Tumor necrosis factor-alpha as a contributor in fumonisin B1 toxicity

Fumonisin B1 is a toxic product of Fusarium moniliforme, which inhibits ceramide synthase, leading to accumulation of free sphingoid bases. Despite its known biochemical action, the mechanism of toxicity is not fully understood. Male BALB/c mice were injected subcutaneously with 0 to 6.75 mg/kg/day of fumonisin B1 for 5 days. One day after the last treatment, spleens were collected, and peritoneal macrophages were obtained from separate groups after an intraperitoneal injection of thioglycolate broth. Peripheral leukocyte counts were increased and kidney weights were decreased by fumonisin B1 treatment. Presence of apoptotic cells in the liver and kidney of treated mice was confirmed by enzymatic immunoassay. Macrophages cultured with lipopolysaccharide indicated an increased secretion of tumor necrosis factor-alpha (TNF-alpha) but not of interleukin-1alpha. No effect was seen on interferon-gamma production when splenocytes were incubated with concanavalin A. Elevation of leukocyte and reticulocyte counts was abrogated by pretreatment with anti-TNF-alpha antibody before a single dose of fumonisin B1 (25 mg/kg), supporting the hypothesis that the fumonisin B1 toxicity involves TNF-alpha. Cultures of J774A.1 cells, when treated with fumonisin B1, produced TNF-alpha in vitro. Results indicate that fumonisin B1 toxicity may involve secretion of TNF-alpha by TNF-alpha-producing cells without altering interleukin-1alpha or interferon-gamma. The influence on TNF-alpha-production may be a contributing factor to fumonisin B1-induced apoptosis and other observed toxic effects in animals.     

Testicular degeneration induced in rat offspring by maternal treatment with sobuzoxane

Gene therapy is emerging as a potential strategy for the treatment of vasculoproliferative diseases such as restenosis after angioplasty, vascular bypass graft occlusion and transplant coronary vasculopathy for which no known effective therapy exists. Our laboratory has demonstrated that vascular smooth muscle proliferation and lesion formation can be prevented by the blockade of genes regulating cell cycle progression. With this approach it was also shown that genetically engineered bioprostheses can be developed that are resistant to accelerated atherosclerosis and thus to graft failure. We have also reported that the direct in vivo transfer of a cDNA encoding endothelial nitric oxide synthase resulted in inhibition of neointimal lesion formation and improvement of vascular reactivity, demonstrating that therapeutic effects can also be achieved by the in vivo transfer of gene(s) whose product(s) exert a paracrine effect on the vessel wall.     

Oxidative damage and fumonisin B1-induced toxicity in primary rat hepatocytes and rat liver in vivo

The particle size distribution and the metal speciation of the heavy metals were investigated on dredged sediment and on the fractions obtained by mechanical agitated (Denver) flotation. The transition metal ions (cadmium, copper, lead and zinc) were flotated specifically independent of the particle size. Particle size analysis, EDTA extraction and sequential extracts indicated that during flotation a redistribution of metals occurred due to the oxidation of metal sulphides. This oxidation process was more pronounced when the flotation was performed at higher pH values and resulted in a decrease in flotation specificity.     

Effects of maternal ethanol consumption in rats on basal and rhythmic pituitary-adrenal function in neonatal offspring

Neonatal corticoid treatment delays development of the circadian rhythm of plasma corticosterone in rats. We therefore sought to determine whether fetal or neonatal exposure to ethanol, a substance which activates the hypothalamo-pituitary-adrenal axis, produces similar effects. Subjects were the offspring of dams fed a 5.0% w/v ethanol-containing liquid diet or pair-fed an isocaloric control diet during gestation weeks two and three or during postnatal week one. At birth (day 1), the fetal ethanol-exposed pups had significantly higher brain and plasma corticosterone levels than the pair-fed or normal controls; brain and body weights were unaffected. By day 3, brain and plasma corticosterone titers in the fetal ethanol-exposed pups declined to the levels of the pair-fed and normal controls, although brain weights were significantly reduced. Significantly higher p.m. than a.m. levels of plasma corticosterone first occurred on day 18 both in the fetal ethanol-exposed pups and in the pair-fed and normal controls. Thus, despite its causing elevated corticosterone levels at birth, fetal exposure to ethanol did not affect the onset of the pituitary-adrenal circadian rhythm. On the other hand, exposure to ethanol during the first neonatal week delayed the onset of the pituitary-adrenal rhythm from day 18 to day 21. However, even greater delays occurred in the neonatal pair-fed controls, suggesting that the delays following neonatal exposure were due to nutritional deficits rather than to alcohol per se. The developmental and long-term influences of elevated corticoid levels at birth in fetal ethanol-exposed rats on other aspects of pituitary-adrenal function remain to be determined.     

