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Biomedical subjects

J W Dorner

Publications and source records attributed to J W Dorner.

At least 37 records · Page 2Linked to original sources
PubMed1985

Distribution, excretion and skeletal muscle effects of the mycotoxin [14C]cyclopiazonic acid in rats.

The distribution of the mycotoxin, cyclopiazonic acid (CPA), in tissues and its excretion in urine and faeces was studied in male Sprague-Dawley rats. Radiolabelled CPA was biosynthetically produced by cultures of Penicillium griseofulvum and was administered to rats either intraperitoneally (ip) or intragastrically (ig). Radiolabelled material was excreted in both urine and faeces from rats dosed by either route. There was no excretion of radioactivity as expired 14CO2. Biliary excretion apparently had a major role in the disposition of CPA, since 38% of the dose of radioactivity was excreted in the faeces of ip-dosed rats within 72 hr. Skeletal muscle tissue contained 48% of the radioactive dose 6 hr after either ip or ig administration. At 72 hr, skeletal muscle of the ip-dosed rats contained 3% of the dose, whereas rats dosed ig retained 8% of the dose in muscle. Degeneration was observed in muscle from rats treated with 8 mg CPA/kg/day for 4 days. The results indicate that some of the toxic effects observed in animals exposed to CPA (hyperaesthesia, hypokinesis, abnormal posture, opisthotonos and convulsions) may be due in part to direct effects of the toxin on muscle. Furthermore, if CPA or its metabolic products distributes in the tissues of other animals as it does in the rat, the potential exists for the exposure of humans to this mycotoxin by consumption of the meat of domestic animals fed contaminated feed.

Animals↗
PubMed1985

Toxicity and neuropharmacology of cyclopiazonic acid.

Cyclopiazonic acid (CPA) was found to have many pharmacological properties in common with the antipsychotic drugs chlorpromazine and reserpine. Thus, in mice CPA at ip doses of 5-14 mg/kg body weight produced hypokinesia, hypothermia, catalepsy, ptosis, sedation without loss of righting reflex, tremor, gait disturbance, dyspnoea, opisthotonus, atypical convulsion and prolonged barbiturate-induced sleep. The ip LD50 of CPA was found to be 13 +/- 0.05 mg/kg. The tremors induced by near-lethal doses of CPA were associated with voluntary or forced movements (action tremors); they worsened during the days following treatment, but they were weak compared with the exhausting and continuous tremors of the whole body caused by 20 mg tremorine/kg (used for comparison). When death occurred only 24-259 min after administration of CPA (11-14 mg/kg), it was preceded by dypsnoea, cyanosis, opisthotonus and clonic leg movements and tonic extension of hind legs (convulsions). When death was delayed (2-6 days after CPA administration), it was preceded by prostration, ptosis, hypothermia, tremor and cessation of food and water intake resulting in cachexia; convulsions were not seen in this group of mice. CPA did not affect the rate of convulsion or death caused by either maximal electroshock or metrazol administration but it did delay the onset of metrazol-induced seizures. In rabbits, 10 mg CPA/kg body weight initially produced tachycardia, tachypnoea and sedation with an activated electroencephalogram. Of three rabbits given 10 mg CPA/kg one died, and in this rabbit slow delta waves were seen just before and during a brief period with clonic leg movements. In this animal death was accompanied by tonic extension of the hind legs, respiratory arrest and cardiac fibrillation; and epileptiform EEG was not seen at any time. The unexpected EEG activation with sedation in rabbits treated with CPA was similar to the effect of reserpine on EEG.

Animals↗
PubMed1985

Increased accumulation of the lipophilic cation tetraphenylphosphonium+ by cyclopiazonic acid-treated renal epithelial cells.

Pig kidney renal epithelial cells (LLC-PK1) in culture were used to determine the effects of cyclopiazonic acid (CPA) on the uptake of the transmembrane potential probe, [3H]tetraphenylphosphonium bromide (TPP+). CPA had a significant stimulatory effect on TPP+ accumulation, which occurred in a dose-related manner. TPP+ accumulation in the presence of CPA was significantly reduced by high-potassium media (HK) and carbonylcyanide m-chlorophenylhydrazone (CCCP), but neither HK nor the protonophore CCCP, could completely abolish the stimulatory effect of CPA. The apparent transmembrane potential difference (delta psi), calculated based on the difference in accumulation of TPP+ in low-potassium and HK media, ranged from -55.9 to -85.7 mV for control cells and -89.4 to -109.0 mV for CPA-treated cells (20 mg CPA/I). The mechanism of CPA stimulation of TPP+ accumulation was not known. However, it was hypothesized that the effect could be a result of alterations in ion pumps or altered membrane permeability. The fact that the stimulatory effect could not be completely abolished by high potassium or CCCP suggested that there was some interaction between CPA and TPP+ or there were sites of TPP+ accumulation that were insensitive to K+ and H+ permeability.

