1) was detected in urban phutu samples. Because these levels are lower than those published from regions in South Africa with high incidence of esophageal cancer, it may be concluded that the risk of esophageal cancer from FB(1) exposure is lower in the KwaZulu Natal region.
Carboxylic Acids↗
Analytical method for the determination of sphinganine and sphingosine in serum as a potential biomarker for fumonisin exposure.
The toxins produced by Fusarium moniliforme, which include fumonisins, are possible human carcinogens. Fumonisins are inhibitors of de novo sphingolipid biosynthesis. Alterations of the ratio of sphinganine (Sa) to sphingosine (So) in urine and serum has been proposed as a possible biomarker of exposure to this toxin. A new method was developed for their analysis in tissues and urine. This work describes the further adaptation of the method to the analysis of Sa and So in serum and its validation in sera of untreated and fumonisin B1 (FB1 ) treated rats and mice. No significant differences in the Sa/So ratios were observed in the FB1 treated rats. In mice, the increase was only of marginal statistical significance. Determination of Sa/So ratios in human sera could readily be made in small volumes (from 0.3 to 0.5 ml) of serum.
Animals↗
The response of the dietary anti-oxidants vitamin E and vitamin C to oxidative stress in pre-eclampsia.
The relationship of oxidants and anti-oxidants in preeclampsia with reference to the dietary anti-oxidants vitamin C and vitamin E was investigated. Three groups of patients were studied in the third trimester of pregnancy: normotensives ( n = 32), mild pre-eclamptics ( n = 15) and severe pre-eclamptics ( n = 31) with a group of healthy non-pregnant women ( n = 18) serving as a control. Total anti-oxidant concentration, the concentrations of vitamin C, vitamin E, superoxide dismutase, uric acid and the concentration of total oxidant activity, as reflected by lipid peroxides, were measured in plasma or red blood cells. Total anti-oxidants and vitamin C concentrations were significantly lower in pre-eclamptic patients than in pregnant controls (P < 0.05), with the concentrations in the pregnant controls being significantly lower than in the non-pregnant controls (P < 0.05). There was no significant difference in vitamin E concentration for all four groups. Superoxide dismutase activity was significantly lower in the normal pregnancy group. Lipid peroxides were significantly increased in the three pregnant groups (P < 0.05) with no differences noted between these groups. The relationship of oxidants to anti-oxidants in pregnancy and pre-eclampsia is dependent on many factors but balance appears to be upset in pre-eclampsia. The reduction in anti-oxidant concentrations in pre-eclampsia suggests either a primary deficit or consumption of the anti-oxidants measured. Of the dietary anti-oxidants studied, vitamin C was most affected in pre-eclampsia.
Journal Article↗
Fumonisins, mycotoxins of increasing importance: their nature and their effects.
The fumonisins (FBs) are a group of closely related mycotoxins that are prevalent in maize. They were isolated from strains of Fusarium moniliforme (Sheldon), which were implicated in the aetiology of human oesophageal cancer in the Transkei, South Africa. Their discovery explained the cause of equine encephalomalacia, or "hole in the head" syndrome, when it was found by feeding trials in horses that they elicited the disease. Subsequently, they were found to cause hepatic cancer in rats and pulmonary oedema in pigs, with most animal species tested showing liver and kidney damage. FB1 is the most important of the group and, although poorly absorbed from the gastrointestinal tract, its action is at the cellular level, affecting sphingolipid metabolism. Ceramides derived from sphingosine metabolism are cell regulatory factors affecting, among other things, DNA synthesis. Because FB1 has a close molecular resemblance to sphinganine, it interferes with ceramide biosynthesis and, hence, the processes that it regulates, which is thought to explain its carcinogenic properties. Studies on the FBs are still at a relatively early stage, but it is already clear that they play an important role in animal mycotoxicoses and, by implication, in human disease. A more positive aspect is that they will be used in elucidating the role of sphingolipids in cellular regulation.
Animal Diseases↗
Occurrence of mycotoxins in cereals and animal feedstuffs in Natal, South Africa 1994.
During the year of 1994, 417 samples of agricultural commodities, comprising: maize, compound animal feeds, oil seeds, soya bean, fish meal and forage were examined for fungi and over 20 mycotoxins using a multi-screen augmented with individual assays. Trichothecenes had the highest incidence of over 19% in all samples received, followed by aflatoxin at 6% and then zearalenone at 3%. Selected samples (73) were analyzed for fumonisin B1 and of these, 69 (94%) were found to be positive. Because of this result and high incidence of Fusarium spp. (over 70%) in maize and maize containing feeds, which was higher than either Aspergillus spp. (19%) or Penicillium spp. (33%), attention is drawn to the actual and potential presence of fumonisin in the food chain.
Animal Feed↗
Cellular interactions and metabolism of aflatoxin: an update.
