Effects of zearalenone on in utero development in rats.
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 maternal and fetal toxicity in all treated groups, the NOEL for reproductive and teratogenic effects was less than 1 mg/kg.
Collins
Thomas F X
TF
Center for Food Safety and Applied Nutrition, US Food and Drug Administration, Laurel, MD 20708, USA. tcollins@cfsan.fda.gov
Sprando
Robert L
RL
Black
Thomas N
TN
Olejnik
Nicholas
N
Eppley
Robert M
RM
Alam
Hamida Z
HZ
Rorie
James
J
Ruggles
Dennis I
DI
D000014:Abnormalities, Drug-Induced; D000284:Administration, Oral; D000818:Animals; D001846:Bone Development / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D047108:Embryonic Development / Q000187:drug effects*; D004968:Estrogens, Non-Steroidal / Q000633:toxicity*; D005260:Female; D005313:Fetal Death / Q000139:chemically induced; D047109:Fetal Development / Q000187:drug effects*; D020567:Fetal Weight / Q000187:drug effects; D005835:Genitalia / Q000187:drug effects / Q000196:embryology; D012739:Gonadal Steroid Hormones / Q000097:blood; D006065:Gonadotropins, Pituitary / Q000097:blood; D008297:Male; D018811:Maternal Exposure; D019055:No-Observed-Adverse-Effect Level; D009929:Organ Size / Q000187:drug effects; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D012098:Reproduction / Q000187:drug effects; D012741:Sexual Maturation / Q000187:drug effects; D015025:Zearalenone / Q000633:toxicity*
D004968:Estrogens, Non-Steroidal; D012739:Gonadal Steroid Hormones; D006065:Gonadotropins, Pituitary; D015025:Zearalenone