Animals↗
PubMed1985

Cyclopiazonic acid mycotoxicosis in the dog.

The subacute toxic effects of cyclopiazonic acid (CPA; given orally) were characterized in the dog (CPA was purified from cultures of Aspergillus flavus). Four groups of dogs were given CPA in gelatin capsules for 90 days at the following dosage levels: 0.05, 0.25, 0.5, and 1.0 mg/kg of body weight; a 5th group was used as controls. All dogs administered the 0.5 and 1.0 mg of CPA/kg dosages and 1 dog given the 0.25 mg of CPA/kg dosage died or were humanely killed before the scheduled termination of the study. Clinical signs of intoxication appeared 2 to 44 days after dosing was started and consisted of anorexia and, in 1 to 2 days, vomiting, diarrhea, pyrexia, dehydration, weight loss, and CNS depression. Grossly, the entire alimentary tract had diffuse hyperemia with focal areas of hemorrhage and ulceration. Other lesions were renal infarcts, necrotizing epididymitis, and ulcerative dermatitis. Microscopic lesions included ulceration, necrosis, vasculitis, lymphoid necrosis, karyomegaly in several organs, and decreased mitotic activity in intestinal crypt epithelium. Ulcerative and necrotic lesions were usually associated with vascular lesions. Clinical pathologic changes were leukocytosis, neutrophilia, lymphopenia, monocytosis, and increased serum alkaline phosphatase activity.

Adrenal Glands↗
PubMed1984

The effects of cyclopiazonic acid on pregnancy and fetal development of Fischer rats.

To assess the potential effect of cyclopiazonic acid (CPA) on pregnancy and fetal development, Fischer-344 rats were dosed daily with 0, 1, 5, or 10 mg CPA/kg body weight on either d 8-11 or d 12-15 of pregnancy (sperm day = d 1). There were significant (p less than 0.05) decreases in feed consumption by high-dose dams of both groups. One high-dose rat in each group died prior to term, and signs of toxicity were observed in other high-dose animals. Animals that died had histologic lesions in the liver, spleen, kidney, and other organs. Remaining dams were killed on d 21. Compared to controls, there were no significant differences in pup weights, percentage pre- or postimplantation losses, or fetal deaths. Significant differences in skeletal development included retardation of ossification of cervical centra (d 12-15) and caudal vertebrae (d 8-11) in the two highest dose groups. Retardations of development were the most common manifestations of embryotoxicity. Since significant maternal toxicity occurred at the highest dose level in the absence of fetal malformations, the teratogenic potential of CPA is low.

Abnormalities, Drug-Induced↗
PubMed1984

The toxicity of cyclopiazonic acid in weaned pigs.

Five- to six-week-old crossbred pigs weighing 5 to 14 kg were given purified cyclopiazonic acid at dosages of 10, 1.0, 0.1, and 0.01 mg/kg body weight orally for 14 days. Clinical signs observed by day 7 in pigs given 10 mg/kg body weight were weakness, inactivity, anorexia, rough hair coats, and reduced body weights. These pigs also developed diarrhea during week 2 of the experiment. The pigs given 1.0 mg/kg body weight had rough hair coats and were moderately inactive during the second week of the experiment. At necropsy, lesions were observed only in pigs given 10 and 1.0 mg/kg body weight of cyclopiazonic acid. Lesions were gastric ulcers, mucosal hyperemia, and hemorrhage throughout the small and large intestine in pigs given 10 mg/kg body weight of cyclopiazonic acid. The pigs also had yellow, fibrononecrotic material in the lumen of the small intestine and pale livers. One pig given 1.0 mg/kg body weight had gastric ulceration. Microscopic lesions in pigs given 10 mg/kg body weight were necrotizing gastroenteritis, focal hepatocellular necrosis, hepatic peripheral lobular fatty change, and focal renal tubular nephrosis with focal suppurative tubulointerstitial nephritis. Pigs given 1.0 mg/kg body weight of cyclopiazonic acid had necrotizing gastritis and villous blunting in the jejunum and ileum.

