C. J. Mirocha
University of Minnesota
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Toxicon | 2001
W.T. Shier; A.C. Shier; W. Xie; C. J. Mirocha
Zearalenones are estrogenic Fusarium mycotoxins consisting of a resorcinol moiety fused to a 14-member macrocyclic lactone. Using an improved MCF7 human breast cell proliferation assay, we have compared the estrogenicity of 17 chromatographically-homogeneous zearalenones. Both similarities and substantial differences from published results in intact animal systems were observed. Substantial human estrogenicity was retained even in analogs lacking hydroxylation on the aromatic and macrocyclic rings.
Mycopathologia | 1991
W. T. Shier; Hamed K. Abbas; C. J. Mirocha
Fumonisins B1 and B2 and AAL toxin are a series of structurally related mycotoxins. Fumonisins B1 and B2, produced by Fusarium moniliforme Sheldon induce toxic hepatitis and hepatomas in rats and leukoencephalomalacia in horses. The cancer-promotion assay which has been used to guide their purification is slow and consumes large amounts of sample. We have examined a series of cultured mammalian cell lines in order to develop a more rapid and sensitive bioassay system, which may be useful for examining structure-activity relationships and the mechanism(s) of action of these toxins. Of 9 rat hepatoma cell lines tested, all except the two most de-differentiated lines were sensitive to the three toxins, with a toxic response visible by 48 h. Approximate IC50 values for the most sensitive hepatoma line, H4TG, were 4, 2 and 10 μg/ml for fumonisins B1, B2 and AAL toxin, respectively „in 100 μl cultures. Among 15 cell lines from other sources, only MDCK dog kidney epithelial cells were sensitive (IC50 = 2.5, 2 and 5 μg/ml, respectively). Studies in co-cultures of sensitive and insensitive cell lines and in cultures of a sensitive cell line over a range of cell densities indicated that cytotoxicity of fumonisins B1 and B2 does not involve metabolite activation to a derivative stable enough to diffuse to adjacent cells.
Food and Cosmetics Toxicology | 1981
T. Yoshizawa; C. J. Mirocha; J C Behrens; S.P. Swanson
Abstract Excretion, transmission and metabolism of T-2 toxin, a trichothecene mycotoxin produced by Fusarium species, was studied in a lactating Jersey cow. After daily oral administration of unlabelled T-2 toxin by capsule for 3 consecutive days, tritium-labelled T-2 toxin was administered orally on day 4. Maximum levels of radioactivity in excreta and plasma were reached at the following times after dosing (with the concentration, expressed as T-2 toxin, in parenthesis): faeces at 44 hr (9·2 ppm), urine at 16 hr (5·5 ppm), milk at 16 hr (37 ppb) and plasma at 8 hr (64 ppb). By 72 hr almost all of the radioactivity had been eliminated in the urine and faeces, in a ratio of 3:7 respectively, and 0·2% of the dose given to the cow had been transmitted into the milk. Insignificant accumulation of the toxin in specific organs was observed. Chromatographic analyses of the tritium residues in cow tissues and excreta revealed that T-2 toxin was rapidly metabolized, yielding principally three major unknown metabolites (designated TC-1, TC-3 and TC-6) in addition to very polar metabolite(s) designated TC-8. Within the first 24 hr, the three major metabolites accounted for 30–40% of the extractable radioactivity in urine, 60–70% in milk and 50–60% in plasma. Minor amounts of unmetabolized T-2 toxin and of the metabolites HT-2 toxin, neosolaniol, and 4-deacetylneosolaniol were also detected in the cow.
