zearalenone and Abnormalities--Drug-Induced

The use of implants of zeranol (alpha-zearalanol), a widely-used anabolic growth promoter, in food animals results in very low residues of this compound in the edible tissues. In comparison, residues of myco-oestrogens--specifically the beta-resorcylic acid lactones (RALs) such as zearalenone and its metabolites--commonly found as contaminants of cereals are much greater. Zeranol, the RALs and their metabolites are all closely related chemically, sterically and biologically. The biological effects of these compounds on reproduction, oestrogenicity, teratogenicity, genotoxicity and carcinogenicity are compared. No toxicological effects have been reported that cannot be attributed to the oestrogenic character of these molecules. In comparison with oestradiol, zeranol and the related myco-oestrogens are 100-1000 times less active hormonally. It is concluded that a likely no-observed-effect level (NOEL) for these compounds will be of the order of 0.05-0.1 mg/kg body weight/day. This would result in a safety margin greater than 500-fold between the expected dietary exposure to these compounds (considered together) and the likely NOEL. On the basis of exposure to zeranol alone, this margin of safety would increase to more than 35,000.

Topics: Abnormalities, Drug-Induced; Animals; Edible Grain; Estrogens; Female; Fertility; Food Contamination; Humans; Mutagens; Neoplasms, Experimental; Pregnancy; Resorcinols; Risk; Zearalenone; Zeranol

Topics: Abnormalities, Drug-Induced; Aflatoxins; Animals; Climate; Female; Food Analysis; Food Contamination; Gastrointestinal Diseases; Genital Diseases, Female; Humans; Liver Diseases; Mycotoxins; Neoplasms; Neuromuscular Diseases; Plant Poisoning; Respiratory Tract Diseases; Skin Diseases; Sporidesmins; Trichothecenes; Zearalenone

Zearalenone (ZE), an estrogenic mycotoxin produced by Fusarium graminearum or F. roseum, is one of the most common contaminants of cereal grains world-wide. The objective of this study was to determine the effects of ZE on in utero development of rats. Pregnant female Charles River Sprague-Dawley rats were gavaged once daily with ZE (in corn oil) at doses of 0, 1, 2, 4, or 8 mg/kg body weight on gestation days (GD) 6-19. All females survived to cesarean section on GD 20. At cesarean section, reproductive and developmental parameters were measured and blood was taken for hormone analysis. Dose-related decreases were seen in maternal feed consumption and body weight gain in all treated groups. Delayed fetal development was linked to maternal toxicity. Fetal body weight was significantly decreased in both sexes in all treated groups. ZE retarded skeletal ossification at 4 and 8 mg/kg. Fetal anogenital index (anogenital distance normalized for body weight) was increased in all treated groups, indicating an androgenic effect of ZE during fetal development. Fetal viability was significantly decreased at 8 mg/kg; significant decreases were observed in number of viable fetuses, and number of litters totally resorbed. At 4 and 8 mg/kg, maternal liver-body weight ratios were significantly increased and organ-brain weight ratios for weights of liver, heart, spleen, kidneys, and ovaries were significantly decreased. Gonadotropins (LH, FSH, and prolactin) and sex steroids (progesterone and estradiol) were analyzed from the blood serum obtained at cesarean section. LH in the 0, 1, 2, and 4 mg/kg groups showed minimal variation, and slightly increased at 8 mg/kg. FSH was decreased in the 1, 2, and 4 mg/kg groups, but the level at 8 mg/kg was slightly higher than the control level. Prolactin level was not affected at 1 mg/kg, slightly increased at 2 and 4 mg/kg, and significantly increased at 8 mg/kg. Progesterone was decreased at 2, 4, and 8 mg/kg and the decreases were significant at 2 and 4 mg/kg. Estradiol level was not affected at 1mg/kg, but dose-related decreases were observed at 2, 4, and 8 mg/kg. Only the 8 mg/kg level of estradiol was significantly decreased. In summary, ZE was maternally toxic and fetotoxic but not teratogenic. The increased anogenital distance observed in male and female fetuses was considered a hormonal change rather than a teratologic response. The increased anogenital distance indicated an androgenic effect. Based on the dose-related mater