Animals↗
PubMed1983

Cyclopiazonic acid production by Aspergillus flavus and its effects on broiler chickens.

Cyclopiazonic acid (CPA) was purified from cultures of Aspergillus flavus, and ca. 14 g of the toxin was collected for use in feeding studies. Chicken rations were artificially contaminated with purified CPA at concentrations of 10, 50, and 100 ppm (microgram/g) and fed ad libitum to eight groups of chickens for 7 weeks. Chickens receiving feed with 100 ppm of CPA had high mortality, decreased weight gain, and poor feed conversion when compared with birds receiving other doses. Postmortem examination showed that chickens fed the two greatest doses of CPA had proventricular lesions characterized by mucosal erosion and hyperemia (100 ppm) and by thick mucosa and dilated proventricular lumens (50 ppm). Birds given 100 ppm of CPA in feed also had numerous yellow foci in their livers and spleens. Microscopic examination of tissues of birds that received 100 ppm of CPA revealed ulcerative proventriculitis, mucosal necrosis in the gizzard, and hepatic and splenic necrosis and inflammation. Birds given 50 ppm of CPA had hyperplasia of the proventricular mucosal epithelium. Birds given 10 ppm of CPA and control birds had no significant treatment-related lesions.

Animal Feed↗
PubMed1981

Isolation of Citreoviridin from Penicillium charlesii Cultures and Molded Pecan Fragments.

The extraction and systematic fractionation of Penicillium charlesii Smith cultures and contaminated pecan fragments yielded the yellow mycotoxin citreoviridin. Citreoviridin proved acutely toxic to 1-day-old chickens, with an oral 50% lethal dose of 37.5 mg/kg, and showed plant growth inhibition in wheat coleoptiles even at concentrations as low as 10 M. It was toxic to corn seedlings but did not affect young tobacco seedlings.

Journal Article↗
PubMed1977

Mycotoxins produced by Aspergillus fumigatus isolated from silage.

Results are presented which show that Aspergillus fumigatus was one of the predominant fungi contaminating moldy silage. Growth of A. fumigatus on silage appeared to depend on a preliminary aerobic fermentation by other natural microflora in silage. The clavine alkaloid, fumigaclavine A, and a new clavine alkaloid designated fumigaclavine C were produced by A. fumigatus. The LD50 of fumigaclavine C was approximately 150 mg/kg oral dose in day-old cockerels.

Animal Feed↗
PubMedDate not supplied

Age and growth-related changes in cyclopiazonic acid-potentiated lipophilic cation accumulation by cultured cells and binding to freeze-thaw lysed cells.

In a previous study (1) we demonstrated that increased tetraphenylphosphonium (TPP) uptake by renal epithelial cells (LLC-PK1) exposed to the fungal metabolite cyclopiazonic acid (CPA) was not a result of hyperpolarization across the plasma membrane even though CPA-potentiated TPP uptake could be totally inhibited by the depolarizing agent carbonylcyanide-m-chlorophenylhydrazone (CCCP). We now demonstrate that CPA potentiates TPP accumulation by proliferating skeletal muscle (L6) and LLC-PK1 cells but not by nonproliferating primary rat hepatocytes. In LLC-PK1 cells, CPA-potentiated TPP accumulation is observed in cells at all ages. In L6 cells, CPA-potentiated TPP accumulation is maximal soon after subculturing, and as the cells age they become less sensitive to CPA until TPP accumulation by CPA-treated cells approaches that of untreated cells. The temporal change in sensitivity of L6 cells to CPA may be related to biochemical and/or metabolic changes which occur as the cells age in culture. Hepatocytes, LLC-PK1 cells, and L6 cells permeabilized by freeze-thaw lysis, all exhibit CPA-potentiated TPP partitioning, even in the presence of CCCP. This result indicates that both TPP and CPA must have access to the intracellular space in order for potentiated TPP partitioning to be observed. We hypothesize that the site of interaction between CPA and TPP is intracellular and probably associated with the cytoplasmic side of the plasma membrane and possibly the mitochondria.

Animals↗