Mycopathologia | 1992
C. J. Mirocha; David G. Gilchrist; W. T. Shier; Hamed K. Abbas; Yechun Wen; Ronald F. Vesonder
The AAL toxins and the fumonisins (FB1 and FB2) are structurally related and produced respectively by Alternaria alternata f.sp. lycopersici and Fusarium moniliforme. AAL toxin is characterized as a hostspecific toxin, toxic to tomato, whereas fumonisin B1 causes equine leukoencephalomalacia. FB1 and FB2 were biologically active in susceptible tomato tissue (Earlypak-7) and animal tissue culture (rat hepatoma H4TG and dog kidney MDCK). Conversely, AAL toxin was also active in the rat and dog tissue culture cells. Both fungi produce toxin/s in culture that cause death in rats; these toxins are other than AAL and fumonisin. The peracetylated derivatives of AAL and FB1 are biologically inactive in both the tomato bioassay and the animal tissue culture systems. Acetylation of the amine renders AAL inactive. The hydrolysis product of AAL (pentolamine) is toxic to the susceptible tomato line whereas the pentolamine of fumonisin is not.AAL and FB1 can be analyzed by Continuous Flow Fast Atom Bombardment (CFFAB) and Ionspray Mass Spectrometry (ISM), both sensitive to the picomole range. The N-acetyl of the TFA hydrolysis product of AAL and FB1 is determined by comparing the fragment ions at m/z 86 and 140 for FB1 and 72 and 126 for AAL.
Toxicological Sciences | 1984
Sharon A. Watson; C. J. Mirocha; A. W. Hayes
In 1974, the U.S. Government began to receive sporadic reports of chemical warfare attacks in Laos. By 1976, the reports had become regular and each succeeding year showed steady increases in the number of chemical attacks. The attacks are still continuing. Much of the chemical warfare activity in Laos centers around the areas that are highlighted in Fig. 1 (Haig, 1982). Most of these attacks have been directed against H’Mong villages. The villages attacked have usually been centers of resistance activity. The attacks in Laos have been almost exclusively air attacks with the chemical agents delivered by aircraft or helicopter spray, bombs, and air-to-surface rockets. Between 1975 and December 198 1, 260 separate chemical attacks were documented in Laos, resulting in at least 6500 fatalities. Reports of chemical warfare activity in Kampuchea began in 1978 and rapidly increased with the Vietnamese invasion of this country. During the time period from 1978 to December 198 1, 124 separate attacks were reported in which lethal chemicals caused the death of more than 1000 individuals. Although the earliest reports cite attacks in the northeast comer of the country, from 1979 on, the attacks have occurred in the western provinces
Mycopathologia | 1994
C. J. Mirocha; Weiping Xie; Yichun Xu; Roy D. Wilcoxson; R. P. Woodward; R. H. Etebarian; G. Behele
Wheat cultivars (Stoa, MN87150, SuMai-3, YMI-6, Wheaton) and barley cultivars (Robust, Excel, Chevron, M69) were inoculated in the field with isolates ofFusarium graminearum andF. culmorum. The diseased (Fusarium head blight) kernels were analyzed for deoxynivalenol (DON), 15-acetyldeoxynivalenol (15-ADON) and nivalenol (NIV).F. culmorum produced all three trichothecenes on all cultivars tested whereasF. graminearum only produced DON and 15-ADON. There was no well defined correlation between DON production in the host and resistance although the data tended to favor SuMai-3 as having definitive resistance to bothF. graminearum andF. culmorum.
Toxicology and Applied Pharmacology | 1978
M. S. Chi; T.S. Robison; C. J. Mirocha; S.P. Swanson; W. Shimoda
Abstract The excretion and distribution of radioactivity in 6-week-old broiler chicks intubated with a single dose of 3- 3 H-labeled T-2 toxin were investigated during the 48-h period after dosing. Chicks excreted 6.7, 20.7, 42.1, 60.5,and 81.6% of the recovered radioactivity at 4, 8, 12, 24, and 48 h, respectively. The gastrointestinal (GI) tract contained 88.8, 74.0, 63.3, 38.0, 26.9, and 10.4% of the recovered radioactivity at 0.5, 4, 8, 12, 24 and 48 hr, respectively. The abdominal fat and heart contained the least amount of radioactivity among those tissues analyzed. The radioactivity from 3 H-labeled T-2 toxin reached a maximum concentration 4 hr after dosing in most tissues except for the muscle, skin, and bile; in the latter tissues, the maximum radioactivity was attained at 12 hr. The specific radioactivities (disintegrations per minute per milligram of tissue) of the blood, muscle, skin, and heart were similar throughout the 48 hr period. The bile, including the gall bladder, contained the highest specific radioactivity among organs and tissues (except GI tract) during the 48 hr period. The edible portions of the carcass contained 0.06 and 0.04 ppm of T-2 or its metabolites at 24 and 48 hr, respectively after dosing with 0.5 mg of T-2/kg body weight. The patterns of distribution and excretion suggest that T-2 toxin and/or its metabolites are excreted into the intestine through the bile and that the liver is a major organ for excretion of the toxin.
