fumonisin-b1 and Fetal-Resorption

Developmental and toxic effects of aqueous extracts of F. moniliforme culture material containing known levels of fumonisin B1 were recently reported in mice and included maternal hepatotoxicity and lethality, maternal body weight gain reduction, increased embryonic resorptions, reduced offspring body weights, and fetal malformations including cleft palate, hydrocephalus, malformed ribs and incomplete digital and sternal ossification. These studies also suggested that the effects of the fungal extract on the mouse offspring may be mediated via maternal effects. The contribution of fumonisin B1 (FB1), a major toxic metabolite of F. moniliforme, in the induction of these effects was evaluated in this study by administering 0 to 100 mg pure FB1/kg of body weight on gestational days (GD) 7 through 15 to pregnant Charles River CD1 mice and assessing maternal health and fetal development till the end of gestation. Doses of 25 mg/kg or higher of pure FB1 induced maternal liver lesions (mostly necrotic changes), associated with ascites and increased hepatocytic nuclear diameter. Fumonisin doses of 50 mg/kg or higher also resulted in significantly increased maternal ALT on GD12, and reduced offspring bodyweights on GD18. Increased resorptions and decreased numbers of live offspring were only evident at 100 mg FB1/kg body weight. Offspring exhibited dose-dependent increase in the incidence and severity of hydrocephalus of both the lateral and third ventricles at doses of 25 mg/kg or higher. Doses of 25 mg/kg or higher also increased the sphinganine/sphingosine (Sa/So) ratios in maternal but not fetal livers. These results suggest that FB1 may be a developmental toxicant accounting for most but not all earlier reported effects of F. moniliforme culture extract. Association of FB1 effects on the offspring with maternal hepatoxicity and with alteration of Sa/So ratio in maternal but not fetal liver supported the earlier claim that FB1 effects on the mouse offspring are mediated by maternal hepatotoxicity.

Topics: Alanine Transaminase; Animals; Body Weight; Embryonic and Fetal Development; Female; Fetal Resorption; Fumonisins; Hydrocephalus; Litter Size; Liver; Mice; Mycotoxins; Pregnancy; Sphingosine

Pregnant Charles River CD1 mice were treated with a semipurified extract of Fusarium moniliforme culture containing 0, 12.5, 25, 50 or 100 mg FB1/kg each day orally (diluted in distilled water) between gestational days (GD) 7 and 15 to evaluate the developmental toxicity of FB1. Following sacrifice of dams on GD 18, litters were examined for gross abnormalities and divided equally for skeletal or visceral examination by routine techniques. Significant maternal mortality was observed at doses of 50 and 100 mg FB1/kg. Dose-dependent decreases in maternal body weight gains, number of live offsprings per litter, and mean body weight of the offspring were produced at FB1 doses of 25 mg/kg or higher. The percentage of implants resorbed increased at all doses in a dose-dependant manner. A dose-dependant increase, except at the lowest dose tested, in the incidence of ossification deficits involving digits and sternum, short and wavy ribs, and hydrocephalus of lateral and third ventricles was also evident. Cleft palate was seen only at the highest FB1 dose. Maternal intoxication manifested as a dose-dependant increase in the severity of ascites associated mainly with increased histopathologic scores reflecting hepatocellular damage at day 18. Concommittant increases in serum alanine amino transferase (ALT) on GD 12, reflecting parenchymal liver cell damage, was also observed at all doses above 12.5 mg of FB1/kg. These results suggest that FB1-containing F. moniliforme culture extract is developmentally toxic in mice, and that this toxicity may be mediated by maternal hepatotoxicity.

Topics: Abnormalities, Drug-Induced; Animals; Chemical and Drug Induced Liver Injury; Cleft Palate; Dose-Response Relationship, Drug; Female; Fetal Resorption; Fumonisins; Fusarium; Hydrocephalus; Litter Size; Mice; Mycotoxins; Pregnancy; Pregnancy Complications

The purpose of this study was to investigate potential detrimental effects of fumonisin B1 on the developing hamster. In experiments 1 and 2, timed-bred hamsters were dosed with 0.0 to 12.0 mg fumonisin B1/kg from day 8 to day 10 or day 12 of gestation. Clinical signs of material toxicity were not observed. Pregnant animals had reduced weight gains and lower total bilirubin levels than nonpregnant females. Hamsters were euthanized on day 15 of gestation. Histologic evaluation revealed autolytic placental changes expected in terminal gestation, as well as more advanced placental necrosis in association with fetal resorptions. Mean fetal weights and crown-rump lengths of living term fetuses on a per-litter basis did not differ between untreated controls and treated animals given 6.0 mg fumonisin B1/kg or less. However, at higher doses of fumonisin B1, there was an increased incidence of prenatal losses (deaths and resorptions). A greater percentage of litters had 1 or more fetuses affected, and a greater percentage of total fetuses were lost/litter as the fumonisin dosage increased. At 12.0 mg/kg, all litters were affected and 100% of the fetuses were dead and resorbing. Fumonisin B1 appears a developmental toxicant in hamsters. Toxicity is manifest by increased numbers of prenatal deaths and resorptions at doses that do not induce clinicopathologic evidence of maternal toxicity.

Topics: Animal Feed; Animals; Carcinogens, Environmental; Cricetinae; Embryonic and Fetal Development; Female; Fetal Resorption; Fetus; Food Microbiology; Fumonisins; Fusarium; Gestational Age; Liver; Liver Function Tests; Mesocricetus; Mycotoxins; Pregnancy; Weight Gain; Zea mays