The use of the chicken embryo screening test and brine shrimp (Artemia salina) bioassays to assess the toxicity of fumonisin B1 mycotoxin

Chicken embryos and brine shrimp naulpii were utilized in short-term toxicity bioassays to assess their sensitivity to the mycotoxin fumonisin B1 (FB1). Fertile chicken eggs (Cobb x) were dosed with FB1 on day 2 of incubation by the injection of 100 microliters of aqueous solution into the air space of each egg. Eggs were incubated with mechanical rotation until hatch, at which time mortality was assessed. Probit transformation of the mortality data produced a linear line of best fit (P < 0.05), from which an LD50 of 52 micrograms FB1/egg, equivalent to a concentration of 1.3 microns hatched in artificial seawater and exposed to FB1 in an optimized 96-well plate assay with a 48 hr mortality endpoint. Probit transformation of the mortality data resulted in an LC50 of 1.7 microns FB1, or 1.2 micrograms FB1/ml. Thus, at the cellular level, both bioassays appeared sensitive to FB1; however, from the standpoint of use as a screening assay, the chicken embryo bioassay is limited by the relatively high dose of FB1 required per egg. It is anticipated that the design and simplicity of the brine shrimp bioassay will accommodate screening for FB1 toxicity in contaminated samples.     

Dietary Mg and/or K restriction enhances paraquat toxicity in rats

Effect of mineral restriction was studied to clarify which mineral in the diet is most indispensable in preventing paraquat (PQ) toxicosis. ODS rats were chosen as the experimental animal owing to the inability to synthesize vitamin C similarly to humans. Rats were fed with either mineral-adequate or restricted diets dosed with 125 ppm PQ. The mineral-adequate diet was based on the American Institute of Nutrition-76, and the restricted diet was one-half the amounts. Measurements were made on the onset day of PQ toxicosis, body weight changes during the feeding experiment, and changes of two acute phase reactant proteins cysteine proteinase inhibitor and alpha1-proteinase inhibitor. The minerals tested were divided into three classes: I, largely needed, Ca, K, Na, and Mg; II, moderately needed, Mn, Fe, Zn, and Cu; and III, minutely needed, Cr and Se, respectively. Rats fed with a Mg-restricted diet showed a severe toxicosis but those with a K-restricted diet, a mild toxicosis. No appreciable effect was observed by restriction of other minerals. A synergistic effect was observed in the restriction of Mg and K.     

Subchronic toxicity of PCB 105 (2,3,3'',4,4''-pentachlorobiphenyl) in rats

Increases in the intracellular free calcium concentration are of great importance to the initiation of development in deuterostomes. Their involvement has not yet been clearly defined in protostomes. We used endogenous ligands (IP3, cADPR, ryanodine and NAADP) and pharmacological agents (thapsigargin [Tg], thimerosal, caffeine and heparin) to study smooth endoplasmic reticulum Ca2+ pump and release mechanisms in eggs of an annelid, Chaetopterus. Oocyte homogenates effectively sequestered Ca2+ and released it in response to IP3 in a concentration-dependent manner. Repeated additions of IP3 were unable to cause further release. Heparin inhibited Ca2+ release in response to IP3. The homogenates also released Ca2+ in response to thimerosal, and this release was sensitive to heparin. Two antibodies to IP3 receptors recognized an appropriate band in Chaetopterus egg lysates. These results indicate that the oocytes possess type-1 IP3-gated Ca2+ channels. Neither calcium itself, nor strontium, cADPR, ryanodine, caffeine nor NAADP released appreciable Ca2+. At low concentrations, Tg caused a slow release of Ca2+; at higher concentrations, it elicited a rapid release. Release of Ca2+ by Tg activated development. Since one theory of fertilization invokes the introduction of a Ca2+ releasing soluble protein into the egg upon sperm-egg fusion, we also tested whether soluble extracts of Chaetopterus sperm could stimulate Ca2+ release in Chaetopterus egg homogenates. There was no Ca2+ release when the sperm extract was added to the homogenate; however, homogenates exposed to sperm extract became refractory to IP3. Thus, Ca2+ release at fertilization in these oocytes occurs through IP3-gated channels.     