Mycopathologia | 1992
David G. Gilchrist; Barney Ward; Vasiliana Moussato; C. J. Mirocha
The differential phytotoxicity of purified AAL-toxin to lines of tomato isogenic for the Asc gene parallels resistance to Alternaria alternata f.sp. lycopersici. This relationship, as reported earlier, is consistent with the role of AAL-toxin as a host-specific toxin with the role of a primary chemical determinant of Alternaria stem canker. Current results indicate the pathogen and the AAL-toxin also can be recovered from ripe fruit with symptoms of the disease known as black mold. Fumonisins are structurally similar to the AAL-toxins but are secreted by Fusarium moniliforme which is taxonomically distinct from A. alternata. F. moniliforme, is not pathogenic on living tomato tissues but was recovered from ripe tomato fruit with symptoms of black mold. The penetration of ripe fruit and subsequent colonization by both fungi appears to be saprophytic. Fumonisins and AAL-toxins express equivalent genotype-specific activity against the isogenic Asc lines of tomato and produce equivalent necrotic symptoms in tomato leaflet bioassays. Evidence was obtained that the biosynthetic pathway for production of these toxins is present in several species of both Alternaria and Fusarium. Toxin biosynthesis was sensitive to nutritional regulation in both genera. However, pathogenicity on tomato was not altered by the medium used for inoculum production in either genera and remained restricted to A. alternata f.sp. lycopersici in the studies reported here. Differences in the amount of toxin produced were found among isolates of both genera while the magnitude of the differences was defined by the substrate on which the fungi were grown.
Mycopathologia | 1992
Douglas L. Park; Sam M. Rua; C. J. Mirocha; El Sayed A. M. Abd-Alla; Cong Ying Weng
Naturally contaminated corn implicated in an outbreak of equine leukoencephalomalacia (ELEM) in southeastern Arizona was analyzed for mutagenic potential using the Salmonella/microsome mutagenicity assay before and after treatment with the ammonia procedure. Crude acetonitrile: water (1+1) extracts of high-pressure/ambient temperature (HP/AT) ammonia decontaminated, HP/AT plus low pressure/high temperature (LP/HT), and non-ammoniated fumonisin contaminated corn were tested for mutagenic potentials. Relatively pure (approx. 90%) fumonisin B1 standard was also tested for comparison purposes. The results of this experiment indicate that there was no mutagenic potential for the fumonisin B1 standard at the concentrations tested (100 μg/plate). Also, neither the naturally-contaminated corn nor the ammonia decontaminated samples elicited a positive mutagenic response. Fumonisin B1 levels, as determined by HPLC methods, were reduced by an average of 79% via the ammonia decontamination process. It is encouraging to note that, while further work is necessary to increase the efficacy of the ammonia process to reduce fumonisin levels, the ammonia process did reduce fumonisin levels and no mutagenic potentials were apparent in the treated corn.
Mycopathologia | 1989
U. Bosch; C. J. Mirocha; Hamed K. Abbas; M.E. di Menna
Sixty-two isolates of Fusarium were obtained from pasture grass and soil from various areas of New Zealand and identified as F. anthophilum [2], F. avenaceum [17], F. crookwellense [8], F. culmorum [4], F. graminearum [1], F. nivale [3], F. oxysporum [3], F. sambucinum [17], F. semitectum [1], F. tricinctum [1] and an unidentified Fusarium spp. [5]. These isolates were grown on autoclaved rice and tested for toxicity to rats in feeding tests. Eighty two percent of the isolates were toxic, of which twenty-four percent were severely toxic and caused hemorrhages of stomach and intestine, hematuria, and finally death. Cultures of the most toxic isolates contained 0.1 to 104 ppm of deoxynivalenol, 0.7 and 7 ppm of 15- and 3-acetyldeoxynivalenol respectively, 0.2 to 4 ppm of fusarenon- X, 11 to 1021 ppm zearalenone, 40 to 272 ppm of the hemorrhagic factor (wortmannin), 2,100 to 7,200 ppm of moniliformin, 565 ppm of the cytotoxic factor (HM-8) and enniatin in substantial concentrations. F. sambucinum is reported as a moniliformin producer for the first time.