Topics: Abnormalities, Drug-Induced; Administration, Oral; Animals; Bone Development; Dose-Response Relationship, Drug; Embryonic Development; Estrogens, Non-Steroidal; Female; Fetal Death; Fetal Development; Fetal Weight; Genitalia; Gonadal Steroid Hormones; Gonadotropins, Pituitary; Male; Maternal Exposure; No-Observed-Adverse-Effect Level; Organ Size; Pregnancy; Rats; Rats, Sprague-Dawley; Reproduction; Sexual Maturation; Zearalenone

Mycotoxins zearalenone and vomitoxin (4-deoxynivalenol) are often joint contaminants of grains infested by micromycetes of the genus Fusarium. Toxic effects of both mycotoxins on experimental organisms and farm animals are well known, but we have not found any literary reference to toxic effects of the combination zearalenone and vomitoxin. Embryotoxic effects of zearalenone, vomitoxin and combinations of various doses of zearalenone with constant addition of vomitoxin were studied in a three-day chick embryo. The objective of the study was to determine the coaction of vomitoxin on zearalenone embryotoxicity. Thermostat-incubated fertile eggs of White Leghorn hens were candled after three-day incubation, the shell above the embryo was removed, and within the embryotoxicity range zearalenone, vomitoxin and various doses of zearalenone with constant addition of 2 micrograms vomitoxin were applied to morphologically normal embryos. The groups of ten embryos were applied mycotoxins and their combinations in 10 microliters of their solutions to amnions using a special glass micropipette. Control group comprised twenty embryos which were applied 10 microliters of solvents used, 1% NaHCO3 and 10% ethanol. The eggs were covered with glass plates and their incubation was going on until the eighth day of their development. The embryos that died during incubation were discarded. On the eighth day of development, surviving embryos were taken out from the eggs and malformations of head, orofacial region, body wall, limbs and heart were determined microscopically. Tab. I shows total numbers of dead and malformed embryos after application of the particular doses of zearalenone, vomitoxin, their combinations and control solvents. The embryotoxicity range started at a dose of 5 to 20 micrograms per embryo. Zearalanone did not have any teratogenic effects on chick embryos. Applications of high doses of zearalenone (100 and 30 micrograms) instantly caused arrhythmia, atrio-ventricular dissociation or even heart stoppage. The beginning of the embryotoxicity range for vomitoxin was found to be within the narrow range of 1 to 3 micrograms per embryo. Among malformations, only a defect of the interventricular septum of the heart was found in 4% of the cases. The combined embryotoxic effects of zearalenone and vomitoxin were of additive, and mostly embryolethal nature. Among the malformations searched for, only 5% of the embryos exhibited a defect of the interventricular septum

Topics: Abnormalities, Drug-Induced; Animals; Chick Embryo; Mycotoxins; Trichothecenes; Zearalenone

The toxicity of zearalenone was studied in two generations of Wistar rats over approximately 10 months. Zearalenone was administered in the diet; the dose levels used were 0, 0.1, 1.0 and 10.0 mg per kg body weight per day in all generations. Animals in the F0 generation were bred twice to produce F1A and F1B generations. The F1A generation was bred to produce the F2A generation. The only lesion found at necropsy that could be attributed to zearalenone administration was increased medullary trabeculation of the femur in animals given the high dose. A dose-related increase in absolute and relative thyroid, pituitary and adrenal gland weights occurred in male and female rats of both the F1 and F1A generation. The alteration in the weights of these endocrine organs is probably a result of the estrogenic activity of zearalenone. Feeding of zearalenone caused decreases in fertility, number of viable offspring per litter and numbers of corpora lutea, implantations and resorptions per dam. Statistically significant differences were noted in the incidences of a number of skeletal and soft tissue abnormalities in both the F1B and F2A1 fetuses, especially at doses of 1.0 and 10.0 mg kg-1. These lesions most likely indicate a delay in fetal development. Unequivocal teratogenic effects could not be defined.

Topics: Abnormalities, Drug-Induced; Animals; Body Weight; Bone and Bones; Female; Male; Organ Size; Pregnancy; Rats; Rats, Inbred Strains; Reproduction; Resorcinols; Zearalenone

Topics: Abnormalities, Drug-Induced; Aflatoxin B1; Aflatoxins; Animals; Female; Fetal Death; Fetus; Mice; Mice, Inbred CBA; Ochratoxins; Pregnancy; Resorcinols; Zearalenone

Topics: Abnormalities, Drug-Induced; Administration, Oral; Animals; Body Weight; Female; Gestational Age; Pregnancy; Rats; Resorcinols; Teratogens; Zearalenone