In vivo effects of fumonisin B1-producing and fumonisin B1-nonproducing Fusarium moniliforme isolates are similar: fumonisins B2 and B3 cause hepato- and nephrotoxicity in rats

Orellanine, [2,2'-bipyridine]-3,3',4,4'-tetrol-1,1'-dioxide, is the toxin responsible for the lethal nephrotoxicity of some Cortinarius mushrooms. Our present ESR and spin-trapping studies of the redox properties of the system of non-illuminated orellanine, ferrous iron and dioxygen contribute to understanding the molecular mechanism of its toxicity. UV-visible spectrophotometry, cyclic voltammetry and ESR in frozen medium showed the formation of a wine-red tris complex, Fe(III)Or3. This ferric complex is easily reducible (Ep = -565 mV vs Ag/AgCl/3M KCl at pH 7), involving a one-electron reversible process. Spin-trapping using DMPO is employed to detect the generation of superoxide anion and hydroxyl radicals. The instantaneous one-electron oxidation of ferrous ions in the presence of the toxin under air is concomitant with dioxygen consumption as supported by dioxygen consumption. GSH involves the toxin and ferrous ions under air in a redox cycling process resulting in the production of glutathionyl and oxygen free radicals, observed for the first time with an iron complex of a mushroom toxin. In most cases, EDTA is not able to prevent the Fe(III)Or3 and radical formation. The ortho-dihydroxylated groups borne by the di-N-oxidized bipyridine structure and not the bipyridine structure itself, are responsible for the formation of a stable ferric complex at pH 7, as they are for the generation of an apparently stable ortho-semiquinone anion radical. These one-electron mechanisms may play a major role in some of the known toxic effects of orellanine.     

Prenatal alcohol exposure results in hyperactivity of the hypothalamic-pituitary-adrenal axis of the offspring: modulation by fostering at birth and postnatal handling

Exposure of fetal rats to alcohol results in permanent hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis. In contrast, postnatal handling or fostering have been reported to restrain HPA activity. Because of the deleterious consequences of a hyperresponsive HPA axis, we thought that the possibility that postnatal manipulations might be able to reverse the influence of prenatal alcohol treatment deserved investigation. To test this hypothesis, we exposed rat dams to alcohol by inhalation during the second week of gestation. At birth, pups were either fostered or remained with their dam. For the first 3 weeks, litters were handled daily for 15 min or left undisturbed. At 22 days of age, male and female pups were decapitated under basal conditions, after 10 min of mild electro-footshock, or 10 min after footshock had been terminated. As expected, prenatal exposure to alcohol induced increased adrenocorticotropin (ACTH) secretion in response to footshock, and postnatal handling of control pups resulted in a suppression of corticosterone and ACTH release, although changes in this latter hormone did not reach statistical significance. Surprisingly, however, pups exposed to alcohol that were also fostered and handled after birth, showed an ACTH response to footshock stress that was significantly larger than all other groups. This unexpected response may be due to alterations in maternal-pup behaviors and may indicate that these manipulations act on different neuronal substrates within the central HPA of young rats. Further studies are needed to determine whether adrenal regulation is also altered in animals exposed to alcohol prenatally and reared in a similar manner.     