The aflatoxins are a group of closely related mycotoxins that are widely distributed in nature. The most important of the group is aflatoxin B1 (AFB1), which has a range of biological activities, including acute toxicity, teratogenicity, mutagenicity and carcinogenicity. In order for AFB1 to exert its effects, it must be converted to its reactive epoxide by the action of the mixed function mono-oxygenase enzyme systems (cytochrome P450-dependent) in the tissues (in particular, the liver) of the affected animal. This epoxide is highly reactive and can form derivatives with several cellular macromolecules, including DNA, RNA and protein. Cytochrome P450 enzymes may additionally catalyse the hydroxylation (to AFQ1 and AFM1) and demethylation (to AFP1) of the parent AFB1 molecule, resulting in products less toxic than AFB1. Conjugation of AFB1 to glutathione (mediated by glutathione S-transferase) and its subsequent excretion is regarded as an important detoxification pathway in animals. Resistance to AFB1 toxicity has been interpreted in terms of levels and activities of these detoxifying pathways. This article reviews the multiple reactions and effects attributed to aflatoxin, with particular reference to the interaction of aflatoxin with nucleic acids and proteins, and the contribution this mycotoxin has in disease development and in the promotion of hepatocellular carcinoma (HCC). The anti-mutagenic properties of several dietary factors are also considered in this article. Undoubtedly, the most important aspect of aflatoxin action is its putative role in the development of human cancer, in particular, HCC. Recently, there has been a renewed interest in this aspect and experimental evidence is rapidly accumulating at the molecular level, indicating aflatoxin as an important consideration in the aetiology of human HCC.
Abnormalities, Drug-Induced↗
Aflatoxins and kwashiorkor in Durban, South Africa.
The present investigation has indicated that maize seeds stored under various simulated seasonal conditions show a spectrum of fungi that appear as a succession. The aflatoxin-producing fungus, Aspergillus flavus, is favoured by storage conditions of high temperature and humidity (summer and autumn seasons). This coincides with the more frequent admission of children suffering from kwashiorkor at King Edward VIII Hospital in Durban. Aflatoxin analysis was undertaken on 74 children diagnosed at King Edward VIII Hospital in Durban as cases of kwashiorkor, marasmus or underweight (Wellcome classification). The control group consisted of 35 age-matched patients with no symptoms of protein energy malnutrition. Aflatoxins were detected in serum and/or urine from all groups, including the controls. The serum/urine ratio was significantly higher in the kwashiorkor group than in the other groups. The control group, however, had a higher proportion of urine aflatoxins than the kwashiorkor group. These findings were interpreted in terms of impaired liver function in kwashiorkor. Aflatoxins may have a rôle in the pathogenesis of kwashiorkor, although the present findings do not indicate that they are a causal factor.
Aflatoxins↗
Metabolism of aflatoxin B1 by Petroselinum crispum (parsley).
On administration of aflatoxin B1 to whole parsley (Petroselinum crispum) plants, a derivative was formed, which was shown to be aflatoxicol by its chromatographic properties and mass spectrometry. Optimum conditions for the production of the derivative was on the second day after administration of the toxin to the plants, which were 90 days old after germination. Cell-free preparations of parsley were found not to produce aflatoxicol A from added aflatoxin B1; instead they formed two new derivatives, which from chromatographic properties, were shown to be more polar than either aflatoxin B1 or aflatoxicol A.
Aflatoxin B1↗
The isolation of a storage organelle of atractyloside in Callilepis laureola.
A method has been developed for the preparation of protoplasts from both the leaves and tubers of Callilepis laureola, a plant used extensively as a medicament by black people in South Africa. The cellular vacuoles from these protoplasts were isolated and tested for the presence of the nephrotoxic substance, atractyloside, by thin layer chromatography and immunoassay. Both methods indicate that the vacuole of C. laureola is the primary site of storage for atractyloside in the cells of the tuber.
Atractyloside↗
The inappropriate use of traditional medicines in South Africa.
Traditional medicines are culturally very important to the Zulu population of Southern Africa. The inappropriate use of herbs has however, resulted in numerous fatalities, invariably in children. This paper briefly summarises the belief of the Zulu population in traditional remedies, together with an outline of the problems at present being experienced in South Africa. A further note on the personal impressions and experiences of the authors and description of one such toxic herbal remedy, including use, toxic action and research carried out to date, are also given.
Child↗
The affinity purification and characterization of a dehydrogenase from Aspergillus parasiticus involved in aflatoxin B1 biosynthesis.
A two step scheme has been developed for the purification of a dehydrogenase from mycelia of 84 hours old Aspergillus parasiticus (1-11-105 Wh 1), which catalyzes the conversion of norsolorinic acid (NA) to averantin (AVN). The dehydrogenase was purified from cell-free extracts using reactive green 19-agarose and norsolorinic acid-agarose affinity chromatography. The latter affinity matrix was synthesised by attaching norsolorinic acid to omega-aminohexylagarose. The purified protein was shown to be homogenous on non-denaturing polyacrylamide gel electrophoresis. A final purification of 215-fold was achieved. Results of gel filtration chromatography indicated the approximate molecular mass of the native protein to be 140,000 daltons. The isoelectric point of the protein was about 5.5 as determined by chromatofocusing. The reaction catalyzed by the dehydrogenase was optimum at pH 8.5 and between 25 degrees to 35 degrees C. The Km of the enzyme for NA and NADPH was determined to be 3.45 microM and 103 microM respectively.
Aflatoxin B1↗
The preparation of an enzyme associated with aflatoxin biosynthesis by affinity chromatography.
An affinity matrix for the purification of norsolorinic acid dehydrogenase, an enzyme involved in aflatoxin biosynthesis, was prepared by coupling norsolorinic acid to an agarose gel. This matrix was found to be ineffective in isolating active enzyme, and was therefore modified by methylation, using diazomethane. The methylated matrix produced a one-step purification of the enzyme from a crude homogenate, resulting in a 138-fold purification. The active isolate was found to contain one major and two minor bands upon nondenaturing electrophoresis, and all the norsolorinic acid dehydrogenase activity was associated with the major band. It was concluded that the matrix exhibited true affinity for the enzyme, and that affinity chromatography was a valuable approach to isolating other secondary metabolic enzymes involved in the biosynthesis of the aflatoxins.
Aflatoxins↗