Brodifacoum toxicity and treatment in a white-winged wood duck (Cairina scutulata)

BACKGROUND: Patients with AIDS frequently show secondary involvement of the brain by different infectious agents, and Chagas' disease is now recognized as a potential opportunistic infection. To our knowledge, pseudotumoral chagasic meningoencephalitis has not been previously reported as the first manifestation of AIDS. METHODS AND RESULTS: A 30-year-old Argentinian man without any risk factor for HIV infection was admitted to the hospital with an acute onset of drowsiness. A computed tomography scan showed a hypodense parietal tumor-like lesion. Open brain biopsy revealed hemorrhagic necrosis and numerous amastigotes of Trypanosoma cruzi. Nifurtimox was started, but the patient died. CONCLUSIONS: Chagas' disease can reactivate in patients with AIDS and present as a brain mass that is indistinguishable from other infectious or neoplasic processes. Our report demonstrates this entity as the first manifestation of AIDS.     

Duckling toxicity and the production of fumonisin and moniliformin by isolates in the A and E mating populations of Gibberella fujikuroi (Fusarium moniliforme)

Two biological species of Gibberella fujikuroi (A and F mating populations) share the Fusarium moniliforme anamorph. Twenty strains of each of these biological species were tested for the ability to produce fumonisins B1, B2, and B3 and moniliformin and for toxicity to 1-day-old ducklings. Most of the members of the A mating population (19 of 20 strains) produced more than 60 micrograms of total fumonisins per g, whereas only 3 of 20 members of the F mating population produced more than trace levels of these toxins and none produced more than 40 micrograms of total fumonisins per g. In addition, only 3 of 20 members of the A mating population produced more than 1 microgram of moniliformin per g (and none produced more than 175 micrograms/g), while all 20 strains of the F mating population produced more than 85 micrograms of this toxin per g and 1 strain produced 10,345 micrograms/g. The duckling toxicity profiles of the strains of the two mating populations were similar, however, and the level of either toxin by itself was not strongly correlated with duckling toxicity. On the basis of our data we think that it is likely that the members of both of these mating populations produce additional toxins that have yet to be chemically identified. These toxins may act singly or synergistically with other compounds to induce the observed duckling toxicity.     

Development of maternal behavior in nulliparous rats (Rattus norvegicus): Effects of sex and early maternal experience.

72 weanling female and male CD rats were exposed to either pups or pup-sized toys for 10 days beginning at 22 days of age in order to assess differences between pup-directed and toy-directed behaviors and to determine whether exposure to pups at this time increases susceptibility to maternal sensitization in adulthood. Adult sensitization involved exposing each S to pups for 10 days beginning at 78 days of age. Weanlings retrieved, licked, and lay over pups but not toys, and chewed on toys but not pups. Weanling males showed more pup retrieval than weanling females. Females and males preexposed to pups showed more retrieval and licking of pups in adulthood than those not preexposed to pups. Adult females were more fully maternal or nonmaternal than were adult males or weanlings of either sex, as indicated by their lower "partial retrieval" and "inconsistent retrieval" scores, their tendency to retrieve rapidly or not at all, and the greater correlation between their retrieval and nest construction. (14 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Predicting the in vitro toxicity of synthetic beta-amyloid (1-40)

The in vitro toxicity of synthetic beta-amyloid (betaA4) is variable and unpredictable, limiting its use as a research tool. This study describes a method using Congo red (CR) to predict the in vitro toxicity of betaA4 solutions. Histopathologically, CR is used to stain the neuritic, betaA4-containing plaques, one of the hallmarks of Alzheimer's disease. In this study, synthetic betaA4 solutions were incubated with CR at a molar ratio of 1.0:2.5. The solutions were centrifuged and the absorbance of the supernatants were measured. Predictions of nontoxicity correlated with absorbance readings near zero. Toxicity was evaluated relative to control cells (vehicle only), using a hemocytometer to count PC-12 cells that excluded trypan blue. The positive predictive value of the test was 78% and the negative predictive value was 100%. To use this test, the toxic concentration(s) of betaA4 must first be established empirically. Then, the CR test can be used to evaluate the potential toxicity of betaA4 solutions at similar concentrations. Thus, this test can be used under a variety of laboratory circumstances.     

Diazepam treatment of pregnant rats differentially affects interleukin-1 and interleukin-2 secretion in their offspring during different phases of postnatal development

Treatment of pregnant Long Evans rats with benzodiazepines was found to cause alterations in cellular immune responses in their offspring. We now report on changes in interleukin-1 (IL-1) and IL-2 secretion which were analyzed in rats from birth until 12 weeks. Time-pregnant rats were treated with diazepam (1.25 mg/kg/day subcutaneously) from gestational day 14 to 20. Lipopolysaccharide-stimulated release of macrophage-derived IL-1 by spleen cells, determined on D10.G4.1 cells, remained in the control range during the preweaning period (postnatal day 6-28), then decreased in prenatally diazepam-exposed offspring, significantly in males during the postweaning period (postnatal day 34-61) and in both sexes in adults (postnatal day 62-83). Concanavalin A-stimulated release of T lymphocyte-derived IL-2 from spleen cells, determined on CTLL-2 cells, was reduced in male and female offspring during preweaning (postnatal day 3-28) and postweaning (postnatal day 33-55) periods and normalized in adulthood (postnatal day 60-84). The percentage of IL-2 receptor expressing (CD25+) cells was unaffected. From these and our earlier data it is evident that prenatal exposure to low doses of benzodiazepines can result in long-lasting alterations of the cytokine network, as indicated by reduced release of TNF-alpha, IL-1, IL-6, IL-2 and interferon-gamma. The concomitant reduction of peripheral type benzodiazepine receptors on macrophages is discussed as a possible link between prenatal treatment and disturbed function.     

Cocaine treatment and prenatal environment interact to disrupt intergenerational maternal behavior in rats.

The link between impaired maternal behavior (MB) and cocaine treatment could result from drug-induced decreases in maternal reactivity to offspring, prenatal drug exposure (PDE) in offspring that could alter their ability to elicit MB, or the interaction of both, which could subsequently impair MB of the 1st-generation dams. Following chronic or intermittent cocaine or saline treatment during gestation, rat dams rearing natural or cross-fostered litters were compared along with untreated dams for MB. Untreated 1st-generation females with differentially treated rearing dams and PDE were tested for MB with their natural litters. The authors report disruptions in MB in dams and their 1st-generation offspring, attributable to main and interaction effects of maternal treatment, litter PDE, and rearing experience. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The effects of D1 or D2 dopamine receptor antagonism in the medial preoptic area, ventral pallidum, or nucleus accumbens on the maternal retrieval response and other aspects of maternal behavior in rats.

The medial preoptic area (MPOA), ventral pallidum (VP), and nucleus accumbens (NA) receive dopaminergic afferents and are involved in maternal behavior. Experiments investigated whether dopamine (DA) receptor antagonism in NA disrupts maternal behavior, determined the type of DA receptor involved, and investigated the involvement of drug spread to VP or MPOA. Injection of SCH 23390 (D1 DA receptor antagonist) into NA of postpartum rats disrupted retrieving at dosage levels that were ineffective when injected into MPOA or VP. Motor impairment was not the cause of the deficit. Injection of eticlopride (D2 DA receptor antagonist) into NA or VP was without effect. Results emphasize the importance of DA action on D1 receptors in NA for retrieval behavior. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Prenatal diagnosis of supernumerary chromosome derivative (22) due to maternal balanced translocation in association with diaphragmatic hernia: a case report

An aneuploid fetus was detected prenatally by cordocentesis at 27 weeks' gestation following ultrasonographic diagnosis of severe fetal growth retardation and a large diaphragmatic hernia. The fetal karyotype was revealed to be 47,XX,der(22)t(11;22)(q23.3;q11.2) after parental bloods confirmed a balanced reciprocal translocation in the mother. Approximately 85 cases with an unbalanced karyotype 47,XX(or XY),+der(22),t(11;22) due to 3:1 meiotic disjunction in the parental translocation carrier have been reported in the world literature and only one of them was diagnosed prenatally. This is the first detailed case report of a supernumerary derivative (22) chromosome abnormality diagnosed prenatally in association with diaphragmatic hernia.